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Sample records for ph-dependent antitumor activity

  1. Variations of thiaminase I activity pH dependencies among typical Great Lakes forage fish and Paenibacillus thiaminolyticus.

    USGS Publications Warehouse

    Zajicek, J.L.; Brown, L.; Brown, S.B.; Honeyfield, D.C.; Fitzsimons, J.D.; Tillitt, D.E.

    2009-01-01

    The source of thiaminase in the Great Lakes food web remains unknown. Biochemical characterization of the thiaminase I activities observed in forage fish was undertaken to provide insights into potential thiaminase sources and to optimize catalytic assay conditions. We measured the thiaminase I activities of crude extracts from five forage fish species and one strain of Paenibacillus thiaminolyticus over a range of pH values. The clupeids, alewife Alosa pseudoharengus and gizzard shad Dorosoma cepedianum, had very similar thiaminase I pH dependencies, with optimal activity ranges (> or = 90% of maximum activity) between pH 4.6 and 5.5. Rainbow smelt Osmerus mordax and spottail shiner Notropis hudsonius had optimal activity ranges between pH 5.5-6.6. The thiaminase I activity pH dependence profile of P. thiaminolyticus had an optimal activity range between pH 5.4 and 6.3, which was similar to the optimal range for rainbow smelt and spottail shiners. Incubation of P. thiaminolyticus extracts with extracts from bloater Coregonus hoyi (normally, bloaters have little or no detectable thiaminase I activity) did not significantly alter the pH dependence profile of P. thiaminolyticus-derived thiaminase I, such that it continued to resemble that of the rainbow smelt and spottail shiner, with an apparent optimal activity range between pH 5.7 and 6.6. These data are consistent with the hypothesis of a bacterial source for thiaminase I in the nonclupeid species of forage fish; however, the data also suggest different sources of thiaminase I enzymes in the clupeid species.

  2. Alternative exon-encoding regions of Locusta migratoria muscle myosin modulate the pH dependence of ATPase activity.

    PubMed

    Li, J; Lu, Z; He, J; Chen, Q; Wang, X; Kang, L; Li, X-D

    2016-12-01

    Whereas the vertebrate muscle myosin heavy chains (MHCs) are encoded by a family of Mhc genes, most insects examined to date contain a single Mhc gene and produce all of the different MHC isoforms by alternative RNA splicing. Here, we found that the migratory locust, Locusta migratoria, has one Mhc gene, which contains 41 exons, including five alternative exclusive exons and one differently included penultimate exon, and potentially encodes 360 MHC isoforms. From the adult L. migratoria, we identified 14 MHC isoforms (including two identical isoforms): four from flight muscle (the thorax dorsal longitudinal muscle), three from jump muscle (the hind leg extensor tibiae muscle) and seven from the abdominal intersegmental muscle. We purified myosins from flight muscle and jump muscle and characterized their motor activities. At neutral pH, the flight and the jump muscle myosins displayed similar levels of in vitro actin-gliding activity, whereas the former had a slightly higher actin-activated ATPase activity than the latter. Interestingly, the pH dependences of the actin-activated ATPase activity of these two myosins are different. Because the dominant MHC isoforms in these two muscles are identical except for the two alternative exon-encoding regions, we propose that these two alternative regions modulate the pH dependence of L. migratoria muscle myosin.

  3. Exploring the active site of tripeptidyl-peptidase II through studies of pH dependence of reaction kinetics.

    PubMed

    Eklund, Sandra; Lindås, Ann-Christin; Hamnevik, Emil; Widersten, Mikael; Tomkinson, Birgitta

    2012-04-01

    Tripeptidyl-peptidase II (TPP II) is a subtilisin-like serine protease which forms a large enzyme complex (>4MDa). It is considered a potential drug target due to its involvement in specific physiological processes. However, information is scarce concerning the kinetic characteristics of TPP II and its active site features, which are important for design of efficient inhibitors. To amend this, we probed the active site by determining the pH dependence of TPP II catalysis. Access to pure enzyme is a prerequisite for kinetic investigations and herein we introduce the first efficient purification system for heterologously expressed mammalian TPP II. The pH dependence of kinetic parameters for hydrolysis of two different chromogenic substrates, Ala-Ala-Phe-pNA and Ala-Ala-Ala-pNA, was determined for murine, human and Drosophila melanogaster TPP II as well as mutant variants thereof. The investigation demonstrated that TPP II, in contrast to subtilisin, has a bell-shaped pH dependence of k(cat)(app)/K(M) probably due to deprotonation of the N-terminal amino group of the substrate at higher pH. Since both the K(M) and k(cat)(app) are lower for cleavage of AAA-pNA than for AAF-pNA we propose that the former can bind non-productively to the active site of the enzyme, a phenomenon previously observed with some substrates for subtilisin. Two mutant variants, H267A and D387G, showed bell-shaped pH-dependence of k(cat)(app), possibly due to an impaired protonation of the leaving group. This work reveals previously unknown differences between TPP II orthologues and subtilisin as well as features that might be conserved within the entire family of subtilisin-like serine peptidases.

  4. The pH dependence of hairpin ribozyme catalysis reflects ionization of an active site adenine.

    PubMed

    Cottrell, Joseph W; Scott, Lincoln G; Fedor, Martha J

    2011-05-20

    Understanding how self-cleaving ribozymes mediate catalysis is crucial in light of compelling evidence that human and bacterial gene expression can be regulated through RNA self-cleavage. The hairpin ribozyme catalyzes reversible phosphodiester bond cleavage through a mechanism that does not require divalent metal cations. Previous structural and biochemical evidence implicated the amidine group of an active site adenosine, A38, in a pH-dependent step in catalysis. We developed a way to determine microscopic pK(a) values in active ribozymes based on the pH-dependent fluorescence of 8-azaadenosine (8azaA). We compared the microscopic pK(a) for ionization of 8azaA at position 38 with the apparent pK(a) for the self-cleavage reaction in a fully functional hairpin ribozyme with a unique 8azaA at position 38. Microscopic and apparent pK(a) values were virtually the same, evidence that A38 protonation accounts for the decrease in catalytic activity with decreasing pH. These results implicate the neutral unprotonated form of A38 in a transition state that involves formation of the 5'-oxygen-phosphorus bond.

  5. On the pH dependent behavior of the firefly bioluminescence: protein dynamics and water content in the active pocket.

    PubMed

    Kim, Hyun Woo; Rhee, Young Min

    2013-06-20

    Understanding bioluminescence presents fascinating challenges for fundamental sciences and numerous opportunities for practical applications. As a representative example, the firefly bioluminescent system has been intensively studied in both experimental and computational areas. However, there are still remaining questions regarding especially the detailed protein dynamics and the mechanisms of its color modulation. Here, we report on the pH dependent behavior of the firefly bioluminescence primarily based on molecular dynamics simulations. We find that the overall protein structure is generally resilient to pH variations. As the protein does not exhibit any structural distortions that can affect the emission property, we next focus on the dynamics in the active pocket and its effect on color modulation by adopting different protonation states in the pocket. With this, we observe red-shifted emissions at acidic conditions as consistent with previous studies. Most importantly, we find that a water molecule in the active pocket can mediate flexible motions of neighboring groups, which can subsequently modify the emission properties to a substantial degree. Based on the observations, we propose that the active pocket is in a dry condition during the luminescence process. Our results highlight the importance of understanding the role of the dynamics near the active pocket in modulating bioluminescence.

  6. An enzyme kinetics study of the pH dependence of chloride activation of oxygen evolution in photosystem II.

    PubMed

    Baranov, Sergei; Haddy, Alice

    2017-03-01

    Oxygen evolution by photosystem II (PSII) involves activation by Cl(-) ion, which is regulated by extrinsic subunits PsbQ and PsbP. In this study, the kinetics of chloride activation of oxygen evolution was studied in preparations of PSII depleted of the PsbQ and PsbP subunits (NaCl-washed and Na2SO4/pH 7.5-treated) over a pH range from 5.3 to 8.0. At low pH, activation by chloride was followed by inhibition at chloride concentrations >100 mM, whereas at high pH activation continued as the chloride concentration increased above 100 mM. Both activation and inhibition were more pronounced at lower pH, indicating that Cl(-) binding depended on protonation events in each case. The simplest kinetic model that could account for the complete data set included binding of Cl(-) at two sites, one for activation and one for inhibition, and four protonation steps. The intrinsic (pH-independent) dissociation constant for Cl(-) activation, K S, was found to be 0.9 ± 0.2 mM for both preparations, and three of the four pK as were determined, with the fourth falling below the pH range studied. The intrinsic inhibition constant, K I, was found to be 64 ± 2 and 103 ± 7 mM for the NaCl-washed and Na2SO4/pH7.5-treated preparations, respectively, and is considered in terms of the conditions likely to be present in the thylakoid lumen. This enzyme kinetics analysis provides a more complete characterization of chloride and pH dependence of O2 evolution activity than has been previously presented.

  7. The pH dependence of the cathodic peak potential of the active sites in bilirubin oxidase.

    PubMed

    Filip, Jaroslav; Tkac, Jan

    2014-04-01

    This is the first study showing pH dependence of three distinct redox sites within bilirubin oxidase (BOD) adsorbed on a nanocomposite modified electrode. The 1st redox centre with the highest redox potential Ec(1st)=404 mV vs. Ag/AgCl (614 mV vs. NHE at pH7.0) exhibited pH dependence with a slope -dEc(1st)/dpH=66(±3) mV under a non-turnover process. The 2nd redox centre with a potential Ec(2nd)=228 mV vs. Ag/AgCl (438 mV vs. NHE at pH7.0) was not dependent on pH in the absence and presence of O2. Finally, the 3rd redox site with a redox potential Ec(3rd)=92 mV vs. Ag/AgCl (302 mV vs. NHE at pH7.0) exhibited pH dependence for a cathodic process with -dEc(3rd)/dpH=70(±6) mV and for anodic process with -dEa(3rd)/dpH=73(±2) mV, respectively. Moreover, two break points for dependence of Ec(1st) or Ec(3rd) on pH were observed for the 1st (T1) site and the 3rd site assigned to involvement of two acidic amino acids (Asp105 and Glu463). A diagram of a potential difference between cathodic peaks of BOD as a dependence on pH is shown. The results obtained can be of interest for construction of biofuel cells based on BOD such as for generation of a low level of electricity from body fluids.

  8. Characterization of glutamate decarboxylase from Lactobacillus plantarum and its C-terminal function for the pH dependence of activity.

    PubMed

    Shin, Sun-Mi; Kim, Hana; Joo, Yunhye; Lee, Sang-Jae; Lee, Yong-Jik; Lee, Sang Jun; Lee, Dong-Woo

    2014-12-17

    The gadB gene encoding glutamate decarboxylase (GAD) from Lactobacillus plantarum was cloned and expressed in Escherichia coli. The recombinant enzyme exhibited maximal activity at 40 °C and pH 5.0. The 3D model structure of L. plantarum GAD proposed that its C-terminal region (Ile454-Thr468) may play an important role in the pH dependence of catalysis. Accordingly, C-terminally truncated (Δ3 and Δ11 residues) mutants were generated and their enzyme activities compared with that of the wild-type enzyme at different pH values. Unlike the wild-type GAD, the mutants showed pronounced catalytic activity in a broad pH range of 4.0-8.0, suggesting that the C-terminal region is involved in the pH dependence of GAD activity. Therefore, this study may provide effective target regions for engineering pH dependence of GAD activity, thereby meeting industrial demands for the production of γ-aminobutyrate in a broad range of pH values.

  9. Synthesis and activities of antitumor agents.

    PubMed

    Suami, T; Machinami, T; Hisamatsu, T

    1979-03-01

    N-(2-Chloroethyl)-N-nitrosocarbamoyl derivatives of glycosylamines have been prepared. Six N-(2-chloroethyl)-N-nitrosoureas, including three disaccharide derivatives, were submitted to a determination of antitumor activity. All the compounds tested exhibited strong antitumor activity against leukemia L1210 in mice.

  10. Garcinia xanthones as orally active antitumor agents.

    PubMed

    Zhang, Xiaojin; Li, Xiang; Sun, Haopeng; Wang, Xiaojian; Zhao, Li; Gao, Yuan; Liu, Xiaorong; Zhang, Shenglie; Wang, Yanyan; Yang, Yingrui; Zeng, Su; Guo, Qinglong; You, Qidong

    2013-01-10

    Using a newly developed strategy whose key step is the regioselective propargylation of hydroxyxanthone substrates, 99 structurally diverse Garcinia natural-product-like xanthones based on gambogic acid were designed and synthesized and their in vitro antitumor activity was evaluated. A set of 40 related compounds was chosen for determination of their physicochemical properties including polar surface area, log D₇.₄, aqueous solubility, and permeability at pH 7.4. In the light of the in vitro antitumor activity and the physicochemical properties, two compounds were advanced into in vivo efficacy experiments. The antitumor activity of compound 112, administered po, showed more potent in vivo oral antitumor activity than gambogic acid.

  11. Investigation of solubilising effects of bile salts on an active pharmaceutical ingredient with unusual pH dependent solubility by NMR spectroscopy.

    PubMed

    Vogtherr, M; Marx, A; Mieden, A-C; Saal, C

    2015-05-01

    The interaction between an ampholytic and amphiphilic Active Pharmaceutical Ingredient (API) showing unusual pH dependent solubility and Fasted State Simulated Intestinal Fluid (FaSSIF) was studied by NMR spectroscopy. Solubility in FaSSIF was drastically increased, about 30 fold, compared to simulated gastrointestinal fluid without bile salts. Our studies aimed at understanding the mechanisms that lead to this drastic enhancement. All species present in solution at various concentrations of API were characterised by Diffusion Ordered Spectroscopy (DOSY) NMR measurements. These indicated the presence of mixed taurocholate-lecithin and pure taurocholate micelles in pure FaSSIF, and formation of mixed taurocholate-API micelles after addition of API. The formation of taurocholate-API micelles was also supported by Nuclear Overhauser Effect/Enhancement (NOE) contacts between taurocholate and the API. Formation of mixed taurocholate-API micelles took place at the expense of pure taurocholate micelles, whereas mixed taurocholate-lecithin micelles remained uninfluenced by the presence of API. Our results showed that the increase in solubility was due to similar amphiphilic properties of the API and taurocholate which enabled formation of mixed taurocholate-API micelles. From results of determination of solubility as well as NMR experiments a phase diagram comprising several micellar species was derived.

  12. Antitumor Activities of Metal Oxide Nanoparticles

    PubMed Central

    Vinardell, Maria Pilar; Mitjans, Montserrat

    2015-01-01

    Nanoparticles have received much attention recently due to their use in cancer therapy. Studies have shown that different metal oxide nanoparticles induce cytotoxicity in cancer cells, but not in normal cells. In some cases, such anticancer activity has been demonstrated to hold for the nanoparticle alone or in combination with different therapies, such as photocatalytic therapy or some anticancer drugs. Zinc oxide nanoparticles have been shown to have this activity alone or when loaded with an anticancer drug, such as doxorubicin. Other nanoparticles that show cytotoxic effects on cancer cells include cobalt oxide, iron oxide and copper oxide. The antitumor mechanism could work through the generation of reactive oxygen species or apoptosis and necrosis, among other possibilities. Here, we review the most significant antitumor results obtained with different metal oxide nanoparticles.

  13. Structural Antitumoral Activity Relationships of Synthetic Chalcones

    PubMed Central

    Echeverria, Cesar; Santibañez, Juan Francisco; Donoso-Tauda, Oscar; Escobar, Carlos A.; Ramirez-Tagle, Rodrigo

    2009-01-01

    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. PMID:19333443

  14. Antitumoral activity of trisubstituted dihydrobenzo(a)carbazoles. Part III.

    PubMed

    Segall, A; Pizzorno, M T

    2000-10-01

    Two recently synthesized, trisubstituted dihydrobenzo(a)carbazoles were investigated regarding their anti-HIV and antitumoral activity. The compounds showed some activity against melanoma, renal cancer and breast cancer cell lines.

  15. Anti-tumoral activity of native compound morelloflavone in glioma

    PubMed Central

    Li, Xianfeng; Ai, Hongyan; Sun, Deke; Wu, Tao; He, Jian; Xu, Zhai; Ding, Li; Wang, Ling

    2016-01-01

    The aim of the study was to investigate the anti-tumoral activity of morelloflavone substances with different structures. We also studied the possible link between morelloflavone structure and its function. Various types of chromatographic techniques were used to isolate and screen morelloflavone substances from the extracts of gambogic tree trunk and the morelloflavone structures were identified by analytical techniques such as high resolution mass spectrometry and nuclear magnetism. Anti-tumoral activities of different compounds were investigated and the link between the antitumor activity and the structure of compound was exaimed. Our results showed that the isolated morelloflavone substances demonstrated a certain level of antitumor activity. The compound no. 1 had the strongest effect to inhibit glioma U87 and C6 cells followed by compound no. 2 while compound no. 5 was the weakest among them. We conducted a preliminary analysis on the structure-function relationship through the structure comparison and we concluded that the antitumor effects of morelloflavone substances with different structures were significantly different from each other. Thus, the glucose chain in C4 position of biflavone structure can enhance the antitumor activity of the compound in glioma cells. Additionally, the formation of intramolecular hydrogen bonds in biflavone compounds may also play a role in enhancing the antitumor activity and inhibition rate. PMID:27900007

  16. Alocasia cucullata exhibits strong antitumor effect in vivo by activating antitumor immunity.

    PubMed

    Peng, Qiuxian; Cai, Hongbing; Sun, Xuegang; Li, Xin; Mo, Zhixian; Shi, Jue

    2013-01-01

    Chinese herbal medicines have long been used to treat various illnesses by modulating the human immune response. In this study, we investigate the immuno-modulating effect and antitumor activity of Alocasia Cucullata (AC), a Chinese herb traditionally used to treat infection and cancer. We found that the whole water extract of AC roots could significantly attenuate tumor growth in mouse tumor models. The median survival time of the AC-treated mice was 43 days, 16 days longer than that of the control group. Moreover, the AC-treated mice showed substantially higher induction of key antitumor cytokines, such as IL-2, IFN-γ, and TNF-α, indicating that AC may exert antitumor effect by activating antitumor immunity. To further pinpoint the cellular and molecular mechanism of AC, we studied the dose response of a human monocytic cell line, THP-1, to the whole water extract of AC. Treatment of the AC extract significantly induced THP-1 differentiation into macrophage-like cells and the differentiated THP-1 showed expression of specific macrophage surface markers, such as CD11b and CD14, as well as productions of antitumor cytokines, e.g. IFN-γ and TNF-α. Our data thus point to AC as potentially a new, alternative immuno-modulating herbal remedy for anticancer treatment.

  17. Antitumor polysaccharides from mushrooms: a review on the structural characteristics, antitumor mechanisms and immunomodulating activities.

    PubMed

    Meng, Xin; Liang, Hebin; Luo, Lixin

    2016-04-07

    Mushrooms are popular folk medicines that have attracted considerable attention because of their efficient antitumor activities. This review covers existing research achievements on the mechanisms of isolated mushroom polysaccharides, particularly (1→3)-β-D-glucans. Our review also describes the function in modulating the immune system and potential tumor-inhibitory effects of polysaccharides. The antitumor mechanisms of mushroom polysaccharides are mediated by stimulated T cells or other immune cells. These polysaccharides are able to trigger various cellular responses, such as the expression of cytokines and nitric oxide. Most polysaccharides could bind other conjugate molecules, such as polypeptides and proteins, whose conjugation always possess strong antitumor activities. The purpose of this review is to summarize available information, and to reflect the present situation of polysaccharide research filed with a view for future direction.

  18. Advances in antitumor polysaccharides from phellinus sensu lato: Production, isolation, structure, antitumor activity, and mechanisms.

    PubMed

    Yan, Jing-Kun; Pei, Juan-Juan; Ma, Hai-Le; Wang, Zhen-Bin; Liu, Yuan-Shuai

    2017-04-13

    Edible and medicinal fungi (mushrooms) are widely applied to functional foods and nutraceutical products because of their proven nutritive and medicinal properties. Phellinus sensu lato is a well-known medicinal mushroom that has long been used in preventing ailments, including gastroenteric dysfunction, diarrhea, hemorrhage, and cancers, in oriental countries, particularly in China, Japan, and Korea. Polysaccharides represent a major class of bioactive molecules in Phellinus s. l., which have notable antitumor, immunomodulatory, and medicinal properties. Polysaccharides that were isolated from fruiting bodies, cultured mycelia, and filtrates of Phellinus s. l. have not only activated different immune responses of the host organism but have also directly suppressed tumor growth and metastasis. Studies suggest that polysaccharides from Phellinus s. l. are promising alternative anticancer agents or synergizers for existing antitumor drugs. This review summarizes the recent development of polysaccharides from Phellinus s. l., including polysaccharide production, extraction and isolation methods, chemical structure, antitumor activities, and mechanisms of action.

  19. Photodynamic effect on specific antitumor immune activity

    NASA Astrophysics Data System (ADS)

    Vonarx-Coinsmann, Veronique; Foultier, Marie-Therese; Morlet, Laurent; de Brito, Leonor X.; Patrice, Thierry

    1995-03-01

    In this study the effect of PDT on the antitumoral specific immunologic response was evaluated. We compared the specific cytolytic activity (CLA) by a chromium release assay of primed mouse spleen T lymphocytes sensitized against syngeneic mastocytoma P511 cells. P511 cells, or lymphocytes, or both cells were treated or not with photofrin and/or light (514 nm). Photofrin II alone (1 (mu) g/ml, 2 hours) reduced CLA 59% when P511 were treated. Photofrin II (1 (mu) g/ml) followed by light (25 Joules/sq cm) also reduced CLA 35%. Photofrin II alone (0.5 (mu) g/ml, 2 hours) reduced CLA 8% when only lymphocytes were treated. And Photofrin II (0.5 (mu) g/ml) followed by light (25 Joules/sq cm) also reduced CLA 45%. When both cells were treated with Photofrin II alone or followed by light (25 Joules/sq cm) the CLA was also reduced respectively 19, 41%.

  20. pH dependent catalytic activities of platinum nanoparticles with respect to the decomposition of hydrogen peroxide and scavenging of superoxide and singlet oxygen

    NASA Astrophysics Data System (ADS)

    Liu, Yi; Wu, Haohao; Li, Meng; Yin, Jun-Jie; Nie, Zhihong

    2014-09-01

    Recently, platinum (Pt) nanoparticles (NPs) have received increasing attention in the field of catalysis and medicine due to their excellent catalytic activity. To rationally design Pt NPs for these applications, it is crucial to understand the mechanisms underlying their catalytic and biological activities. This article describes a systematic study on the Pt NP-catalyzed decomposition of hydrogen peroxide (H2O2) and scavenging of superoxide (O2&z.rad;-) and singlet oxygen (1O2) over a physiologically relevant pH range of 1.12-10.96. We demonstrated that the catalytic activities of Pt NPs can be modulated by the pH value of the environment. Our results suggest that Pt NPs possess peroxidase-like activity of decomposing H2O2 into &z.rad;OH under acidic conditions, but catalase-like activity of producing H2O and O2 under neutral and alkaline conditions. In addition, Pt NPs exhibit significant superoxide dismutase-like activity of scavenging O2&z.rad;- under neutral conditions, but not under acidic conditions. The 1O2 scavenging ability of Pt NPs increases with the increase in the pH of the environment. The study will provide useful guidance for designing Pt NPs with desired catalytic and biological properties.Recently, platinum (Pt) nanoparticles (NPs) have received increasing attention in the field of catalysis and medicine due to their excellent catalytic activity. To rationally design Pt NPs for these applications, it is crucial to understand the mechanisms underlying their catalytic and biological activities. This article describes a systematic study on the Pt NP-catalyzed decomposition of hydrogen peroxide (H2O2) and scavenging of superoxide (O2&z.rad;-) and singlet oxygen (1O2) over a physiologically relevant pH range of 1.12-10.96. We demonstrated that the catalytic activities of Pt NPs can be modulated by the pH value of the environment. Our results suggest that Pt NPs possess peroxidase-like activity of decomposing H2O2 into &z.rad;OH under acidic conditions

  1. pH dependent catalytic activities of platinum nanoparticles with respect to the decomposition of hydrogen peroxide and scavenging of superoxide and singlet oxygen.

    PubMed

    Liu, Yi; Wu, Haohao; Li, Meng; Yin, Jun-Jie; Nie, Zhihong

    2014-10-21

    Recently, platinum (Pt) nanoparticles (NPs) have received increasing attention in the field of catalysis and medicine due to their excellent catalytic activity. To rationally design Pt NPs for these applications, it is crucial to understand the mechanisms underlying their catalytic and biological activities. This article describes a systematic study on the Pt NP-catalyzed decomposition of hydrogen peroxide (H2O2) and scavenging of superoxide (O2˙(-)) and singlet oxygen ((1)O2) over a physiologically relevant pH range of 1.12-10.96. We demonstrated that the catalytic activities of Pt NPs can be modulated by the pH value of the environment. Our results suggest that Pt NPs possess peroxidase-like activity of decomposing H2O2 into ˙OH under acidic conditions, but catalase-like activity of producing H2O and O2 under neutral and alkaline conditions. In addition, Pt NPs exhibit significant superoxide dismutase-like activity of scavenging O2˙(-) under neutral conditions, but not under acidic conditions. The (1)O2 scavenging ability of Pt NPs increases with the increase in the pH of the environment. The study will provide useful guidance for designing Pt NPs with desired catalytic and biological properties.

  2. Mechanism of phosphoryl transfer by nucleoside diphosphate kinase pH dependence and role of the active site Lys16 and Tyr56 residues.

    PubMed

    Schneider, B; Babolat, M; Xu, Y W; Janin, J; Véron, M; Deville-Bonne, D

    2001-04-01

    Nucleoside diphosphate (NDP) kinase phosphorylates nucleoside diphosphates with little specificity for the base and the sugar. Although nucleotide analogues used in antiviral therapies are also metabolized to their triphosphate form by NDP kinase, their lack of the 3'-hydroxyl of the ribose, which allows them to be DNA chain terminators, severely impairs the catalytic efficiency of NDP kinase. We have analyzed the kinetics parameters of several mutant NDP kinases modified on residues (Lys16, Tyr56, Asn119) interacting with the gamma-phosphate and/or the 3'-OH of the Mg2+-ATP substrate. We compared the relative contributions of the active-site residues and the substrate 3'-OH for point mutations on Lys16, Tyr56 and Asn119. Analysis of additional data from pH profiles identify the ionization state of these residues in the enzyme active form. X-ray structure of K16A mutant NDP kinase shows no detectable rearrangement of the residues of the active site.

  3. In vivo antitumoral activity of stem pineapple (Ananas comosus) bromelain.

    PubMed

    Báez, Roxana; Lopes, Miriam T; Salas, Carlos E; Hernández, Martha

    2007-10-01

    Stem bromelain (EC 3.4.22.32) is a major cysteine proteinase, isolated from pineapple ( Ananas comosus) stem. Its main medicinal use is recognized as digestive, in vaccine formulation, antitumoral and skin debrider for the treatment of burns. To verify the identity of the principle in stem fractions responsible for the antitumoral effect, we isolated bromelain to probe its pharmacological effects. The isolated bromelain was obtained from stems of adult pineapple plants by buffered aqueous extraction and cationic chromatography. The homogeneity of bromelain was confirmed by reverse phase HPLC, SDS-PAGE and N-terminal sequencing. The in vivo antitumoral/antileukemic activity was evaluated using the following panel of tumor lines: P-388 leukemia, sarcoma (S-37), Ehrlich ascitic tumor (EAT), Lewis lung carcinoma (LLC), MB-F10 melanoma and ADC-755 mammary adenocarcinoma. Intraperitoneal administration of bromelain (1, 12.5, 25 mg/kg), began 24 h after tumor cell inoculation in experiments in which 5-fluorouracil (5-FU, 20 mg/kg) was used as positive control. The antitumoral activity was assessed by the survival increase (% survival index) following various treatments. With the exception of MB-F10 melanoma, all other tumor-bearing animals had a significantly increased survival index after bromelain treatment. The largest increase ( approximately 318 %) was attained in mice bearing EAT ascites and receiving 12.5 mg/kg of bromelain. This antitumoral effect was superior to that of 5-FU, whose survival index was approximately 263 %, relative to the untreated control. Bromelain significantly reduced the number of lung metastasis induced by LLC transplantation, as observed with 5-FU. The antitumoral activity of bromelain against S-37 and EAT, which are tumor models sensitive to immune system mediators, and the unchanged tumor progression in the metastatic model suggests that the antimetastatic action results from a mechanism independent of the primary antitumoral effect.

  4. An Update on Antitumor Activity of Naturally Occurring Chalcones

    PubMed Central

    Zhang, En-Hui; Wang, Ru-Feng; Guo, Shu-Zhen; Liu, Bin

    2013-01-01

    Chalcones, which have characteristic 1,3-diaryl-2-propen-1-one skeleton, are mainly produced in roots, rhizomes, heartwood, leaves, and seeds of genera Angelica, Sophora, Glycyrrhiza, Humulus, Scutellaria, Parartocarpus, Ficus, Dorstenia, Morus, Artocarpus, and so forth. They have become of interest in the research and development of natural antitumor agents over the past decades due to their broad range of mechanisms including anti-initiation, induction of apoptosis, antiproliferation, antimetastasis, antiangiogenesis, and so forth. This review summarizes the studies on the antitumor activity of naturally occurring chalcones and their underlying mechanisms in detail during the past decades. PMID:23690855

  5. Effect of levan's branching structure on antitumor activity.

    PubMed

    Yoon, Eun Ju; Yoo, Sang-Ho; Cha, Jaeho; Gyu Lee, Hyeon

    2004-06-01

    Levan produced from Microbacterium laevaniformans KCTC 9732 (M-levan) was isolated and treated with an inulinase to modify its branching structure. The chemical structures of levans were characterized, and the modified levans were applied on animal tumor cells to evaluate their antitumor activity. The GC-MS analysis indicated that beta-(2,1)-linked branches of M-levan were specifically hydrolyzed. As the ratio of applied inulinase to levan increased, the branching degree decreased proportionally. Sequential degrees of branching were obtained from 12.3 to 4.2%. Strong levan-induced inhibition of cell growth was detected on SNU-1 and HepG2 tumor cell lines. As the branching degree of M-levan reduced, antitumor activity on SNU-1 linearly decreased (r2=0.96). In HepG2, the antitumor activity rapidly dropped when the branching reached up to 9.3%, then slightly increased as the branching degree of M-levan further decreased. These results suggested that the branch structure would play a crucial role in levan's antitumor activity.

  6. Antitumor activity of fermented noni exudates and its fractions

    PubMed Central

    LI, JINHUA; CHANG, LENG-CHEE; WALL, MARISA; WONG, D.K.W.; YU, XIANZHONG; WEI, YANZHANG

    2013-01-01

    Noni has been extensively used in folk medicine by Polynesians for over 2000 year. Recent studies have shown that noni has a wide spectrum of therapeutic activities including inhibition of angiogenesis, anti-inflammatory effects and anti-cancer activities. Intraperitoneal (i.p.) injection of fermented noni exudates (fNE) were previously found to induce significant tumor rejection in a S180 mouse sarcoma tumor model, while natural killer (NK) cells were demonstrated to be markedly involved in fNE-induced antitumor activity. In this study, fNE was partitioned into three fractions and their antitumor effects were examined using i.p. injection or as water supplement. The in vivo animal study results showed that when delivered by i.p. injection, n-butanol fraction of fNE (BuOH) effectively rejected (100%) tumor challenge and eradicated existing tumors (75%). When delivered as a water supplement, 62.5% of the mice receiving the n-butanol or ethyl acetate fractions resisted tumor cells. The tumor-resistant mice effectively rejected more and higher doses of tumor challenge, indicating that the immune system was activated. The findings confirm those of an earlier study showing fNE to have anti-tumor activity and demonstrating that the n-butanol fraction of fNE contains active antitumor components, to be further identified. More importantly, the antitumor effect of fNE and its fractions as water supplements renders a significant potential for identifying novel and powerful new dietary products for cancer prevention. PMID:24649140

  7. Antitumor activity of fermented noni exudates and its fractions.

    PubMed

    Li, Jinhua; Chang, Leng-Chee; Wall, Marisa; Wong, D K W; Yu, Xianzhong; Wei, Yanzhang

    2013-01-01

    Noni has been extensively used in folk medicine by Polynesians for over 2000 year. Recent studies have shown that noni has a wide spectrum of therapeutic activities including inhibition of angiogenesis, anti-inflammatory effects and anti-cancer activities. Intraperitoneal (i.p.) injection of fermented noni exudates (fNE) were previously found to induce significant tumor rejection in a S180 mouse sarcoma tumor model, while natural killer (NK) cells were demonstrated to be markedly involved in fNE-induced antitumor activity. In this study, fNE was partitioned into three fractions and their antitumor effects were examined using i.p. injection or as water supplement. The in vivo animal study results showed that when delivered by i.p. injection, n-butanol fraction of fNE (BuOH) effectively rejected (100%) tumor challenge and eradicated existing tumors (75%). When delivered as a water supplement, 62.5% of the mice receiving the n-butanol or ethyl acetate fractions resisted tumor cells. The tumor-resistant mice effectively rejected more and higher doses of tumor challenge, indicating that the immune system was activated. The findings confirm those of an earlier study showing fNE to have anti-tumor activity and demonstrating that the n-butanol fraction of fNE contains active antitumor components, to be further identified. More importantly, the antitumor effect of fNE and its fractions as water supplements renders a significant potential for identifying novel and powerful new dietary products for cancer prevention.

  8. Jacalin-Activated Macrophages Exhibit an Antitumor Phenotype

    PubMed Central

    Danella Polli, Cláudia; Pereira Ruas, Luciana; Chain Veronez, Luciana; Herrero Geraldino, Thais; Rossetto de Morais, Fabiana; Roque-Barreira, Maria Cristina; Pereira-da-Silva, Gabriela

    2016-01-01

    Tumor-associated macrophages (TAMs) have an ambiguous and complex role in the carcinogenic process, since these cells can be polarized into different phenotypes (proinflammatory, antitumor cells or anti-inflammatory, protumor cells) by the tumor microenvironment. Given that the interactions between tumor cells and TAMs involve several players, a better understanding of the function and regulation of TAMs is crucial to interfere with their differentiation in attempts to skew TAM polarization into cells with a proinflammatory antitumor phenotype. In this study, we investigated the modulation of macrophage tumoricidal activities by the lectin jacalin. Jacalin bound to macrophage surface and induced the expression and/or release of mainly proinflammatory cytokines via NF-κB signaling, as well as increased iNOS mRNA expression, suggesting that the lectin polarizes macrophages toward the antitumor phenotype. Therefore, tumoricidal activities of jacalin-stimulated macrophages were evaluated. High rates of tumor cell (human colon, HT-29, and breast, MCF-7, cells) apoptosis were observed upon incubation with supernatants from jacalin-stimulated macrophages. Taken together, these results indicate that jacalin, by exerting a proinflammatory activity, can direct macrophages to an antitumor phenotype. Deep knowledge of the regulation of TAM functions is essential for the development of innovative anticancer strategies. PMID:27119077

  9. Antitumor Activity of Monoterpenes Found in Essential Oils

    PubMed Central

    Sobral, Marianna Vieira; Xavier, Aline Lira; Lima, Tamires Cardoso; de Sousa, Damião Pergentino

    2014-01-01

    Cancer is a complex genetic disease that is a major public health problem worldwide, accounting for about 7 million deaths each year. Many anticancer drugs currently used clinically have been isolated from plant species or are based on such substances. Accumulating data has revealed anticancer activity in plant-derived monoterpenes. In this review the antitumor activity of 37 monoterpenes found in essential oils is discussed. Chemical structures, experimental models, and mechanisms of action for bioactive substances are presented. PMID:25401162

  10. Mucin-like peptides from Echinococcus granulosus induce antitumor activity.

    PubMed

    Noya, Verónica; Bay, Sylvie; Festari, María Florencia; García, Enrique P; Rodriguez, Ernesto; Chiale, Carolina; Ganneau, Christelle; Baleux, Françoise; Astrada, Soledad; Bollati-Fogolín, Mariela; Osinaga, Eduardo; Freire, Teresa

    2013-09-01

    There is substantial evidence suggesting that certain parasites can have antitumor properties. We evaluated mucin peptides derived from the helminth Echinococcus granulosus (denominated Egmuc) as potential inducers of antitumor activity. We present data showing that Egmuc peptides were capable of inducing an increase of activated NK cells in the spleen of immunized mice, a fact that was correlated with the capacity of splenocytes to mediate killing of tumor cells. We demonstrated that Egmuc peptides enhance LPS-induced maturation of dendritic cells in vitro by increasing the production of IL-12p40p70 and IL-6 and that Egmuc-treated DCs may activate NK cells, as judged by an increased expression of CD69. This evidence may contribute to the design of tumor vaccines and open new horizons in the use of parasite-derived molecules in the fight against cancer.

  11. A phosphotyrosine switch determines the antitumor activity of ERβ

    PubMed Central

    Yuan, Bin; Cheng, Long; Chiang, Huai-Chin; Xu, Xiaojie; Han, Yongjian; Su, Hang; Wang, Lingxue; Zhang, Bo; Lin, Jing; Li, Xiaobing; Xie, Xiangyang; Wang, Tao; Tekmal, Rajeshwar R.; Curiel, Tyler J.; Yuan, Zhi-Min; Elledge, Richard; Hu, Yanfen; Ye, Qinong; Li, Rong

    2014-01-01

    Estrogen receptors ERα and ERβ share considerable sequence homology yet exert opposite effects on breast cancer cell proliferation. While the proliferative role of ERα in breast tumors is well characterized, it is not clear whether the antitumor activity of ERβ can be mobilized in breast cancer cells. Here, we have shown that phosphorylation of a tyrosine residue (Y36) present in ERβ, but not in ERα, dictates ERβ-specific activation of transcription and is required for ERβ-dependent inhibition of cancer cell growth in culture and in murine xenografts. Additionally, the c-ABL tyrosine kinase and EYA2 phosphatase directly and diametrically controlled the phosphorylation status of Y36 and subsequent ERβ function. A nonphosphorylatable, transcriptionally active ERβ mutant retained antitumor activity but circumvented control by upstream regulators. Phosphorylation of Y36 was required for ERβ-mediated coactivator recruitment to ERβ target promoters. In human breast cancer samples, elevated phosphorylation of Y36 in ERβ correlated with high levels of c-ABL but low EYA2 levels. Furthermore, compared with total ERβ, the presence of phosphorylated Y36–specific ERβ was strongly associated with both disease-free and overall survival in patients with stage II and III disease. Together, these data identify a signaling circuitry that regulates ERβ-specific antitumor activity and has potential as both a prognostic tool and a molecular target for cancer therapy. PMID:24960160

  12. A promising camptothecin derivative: Semisynthesis, antitumor activity and intestinal permeability.

    PubMed

    Rodríguez-Berna, Guillermo; Mangas-Sanjuán, Víctor; Gonzalez-Alvarez, Marta; Gonzalez-Alvarez, Isabel; García-Giménez, José Luis; Díaz Cabañas, María José; Bermejo, Marival; Corma, Avelino

    2014-08-18

    Oral administration of camptothecin (CPT) derivatives and other antitumoral agents is being actively developed in order to improve the quality of life of patients with cancer. Though several lipophilic derivatives of CPT have shown interesting oral bioavailability in preclinical and clinical studies, only Topotecan has been approved for this route of administration. Semisynthesis, antitumor activity, biological inhibition mechanism, and in situ intestinal permeability of 9, 10-[1,3]-Dioxinocamptothecin (CDiox), an unexplored CPT derivative, have been studied in this paper. The hexacyclic analog was as effective as Topotecan and CPT in different tumor cell lines, showing an expected similar apoptosis cell mechanism and high ability to inhibit DNA synthesis in HeLa, Caco-2, A375 and MDA-MB-231 cell lines. Furthermore, in vitro and in situ pharmacokinetics transport values obtained for CDiox displayed more favorable absorption profile than CPT and Topotecan.

  13. Piper betle extracts exhibit antitumor activity by augmenting antioxidant potential.

    PubMed

    Alam, Badrul; Majumder, Rajib; Akter, Shahina; Lee, Sang-Han

    2015-02-01

    The present study was conducted to evaluate the methanolic extract of Piper betle leaves (MPBL) and its organic fractions with regard to antitumor activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice and to confirm their antioxidant activities. At 24 h post-intraperitoneal inoculation of tumor cells into mice, extracts were administered at 25, 50 and 100 mg/kg body weight for nine consecutive days. The antitumor effects of the extracts were then assessed according to tumor volume, packed cell count, viable and non-viable tumor cell count, median survival time and increase in life span of EAC-bearing mice. Next, hematological profiles and serum biochemical parameters were calculated, and antioxidant properties were assessed by estimating lipid peroxidation, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels. MPBL and the ethylacetate fraction (EPBL) at a dose of 100 mg/kg induced a significant decrease in tumor volume, packed cell volume and viable cell count and increased the life span of the EAC-bearing mice (P<0.05). Hematological and serum biochemical profiles were restored to normal levels in the extract-treated mice compared with the EAC control mice. MPBL and EPBL treatment significantly decreased lipid peroxidation (P<0.05) and restored GSH, SOD and CAT levels towards normal compared with the EAC control. Taken together, the results of the present study demonstrated that Piper betle extracts exhibit significant antitumor activity, which may be attributed to the augmentation of endogenous antioxidant potential.

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

    PubMed

    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.

  15. Site-specific PEGylation of lidamycin and its antitumor activity

    PubMed Central

    Li, Liang; Shang, Boyang; Hu, Lei; Shao, Rongguang; Zhen, Yongsu

    2015-01-01

    In this study, N-terminal site-specific mono-PEGylation of the recombinant lidamycin apoprotein (rLDP) of lidamycin (LDM) was prepared using a polyethyleneglycol (PEG) derivative (Mw 20 kDa) through a reactive terminal aldehyde group under weak acidic conditions (pH 5.5). The biochemical properties of mPEG-rLDP-AE, an enediyne-integrated conjugate, were analyzed by SDS-PAGE, RP-HPLC, SEC-HPLC and MALDI-TOF. Meanwhile, in vitro and in vivo antitumor activity of mPEG-rLDP-AE was evaluated by MTT assays and in xenograft model. The results indicated that mPEG-rLDP-AE showed significant antitumor activity both in vitro and in vivo. After PEGylation, mPEG-rLDP still retained the binding capability to the enediyne AE and presented the physicochemical characteristics similar to that of native LDP. It is of interest that the PEGylation did not diminish the antitumor efficacy of LDM, implying the possibility that this derivative may function as a payload to deliver novel tumor-targeted drugs. PMID:26579455

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

    SciTech Connect

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

    1999-11-16

    This application describes a bacterial preparation from Pseudomonas species isolated {number{underscore}sign}15 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.

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

    DOEpatents

    Vass, Arpad A.; Tyndall, Richard L.; Terzaghi-Howe, Peggy

    1999-01-01

    A bacterial preparation from Pseudomonas species isolated #15 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.

  18. Antitumor activity of levan polysaccharides from selected microorganisms.

    PubMed

    Yoo, Sang-Ho; Yoon, Eun Ju; Cha, Jaeho; Lee, Hyeon Gyu

    2004-04-01

    Levans were isolated from the cultures of Gluconoacetobacter xylinus (G-levan; Mw = 40,000), Microbacterium laevaniformans (M; Mw = 710,000), Rahnella aquatilis (R; Mw = 380,000), and Zymomonas mobilis (Z; Mw = 570,000). The levans were composed mainly of fructose residues when analyzed by TLC and HPLC, and their main backbones were beta-(2,6)-linkages with beta-(2,1)-branches by GC-MS and NMR. In the in vitro antitumor activity test of the levans against eight different tumor cell lines, relatively stronger activity was observed from the SNU-1 and HepG2. The M- (52.54-62.05%) and R-levan (52.15-58.58%) showed the significantly high activity against SNU-1, while M-levan showed the highest (49.93-61.82%) activity against HepG2. During the in vivo analysis of inhibitory activity of the levans against Sarcoma-180 growth, M-, R- and Z-levans showed strong antitumor activity (average 66%) but G-levan (42%) had significantly lower activity.

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

    PubMed

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

    2013-08-22

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

  20. Phenylethylchromones with In Vitro Antitumor Promoting Activity from Aquilaria filaria.

    PubMed

    Suzuki, Airi; Miyake, Katsunori; Saito, Yohei; Rasyid, Faradiba Abdul; Tokuda, Harukuni; Takeuchi, Misa; Suzuki, Nobutaka; Ichiishi, Eiichiro; Fujie, Tetsuo; Goto, Masuo; Sasaki, Yohei; Nakagawa-Goto, Kyoko

    2017-02-01

    A new chromone, 2-(2-hydroxy-2-phenylethyl)chromone (1), was isolated together with ten known phenylethyl chromones from MeOH extracts of agarwood (Aquilaria filaria). The selected compounds were evaluated in an antiproliferative assay against five human tumor cell lines, including a multidrug-resistant cell line. They were also tested for antitumor promoting activity, as mediated by 12-O-tetradecanoylphorbol-13-acetate-induced activation of the Epstein-Barr virus early antigen in Raji cells. Among all compounds, 4',7-dimethyoxy-6-hydroxychromone (2) displayed broad spectrum antiproliferative activity against all tumor cell lines tested with IC50 values of 25-38 µM, while 8 was selectively inhibitory against multidrug-resistant cells. All tested compounds suppressed tumor promotion at noncytotoxic concentrations. 4',6-Dihydroxyphenylethylchromone (7) exhibited the most potent effect with an IC50 value of 319 mol ratio relative to 12-O-tetradecanoylphorbol-13-acetate. This study is the first to report the antitumor promoting activity of 2-(2-phenylethyl)chromone derivatives, as well as the selective antiproliferative activity of 8 against a multidrug-resistant tumor cell line.

  1. Antitumor Activity of 3-Indolylmethanamines 31B and PS121912

    PubMed Central

    Guthrie, Margaret L; Sidhu, Preetpal S.; Hill, Emily K.; Horan, Timothy C.; Nandhikonda, Premchendar; Teske, Kelly A.; Yuan, Nina Y.; Sidorko, Marina; Kodali, Revathi; Cook, James M.; Han, Lanlan; Silvaggi, Nicholas R.; Bikle, Daniel D.; Moore, Richard G.; Singh, Rakesh K.; Arnold, Leggy A.

    2015-01-01

    Aim To investigate the in vivo effects of 3-indolylmethanamines 31B and PS121912 in treating ovarian cancer and leukemia, respectively. Materials and Methods Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and western blotting were applied to demonstrate the induction of apoptosis. Xenografted mice were investigated to show the antitumor effects of 3-indolylmethanamines. 13C-Nuclear magnetic resource (NMR) and western blotting were used to demonstrate inhibition of glucose metabolism. Results 31B inhibited ovarian cancer cell proliferation and activated caspase-3, cleaved poly [ADP-ribose] polymerase 1 (PARP-1), and phosphorylated mitogen-activated protein kinases (MAPK), jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38. 31B reduced ovarian cancer xenograft tumor growth and PS121912 inhibited the growth of HL-60 derived xenografts without any sign of toxicity. Compound 31B inhibited de novo glycolysis and lipogenesis mediated by the reduction of fatty acid synthase and lactate dehydrogenase-A expression. Conclusion 3-Indolylmethanamines represent a new class of antitumor agents. We have shown for the first time the in vivo anticancer effects of 3-indolylmethanamines 31B and PS121912. PMID:26504023

  2. Anordrin Eliminates Tamoxifen Side Effects without Changing Its Antitumor Activity

    PubMed Central

    Gu, Wenwen; Xu, Wenping; Sun, Xiaoxi; Zeng, Bubing; Wang, Shuangjie; Dong, Nian; Zhang, Xu; Chen, Chengshui; Yang, Long; Chen, Guowu; Xin, Aijie; Ni, Zhong; Wang, Jian; Yang, Jun

    2017-01-01

    Tamoxifen is administered for estrogen receptor positive (ER+) breast cancers, but it can induce uterine endometrial cancer and non-alcoholic fatty liver disease (NAFLD). Importantly, ten years of tamoxifen treatment has greater protective effect against ER+ breast cancer than five years of such treatment. Tamoxifen was also approved by the FDA as a chemopreventive agent for those deemed at high risk for the development of breast cancer. The side effects are of substantial concern because of these extended methods of tamoxifen administration. In this study, we found that anordrin, marketed as an antifertility medicine in China, inhibited tamoxifen-induced endometrial epithelial cell mitosis and NAFLD in mouse uterus and liver as an anti-estrogenic and estrogenic agent, respectively. Additionally, compared with tamoxifen, anordiol, the active metabolite of anordrin, weakly bound to the ligand binding domain of ER-α. Anordrin did not regulate the classic estrogen nuclear pathway; thus, it did not affect the anti-tumor activity of tamoxifen in nude mice. Taken together, these data suggested that anordrin could eliminate the side effects of tamoxifen without affecting its anti-tumor activity. PMID:28266626

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

    PubMed

    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 effect of seaweeds. II. Fractionation and partial characterization of the polysaccharide with antitumor activity from Sargassum fulvellum.

    PubMed

    Yamamoto, I; Nagumo, T; Fujihara, M; Takahashi, M; Ando, Y

    1977-06-01

    An almost purified antitumor polysaccharide fraction (SFPP) was obtained by fractional precipitation with ethanol from hot-water extract of Sargassum fulvellum. The fraction showed remarkable tumor-inhibiting effect against sarcoma-180 implanted subcutaneously in mice. The results of chemical and physical analyses suggested that the active substance may be either a sulphated peptidoglycuronoglycan or a sulphated glycuronoglycan.

  5. Platinum (II) Compounds With Antitumor Activity Studied by Molecular Mechanics

    PubMed Central

    Georgieva, Ivelina; Nikolov, George St.

    1998-01-01

    A series of Pt(ll) complexes with antitumor properties: [1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]PtL2 (meso-1-PtL2) and [erythro-1-(2,6-dichloro-4-hydroxyphenyl)-2-(2-halo-4-hydroxyphenyl)ethylenediamine]PtL2, [2L=2Cl−,2I−,SO42−; halo = F (erythro-8-PtL2),halo = Cl (erythro-9-PtL2)] has been modelled by molecular mechanics (MM). The MM calculations were carried out for different isomers and ligand conformations meso-δ, meso-λ, d,l-δ, d,I-λ. The compounds with the lowest MM energies have the same geometries as those obtained by X-ray analysis. The calculated MMX energy orders: meso-1-PtL2 < erythro-9-PtL2 < erythro-8-PtL2 for L=I−, Cl− and SO42− are reverse to the known antitumor activity order - the lowest energy complex (the most stable one)is the one with the highest estrogen activity (meso-1-PtL2). The type of the leaving group (L) does not alter the energy order, which is in agreement with the biological experiments that show a slight dependence of the estrogen properties on the leaving group type. PMID:18475828

  6. Platinum (II) Compounds With Antitumor Activity Studied by Molecular Mechanics.

    PubMed

    Trendafilova, N; Georgieva, I; Nikolov, G S

    1998-01-01

    A SERIES OF PT(LL) COMPLEXES WITH ANTITUMOR PROPERTIES: [1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]PtL(2) (meso-1-PtL(2)) and [erythro-1-(2,6-dichloro-4-hydroxyphenyl)-2-(2-halo-4-hydroxyphenyl)ethylenediamine]PtL(2), [2L=2Cl-,2I-,SO(4) (2)-; halo = F (erythro-8-PtL(2)),halo = Cl (erythro-9-PtL(2))] has been modelled by molecular mechanics (MM). The MM calculations were carried out for different isomers and ligand conformations meso-delta, meso-lambda, d,l-delta, d,I-lambda. The compounds with the lowest MM energies have the same geometries as those obtained by X-ray analysis. The calculated MMX energy orders: meso-1-PtL(2) < erythro-9-PtL(2) < erythro-8-PtL(2) for L=I-, Cl- and SO(4) (2-) are reverse to the known antitumor activity order - the lowest energy complex (the most stable one)is the one with the highest estrogen activity (meso-1-PtL(2)). The type of the leaving group (L) does not alter the energy order, which is in agreement with the biological experiments that show a slight dependence of the estrogen properties on the leaving group type.

  7. Synthesis and antitumor activity of natural compound aloe emodin derivatives.

    PubMed

    Thimmegowda, Naraganahalli R; Park, Chanmi; Shwetha, Bettaswamigowda; Sakchaisri, Krisada; Liu, Kangdong; Hwang, Joonsung; Lee, Sangku; Jeong, Sook J; Soung, Nak K; Jang, Jae H; Ryoo, In-Ja; Ahn, Jong S; Erikson, Raymond L; Kim, Bo Y

    2015-05-01

    In this study, we have synthesized novel water soluble derivatives of natural compound aloe emodin 4(a-j) by coupling with various amino acid esters and substituted aromatic amines, in an attempt to improve the anticancer activity and to explore the structure-activity relationships. The structures of the compounds were determined by (1) H NMR and mass spectroscopy. Cell growth inhibition assays revealed that the aloe emodin derivatives 4d, 4f, and 4i effectively decreased the growth of HepG2 (human liver cancer cells) and NCI-H460 (human lung cancer cells) and some of the derivatives exhibited comparable antitumor activity against HeLa (Human epithelial carcinoma cells) and PC3 (prostate cancer cells) cell lines compared to that of the parent aloe emodin at low micromolar concentrations.

  8. Antitumoral activity of allicin in murine lymphoma L5178Y.

    PubMed

    Padilla-Camberos, Eduardo; Zaitseva, Galina; Padilla, Claudia; Puebla, Ana Maria

    2010-01-01

    Epidemiological studies link increased garlic (Allium sativum) consumption with a reduced incidence of cancer in various human populations. Experimental carcinogenesis studies in animal models and in cell culture systems indicate that several allium-derived compounds exhibit inhibitory effects and that the underlying mechanisms may involve apoptosis. To provide a better understanding of the effects of allium derivatives regarding prevention of cancer, we examined antitumoral activity of allicin, a major component of garlic, in L5178Y lymphoma bearing mice. For in vitro studies, we utilized cell proliferation and apoptosis in the same tumor cell line. We found that allicin inhibited the growth of tumor cells at doses two fold superior to that in normal splenocytes. Allicin also induced apoptosis, and this was associated with an increase in caspase3 activity.

  9. Toward the definition of immunosuppressive regimens with antitumor activity.

    PubMed

    Casadio, F; Croci, S; D'Errico Grigioni, A; Corti, B; Grigioni, W F; Landuzzi, L; Lollini, P-L

    2005-06-01

    Immunosuppressive therapies associated with organ transplantation produce an increased risk of cancer development. Malignancies are increased in transplant recipients because of the impaired immune system. Moreover, experimental data point to a tumor-promoting activity of various immunosuppressive agents. In this study, we compared the effects of 4 immunosuppressive agents with different mechanisms of action (cyclosporine, rapamycin, mycophenolic acid, and leflunomide) on the in vitro growth of various tumor cell lines and umbilical vein endothelial cells. To varying degrees rapamycin (10 ng/mL), mycophenolic acid (300 nmol/L), and leflunomide (30 micromol/L) highly inhibited the growth of human rhabdomyosarcoma, hepatocellular carcinoma, colorectal carcinoma, and endothelial cells. In contrast, cyclosporine (100 ng/mL) did not affect their growth. Our data suggest that regimens containing rapamycin, mycophenolic acid, or leflunomide, which have both immunosuppressive and antitumor activities, should be preferred in transplant recipients to minimize the risk of tumors.

  10. Antitumor Activity of Peptide Amphiphile Nanofiber-Encapsulated Camptothecin

    SciTech Connect

    Soukasene, Stephen; Toft, Daniel J.; Moyer, Tyson J.; Lu, Hsuming; Lee, Hyung-Kun; Standley, Stephany M.; Cryns, Vincent L.; Stupp, Samuel I.

    2012-04-02

    Self-assembling peptide amphiphile (PA) nanofibers were used to encapsulate camptothecin (CPT), a naturally occurring hydrophobic chemotherapy agent, using a solvent evaporation technique. Encapsulation by PA nanofibers was found to improve the aqueous solubility of the CPT molecule by more than 50-fold. PAs self-assembled into nanofibers in the presence of CPT as demonstrated by transmission electron microscopy. Small-angle X-ray scattering results suggest a slight increase in diameter of the nanofiber to accommodate the hydrophobic cargo. In vitro studies using human breast cancer cells show an enhancement in antitumor activity of the CPT when encapsulated by the PA nanofibers. In addition, using a mouse orthotopic model of human breast cancer, treatment with PA nanofiber-encapsulated CPT inhibited tumor growth. These results highlight the potential of this model PA system to be adapted for delivery of hydrophobic therapies to treat a variety of diseases including cancer.

  11. Antitumor Activity of Ionic Liquids Based on Ampicillin.

    PubMed

    Ferraz, Ricardo; Costa-Rodrigues, João; Fernandes, Maria H; Santos, Miguel M; Marrucho, Isabel M; Rebelo, Luís Paulo N; Prudêncio, Cristina; Noronha, João Paulo; Petrovski, Željko; Branco, Luís C

    2015-09-01

    Significant antiproliferative effects against various tumor cell lines were observed with novel ampicillin salts as ionic liquids. The combination of anionic ampicillin with appropriate ammonium, imidazolium, phosphonium, and pyridinium cations yielded active pharmaceutical ingredient ionic liquids (API-ILs) that show potent antiproliferative activities against five different human cancer cell lines: T47D (breast), PC3 (prostate), HepG2 (liver), MG63 (osteosarcoma), and RKO (colon). Some API-ILs showed IC50 values between 5 and 42 nM, activities that stand in dramatic contrast to the negligible cytotoxic activity level shown by the ampicillin sodium salt. Moreover, very low cytotoxicity against two primary cell lines-skin (SF) and gingival fibroblasts (GF)-indicates that the majority of these API-ILs are nontoxic to normal human cell lines. The most promising combination of antitumor activity and low toxicity toward healthy cells was observed for the 1-hydroxyethyl-3-methylimidazolium-ampicillin pair ([C2 OHMIM][Amp]), making this the most suitable lead API-IL for future studies.

  12. Design, synthesis and in vitro and in vivo antitumor activities of novel bivalent β-carbolines.

    PubMed

    Shi, Buxi; Cao, Rihui; Fan, Wenxi; Guo, Liang; Ma, Qin; Chen, Xuemei; Zhang, Guoxian; Qiu, Liqin; Song, Huacan

    2013-02-01

    A series of bivalent β-carbolines with a spacer of three to ten methylene units between the indole nitrogen was synthesized and evaluated as antitumor agents. The results demonstrated that compounds 18c, 21b, 25a and 31b exhibited strong cytotoxic activities with IC(50) value of lower than 20 μM against four tumor cell lines. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, compounds 18b, 21b, 26a and 31b exhibited potent antitumor activities with tumor inhibition rate of over 40% in animal models. Preliminary structure-activity relationships analysis indicated that (1) the spacer length affected antitumor potencies, and four to six methylene units were more favorable; (2) the introduction of appropriate substituent into position-1 of β-carboline facilitated antitumor potencies.

  13. Antitumor activity of an anti-CD98 antibody.

    PubMed

    Hayes, Gregory M; Chinn, Lawrence; Cantor, Joseph M; Cairns, Belinda; Levashova, Zoia; Tran, Hoang; Velilla, Timothy; Duey, Dana; Lippincott, John; Zachwieja, Joseph; Ginsberg, Mark H; H van der Horst, Edward

    2015-08-01

    CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors.

  14. Antitumor activity and structure-activity relationship of diterpenoids with a dehydroabietyl skeleton.

    PubMed

    Rao, Xiaoping; Huang, Xiuzhi; He, Ling; Song, Jie; Song, Zhanqian; Shang, Shibin

    2012-12-01

    A series of novel diterpenoids including imines, amides and ureas with a dehydroabietyl skeleton were screened to hepatocellular carcinoma (SMMC-7721), lung cancer (A-549), glioma (C-6) and breast carcinoma (MCF-7) tumor cells by MTT method. Their antitumor activity and structure activity relationship were analyzed. Several of the title compounds such as I-2, I-10, I-6 and I-5, possess noticeable antitumor activity against SMMC-7721, A-549, C-6 and MCF-7 tumor cells, with lowest IC(50) values of 6.65, 0.75, 0.81 and 10.65μM, respectively. Based on the structure-activity relationship investigation, the three kinds of diterpenoids with a dehydroabietyl skeleton show high activity to SMMC-7721 cells. Imines derivatives exhibit broad spectrum and highly efficient activities to the selected four kinds of tumor cells.

  15. In vitro and in vivo antitumor activity of oridonin nanosuspension.

    PubMed

    Lou, Haiyan; Zhang, Xiumei; Gao, Lei; Feng, Feifei; Wang, Juying; Wei, Xinbing; Yu, Zongqin; Zhang, Dianrui; Zhang, Qiang

    2009-09-08

    The aim of the present study was to evaluate the antitumor activity of an oridonin (ORI) nanosuspension relative to ORI solution both in vitro and in vivo. ORI nanosuspension with a particle size of 897.2+/-14.2 nm was prepared by the high pressure homogenization method (HPH). MTT assay showed that ORI nanosuspension could significantly enhance the in vitro cytotoxicity against K562 cells compared to the ORI solution, the IC(50) value at 36 h was reduced from 12.85 micromol/L for ORI solution to 8.11 micromol/L for ORI nanosuspension. Flow cytometric analysis demonstrated that the ORI nanosuspension also induced a higher apoptotic rate in K562 cells compared to ORI solution. In vivo studies in a mouse model of sarcoma-180 solid tumors demonstrated significantly greater inhibition of tumor growth following treatment with ORI nanosuspension than ORI solution at the same dosage. The mice injected with ORI nanosuspension showed a higher reduction in tumor volume and tumor weight at the dose of 20mg/kg compared to the ORI solution (P<0.01), with the tumor inhibition rate increased from 42.49% for ORI solution to 60.23% for the ORI nanosuspension. Taken together, these results suggest that the delivery of ORI in nanosuspension is a promising approach for the treatment of the tumor.

  16. CpG oligodeoxynucleotides potentiate the antitumor activity of anti-BST2 antibody.

    PubMed

    Hiramatsu, Kosuke; Serada, Satoshi; Kobiyama, Kouji; Nakagawa, Satoshi; Morimoto, Akiko; Matsuzaki, Shinya; Ueda, Yutaka; Fujimoto, Minoru; Yoshino, Kiyoshi; Ishii, Ken J; Enomoto, Takayuki; Kimura, Tadashi; Naka, Tetsuji

    2015-10-01

    Numerous monoclonal antibodies (mAb) targeting tumor antigens have recently been developed. Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) via effector cells such as tumor-infiltrating natural killer (NK) cells and macrophages are often involved in mediating the antitumor activity of mAb. CpG oligodeoxynucleotides (ODN) have a potent antitumor activity and are considered to increase tumor infiltration of NK cells and macrophages. Our group previously reported significant antitumor activity of anti-bone marrow stromal antigen 2 (BST2) mAb against BST2-positive endometrial cancer cells through ADCC. In this study, we evaluated the synergistic antitumor activity of combination therapy with anti-BST-2 mAb and CpG ODN using SCID mice and elucidated the mechanisms underlying this activity. Anti-BST2 mAb and CpG ODN monotherapy had a significant dose-dependent antitumor activity (P = 0.0135 and P = 0.0196, respectively). Combination therapy with anti-BST2 mAb and CpG ODN had a significant antitumor activity in SCID mice (P < 0.01), but not in NOG mice. FACS analysis revealed significantly increased numbers of NK cells and macrophages in tumors treated with a combination of anti-BST2 mAb and CpG ODN and with CpG ODN alone in SCID mice (P < 0.05 and P < 0.01, respectively). These results suggested that the combination therapy with anti-BST2 mAb and CpG ODN has a significant antitumor activity and induces tumor infiltration of NK cells and macrophages. Combination therapy with CpG ODN and anti-BST2 mAb or other antitumor mAb depending on ADCC may represent a new treatment option for cancer.

  17. A review about the development of fucoidan in antitumor activity: Progress and challenges.

    PubMed

    Wu, Lei; Sun, Jing; Su, Xitong; Yu, Qiuli; Yu, Qiuyang; Zhang, Peng

    2016-12-10

    Fucoidan is composed of l-fucose, sulfate groups and one or more small proportions of d-xylose, d-mannose, d-galactose, l-rhamnose, arabinose, glucose, d-glucuronic acid and acetyl groups in different kinds of brown seaweeds. Many reports have demonstrated that fucoidan has antitumor activities on various cancers. However, until now, few reviews have discussed the antitumor activity of fucoidan and few reports have summarized detailed molecular mechanisms of its actions and antitumor challenges of fucoidan specially. In this review, the antitumor signaling pathway mechanisms related to fucoidan are elucidated as much detail as possible. Besides, the factors affecting the anticancer effects of fucoidan, the structural characteristics of fucoidan with anticancer activities and the challenges for the further development of fucoidan are also summarized and evaluated. The existing similar and different conclusions are summarized in an attempt to provide guidelines to help further research, and finally contribute to go into market as chemotherapeumtics.

  18. RIG-I activation induces the release of extracellular vesicles with antitumor activity

    PubMed Central

    Daßler-Plenker, Juliane; Reiners, Katrin S.; van den Boorn, Jasper G.; Hansen, Hinrich P.; Putschli, Bastian; Barnert, Sabine; Schuberth-Wagner, Christine; Schubert, Rolf; Tüting, Thomas; Hallek, Michael; Schlee, Martin; Hartmann, Gunther; Pogge von Strandmann, Elke; Coch, Christoph

    2016-01-01

    ABSTRACT Activation of the innate immune receptor retinoic acid-inducible gene I (RIG-I) by its specific ligand 5′-triphosphate-RNA (3pRNA) triggers antitumor immunity predominantly via NK cell activation and direct apoptosis induction in tumor cells. However, how NK cells are mobilized to attack the tumor cells remains elusive. Here, we show that RIG-I activation induced the secretion of extracellular vesicles (EVs) from melanoma cells, which by themselves revealed antitumor activity in vitro and in vivo. RIG-I-induced EVs from melanoma cells exhibited an increased expression of the NKp30-ligand (BAG6, BAT3) on their surface triggering NK cell-mediated lysis of melanoma cells via activation of the cytotoxicity NK cell-receptor NKp30. Moreover, systemic administration of RIG-I-induced melanoma-EVs showed a potent antitumor activity in a melanoma mouse model in vivo. In conclusion, our data establish a new RIG-I-dependent pathway leading to NK cell-mediated tumor cell killing. PMID:27853642

  19. Pharmacokinetic evaluation and antitumor activity of 2-methoxyestradiol nanosuspension.

    PubMed

    Du, Shuzhang; Zhu, Ling; Du, Bin; Shi, Xiufang; Zhang, Zhenzhong; Wang, Shuyu; Zhang, Chaofeng

    2012-04-01

    The aim of the present study was to evaluate the pharmacokinetic and antitumor activity of 2-methoxyestradiol (2-ME) nanosuspension relative to 2-ME solution both in vitro and in vivo. The pharmacokinetics of 2-ME administered either as a nanosuspension or as a solution were compared after I.V. administration to rats. In plasma, 2-ME nanosuspension exhibited a significantly (p < 0.01) reduced C(max) (1022.8 ± 467.4 ng/mL versus 2559.2 ± 775.8 ng/mL) and AUC(0-240min) (41566.8 ± 965.5 ng/mL min versus 79557.7 ± 256.2 ng/mL min), and a significantly (p < 0.01) greater volume of distribution (3.18-fold), clearance (1.85-fold), and elimination half-life (156.6 ± 33.5 min versus 70.0 ± 22.6 min) compared to the 2-ME solution. Methyl tetrazolium (MTT) assay showed that nanosuspension could significantly enhance the cytotoxicity of 2-ME on EC9706 cells in vitro. After 72 h exposure, the IC(50) value of 2-ME nanosuspension was much lower than that of 2-ME solution (1.81 ± 0.15 μmol/L versus 4.14 ± 0.30 μmol/L). Studies on BALB/c mice with EC9706 solid tumors demonstrated significantly greater inhibition of tumor growth following treatment with 2-ME nanosuspension than 2-ME solution at the same dosage. These results suggest that the delivery of 2-ME nanosuspension is a promising approach for the treatment of tumors.

  20. Antitumor activity of tumor necrosis factor-alpha conjugated with polyvinylpyrrolidone on solid tumors in mice.

    PubMed

    Kamada, H; Tsutsumi, Y; Yamamoto, Y; Kihira, T; Kaneda, Y; Mu, Y; Kodaira, H; Tsunoda, S I; Nakagawa, S; Mayumi, T

    2000-11-15

    We attempted the development of a novel polymer conjugation to further improve the therapeutic potency of antitumor cytokines compared with PEGylation for clinical application. Compared with native tumor necrosis factor (TNF)-alpha in vitro, specific bioactivities of polyvinyl-pyrrolidone (PVP)-modified TNF-alphas (PVP-TNF-alphas) were decreased by increasing the degree of PVP attachment. PVP-TNF-alpha fraction 3, Mr 101,000, had the most effective antitumor activity of the various PVP-TNF-alphas in vivo. PVP-TNF-alpha fraction 3 had >200-fold higher antitumor effect than native TNF-alpha, and the antitumor activity of PVP-TNF-alpha fraction 3 was >2-fold higher than that of MPEG-TNF-alpha (Mr 108,000), which had the highest antitumor activity among the polyethylene glycol (PEG)-conjugated TNF-alphas. Additionally, a high dose of native TNF-alpha induced toxic side effects such as body weight reduction, piloerection. and tissue inflammation, whereas no side effects were observed after i.v. administration of PVP-TNF-alpha fraction 3. The plasma half-life of PVP-TNF-alpha fraction 3 (360 min) was about 80- and 3-fold longer than those of native TNF-alpha (4.6 mm) and MPEG-TNF-alpha (122 min), respectively. The mechanism of increased antitumor effect in vivo caused the prolongation of plasma half-life and increase in stability. These results suggested that PVP is a useful polymeric modifier for bioconjugation of TNF-alpha to increase its antitumor potency, and multifunctionally bioconjugated TNF-alpha may be a potentiated antitumor agent for clinical use.

  1. Synthesis, in vitro and in vivo antitumor activity of pyrazole-fused 23-hydroxybetulinic acid derivatives.

    PubMed

    Zhang, Hengyuan; Zhu, Peiqing; Liu, Jie; Lin, Yan; Yao, Hequan; Jiang, Jieyun; Ye, Wencai; Wu, Xiaoming; Xu, Jinyi

    2015-02-01

    A collection of pyrazole-fused 23-hydroxybetulinic acid derivatives were designed, synthesized and evaluated for their antitumor activity. Most of the newly synthesized compounds exhibited significant antiproliferative activity. Especially compound 15e displayed the most potent activity with the IC50 values of 5.58 and 6.13μM against B16 and SF763 cancer cell lines, respectively. Furthermore, the significant in vivo antitumor activity of 15e was validated in H22 liver cancer and B16 melanoma xenograft mouse models. The structure-activity relationships of these 23-hydroxybetulinic acid derivatives were also discussed based on the present investigation.

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

    PubMed

    Wang, Xiaomei; Zhang, Zhongshan

    2014-08-01

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

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

    PubMed Central

    Masuda, Yuki; Nakayama, Yoshiaki; Tanaka, Akihiro; Naito, Kenta; Konishi, Morichika

    2017-01-01

    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. PMID:28278221

  4. Antitumor effect of sonodynamically activated pyrrolidine tris-acid fullerene

    NASA Astrophysics Data System (ADS)

    Iwase, Yumiko; Nishi, Koji; Fujimori, Junya; Fukai, Toshio; Yumita, Nagahiko; Ikeda, Toshihiko; Chen, Fu-shin; Momose, Yasunori; Umemura, Shin-ichiro

    2016-07-01

    In this study, the sonodynamically induced antitumor effect of pyrrolidine tris-acid fullerene (PTF) was investigated. Sonodynamically induced antitumor effects of PTF by focused ultrasound were investigated using isolated sarcoma-180 cells and mice bearing ectopically-implanted colon 26 carcinoma. Cell damage induced by ultrasonic exposure was enhanced by 5-fold in the presence of 80 µM PTF. The combined treatment of ultrasound and PTF suppressed the growth of the implanted colon 26 carcinoma. Ultrasonically induced 2,2,6,6-tetramethyl-4-piperidone-1-oxyl (4oxoTEMPO) production in the presence and absence of PTF was assessed, and it was shown that 80 µM PTF enhanced 4oxoTEMPO production as measured by ESR spectroscopy. Histidine, a reactive oxygen scavenger, significantly reduced cell damage and 4oxoTEMPO generation caused by ultrasonic exposure in the presence of PTF. These results suggest that singlet oxygen is likely to be involved in the ultrasonically induced cell damage enhanced by PTF.

  5. Assessment of antitumor activity for tumor xenograft studies using exponential growth models.

    PubMed

    Wu, Jianrong

    2011-05-01

    In preclinical tumor xenograft experiments, the antitumor activity of the tested agents is often assessed by endpoints such as tumor doubling time, tumor growth delay (TGD), and log10 cell kill (LCK). In tumor xenograft literature, the values of these endpoints are presented without any statistical inference, which ignores the noise in the experimental data. However, using exponential growth models, these endpoints can be quantified by their growth curve parameters, thus allowing parametric inference, such as an interval estimate, to be used to assess the antitumor activity of the treatment.

  6. Identification of the anti-tumor activity and mechanisms of nuciferine through a network pharmacology approach

    PubMed Central

    Qi, Quan; Li, Rui; Li, Hui-ying; Cao, Yu-bing; Bai, Ming; Fan, Xiao-jing; Wang, Shu-yan; Zhang, Bo; Li, Shao

    2016-01-01

    Aim: Nuciferine is an aporphine alkaloid extracted from lotus leaves, which is a raw material in Chinese medicinal herb for weight loss. In this study we used a network pharmacology approach to identify the anti-tumor activity of nuciferine and the underlying mechanisms. Methods: The pharmacological activities and mechanisms of nuciferine were identified through target profile prediction, clustering analysis and functional enrichment analysis using our traditional Chinese medicine (TCM) network pharmacology platform. The anti-tumor activity of nuciferine was validated by in vitro and in vivo experiments. The anti-tumor mechanisms of nuciferine were predicted through network target analysis and verified by in vitro experiments. Results: The nuciferine target profile was enriched with signaling pathways and biological functions, including “regulation of lipase activity”, “response to nicotine” and “regulation of cell proliferation”. Target profile clustering results suggested that nuciferine to exert anti-tumor effect. In experimental validation, nuciferine (0.8 mg/mL) markedly inhibited the viability of human neuroblastoma SY5Y cells and mouse colorectal cancer CT26 cells in vitro, and nuciferine (0.05 mg/mL) significantly suppressed the invasion of 6 cancer cell lines in vitro. Intraperitoneal injection of nuciferine (9.5 mg/mL, ip, 3 times a week for 3 weeks) significantly decreased the weight of SY5Y and CT26 tumor xenografts in nude mice. Network target analysis and experimental validation in SY5Y and CT26 cells showed that the anti-tumor effect of nuciferine was mediated through inhibiting the PI3K-AKT signaling pathway and IL-1 levels in SY5Y and CT26 cells. Conclusion: By using a TCM network pharmacology method, nuciferine is identified as an anti-tumor agent against human neuroblastoma and mouse colorectal cancer in vitro and in vivo, through inhibiting the PI3K-AKT signaling pathways and IL-1 levels. PMID:27180984

  7. Intermittent Metronomic Drug Schedule Is Essential for Activating Antitumor Innate Immunity and Tumor Xenograft Regression12

    PubMed Central

    Chen, Chong-Sheng; Doloff, Joshua C; Waxman, David J

    2014-01-01

    Metronomic chemotherapy using cyclophosphamide (CPA) is widely associated with antiangiogenesis; however, recent studies implicate other immune-based mechanisms, including antitumor innate immunity, which can induce major tumor regression in implanted brain tumor models. This study demonstrates the critical importance of drug schedule: CPA induced a potent antitumor innate immune response and tumor regression when administered intermittently on a 6-day repeating metronomic schedule but not with the same total exposure to activated CPA administered on an every 3-day schedule or using a daily oral regimen that serves as the basis for many clinical trials of metronomic chemotherapy. Notably, the more frequent metronomic CPA schedules abrogated the antitumor innate immune and therapeutic responses. Further, the innate immune response and antitumor activity both displayed an unusually steep dose-response curve and were not accompanied by antiangiogenesis. The strong recruitment of innate immune cells by the 6-day repeating CPA schedule was not sustained, and tumor regression was abolished, by a moderate (25%) reduction in CPA dose. Moreover, an ∼20% increase in CPA dose eliminated the partial tumor regression and weak innate immune cell recruitment seen in a subset of the every 6-day treated tumors. Thus, metronomic drug treatment must be at a sufficiently high dose but also sufficiently well spaced in time to induce strong sustained antitumor immune cell recruitment. Many current clinical metronomic chemotherapeutic protocols employ oral daily low-dose schedules that do not meet these requirements, suggesting that they may benefit from optimization designed to maximize antitumor immune responses. PMID:24563621

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

    PubMed Central

    Nosaki, Kaname; Hamada, Katsuyuki; Takashima, Yuto; Sagara, Miyako; Matsumura, Yumiko; Miyamoto, Shohei; Hijikata, Yasuki; Okazaki, Toshihiko; Nakanishi, Yoichi; Tani, Kenzaburo

    2016-01-01

    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. PMID:27847861

  9. Characterization and in vitro antitumor activity of polysaccharides from the mycelium of Sarcodon aspratus.

    PubMed

    Chen, Yan; Hu, Meili; Wang, Cui; Yang, Yuling; Chen, Jianhua; Ding, Jingna; Guo, Wenqiang

    2013-01-01

    Polysaccharides extracted from mushrooms have shown a variety of medical activities, such as antitumor, immunostimulatory and hypoglycemic activity. In this study, characteristics and the antitumor activities of Sarcodon aspratus polysaccharides were investigated for the possibility of application of S. aspratus in health care and medicine. Two polysaccharide fractions (PSAN and PSAA) were extracted and isolated from the mycelium of S. aspratus. The average molecular weight of PSAN and PSAA were approximately 5.6×10(4) Da and 3.83×10(5) Da, respectively. PSAN was composed of L-rhamnose, D-xylose and D-mannose, with molar ratios of 1:10:21; PSAA consisted of L-rhamnose, D-xylose, D-mannose, D-glucose and D-galactose, with molar ratios of 1:39:76:10:21. Both PSAN and PSAA presented high antitumor activity against Hela cells in vitro. At a concentration of 400 mg/L and an exposure time of 24h, the inhibition rates for PSAN and PSAA were 65% and 80%, respectively. PSAN and PSAA exhibited significantly lower cytotoxicity against human normal liver cell line L-02 than Hela tumor cells in comparison with 5-Fu. Polysaccharide extracted from an edible mushroom S. aspratus may be a potential candidate for developing a novel low toxicity antitumor agent.

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

    PubMed

    Nosaki, Kaname; Hamada, Katsuyuki; Takashima, Yuto; Sagara, Miyako; Matsumura, Yumiko; Miyamoto, Shohei; Hijikata, Yasuki; Okazaki, Toshihiko; Nakanishi, Yoichi; Tani, Kenzaburo

    2016-01-01

    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.

  11. The introduction of antibacterial drug pipemidic acid into the POM field: Syntheses, characterization and antitumor activity

    NASA Astrophysics Data System (ADS)

    Sha, Jing-Quan; Li, Xin; Zhou, Ying-Hua; Yan, Peng-Fei; Li, Guang-Ming; Wang, Cheng

    2011-11-01

    Two new compounds based on polyoxometalates (POMs) and the quinolone antibacterial drug pipemidic acid (HPPA), {[Ni(PPA) 2]H 4[SiW 12O 40]}·HPPA·3H 2O ( 1), and {[Zn(PPA) 2] 2H 4[SiW 12O 40]}·3H 2O ( 2), have been synthesized under hydrothermal conditions and structurally characterized by routine technique. Single-crystal X-Ray diffraction analysis shows that compound 1 is constructed by Keggin clusters grafted by binuclear nickel clusters, isolated HPPA and water molecules, while compound 2 consists of Keggin clusters grafted by binuclear zinc clusters and water molecules. Due to the selection of different transition metal (TM) ions, compounds 1 and 2 exhibit different structures and antitumor activities. Compound 1 possesses 0D structure and shows no antitumor activities. However, compound 2 possesses 1D structure and exhibits higher antitumor activities than its parent compound. The results show that introduction of different TM-PPA moieties onto the polyoxoanion surface can affect not only the final structures but also their antitumor activities.

  12. Bioactive Components of Chinese Propolis Water Extract on Antitumor Activity and Quality Control

    PubMed Central

    Xuan, Hongzhuan; Wang, Yuehua; Li, Aifeng; Fu, Chongluo; Wang, Yuanjun; Peng, Wenjun

    2016-01-01

    To understand the material basis of antitumor activity of Chinese propolis water extract (CPWE), we developed a simple and efficient method using macroporous absorptive resin coupled with preparative high performance liquid chromatography and separated and purified eleven chemical components (caffeic acid, ferulic acid, isoferulic acid, 3,4-dimethoxycinnamic acid, pinobanksin, caffeic acid benzyl ester, caffeic acid phenethyl ester, apigenin, pinocembrin, chrysin, and galangin) from CPWE; then we tested the antitumor activities of these eleven components using different human tumor cell lines (MCF-7, MDA-MB-231, HeLa, and A549). Furthermore, cell migration, procaspase 3 level, and reactive oxygen species (ROS) of effective components from CPWE were investigated. Our data showed that antitumor activities of the eleven components from CPWE were different from each other. CPWE and its effective components induced apoptosis by inhibiting tumor cell migration, activating caspase 3, and promoting ROS production. It can be deduced that the antitumor effects of propolis did not depend on a single component, and there must exist “bioactive components,” which also provides a new idea for Chinese propolis quality control. PMID:27123037

  13. [Antitumor components screening of Stellera chamaejasme L. under the case of discrete distribution of active data].

    PubMed

    Yang, Qian-Xu; Cheng, Meng-Chun; Wang, Li; Kan, Xiao-Xi; Zhu, Xiao-Xin; Xiao, Hong-Bin

    2014-06-01

    This is to report the screening, extracting and validating antitumor components and compounds from Stellera chamaejasme L. under the case of discrete distribution of active data. In this work, different components from Stellera chamaejasme L. were collected by HPD macroporous resin and polyamide resin column, and their antitumor activity on A549 were tested by MTT assay. Activity results indicate that activity of components at 30-39 min is more potent than that of Stellera chamaejasme L. extract, and the activity of components at 33.97 min is equivalent to positive drug, cis-platinum at 100 microg x mL(-1), but with totally different mode of action. Under the case of discrete activity, the weight analysis is capable of screening active components and compounds from natural products.

  14. Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles

    PubMed Central

    Cabeza, Laura; Ortiz, Raúl; Arias, José L; Prados, Jose; Ruiz Martínez, Maria Adolfina; Entrena, José M; Luque, Raquel; Melguizo, Consolación

    2015-01-01

    The use of doxorubicin (DOX), one of the most effective antitumor molecules in the treatment of metastatic breast cancer, is limited by its low tumor selectivity and its severe side effects. Colloidal carriers based on biodegradable poly(butylcyanoacrylate) nanoparticles (PBCA NPs) may enhance DOX antitumor activity against breast cancer cells, thus allowing a reduction of the effective dose required for antitumor activity and consequently the level of associated toxicity. DOX loading onto PBCA NPs was investigated in this work via both drug entrapment and surface adsorption. Cytotoxicity assays with DOX-loaded NPs were performed in vitro using breast tumor cell lines (MCF-7 human and E0771 mouse cancer cells), and in vivo evaluating antitumor activity in immunocompetent C57BL/6 mice. The entrapment method yielded greater drug loading values and a controlled drug release profile. Neither in vitro nor in vivo cytotoxicity was observed for blank NPs. The 50% inhibitory concentration (IC50) of DOX-loaded PBCA NPs was significantly lower for MCF-7 and E0771 cancer cells (4 and 15 times, respectively) compared with free DOX. Furthermore, DOX-loaded PBCA NPs produced a tumor growth inhibition that was 40% greater than that observed with free DOX, thus reducing DOX toxicity during treatment. These results suggest that DOX-loaded PBCA NPs have great potential for improving the efficacy of DOX therapy against advanced breast cancers. PMID:25709449

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

    PubMed Central

    Melguizo, Consolación; Cabeza, Laura; Prados, Jose; Ortiz, Raúl; Caba, Octavio; Rama, Ana R; Delgado, Ángel V; Arias, José L

    2015-01-01

    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. PMID:26715840

  16. Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles.

    PubMed

    Cabeza, Laura; Ortiz, Raúl; Arias, José L; Prados, Jose; Ruiz Martínez, Maria Adolfina; Entrena, José M; Luque, Raquel; Melguizo, Consolación

    2015-01-01

    The use of doxorubicin (DOX), one of the most effective antitumor molecules in the treatment of metastatic breast cancer, is limited by its low tumor selectivity and its severe side effects. Colloidal carriers based on biodegradable poly(butylcyanoacrylate) nanoparticles (PBCA NPs) may enhance DOX antitumor activity against breast cancer cells, thus allowing a reduction of the effective dose required for antitumor activity and consequently the level of associated toxicity. DOX loading onto PBCA NPs was investigated in this work via both drug entrapment and surface adsorption. Cytotoxicity assays with DOX-loaded NPs were performed in vitro using breast tumor cell lines (MCF-7 human and E0771 mouse cancer cells), and in vivo evaluating antitumor activity in immunocompetent C57BL/6 mice. The entrapment method yielded greater drug loading values and a controlled drug release profile. Neither in vitro nor in vivo cytotoxicity was observed for blank NPs. The 50% inhibitory concentration (IC50) of DOX-loaded PBCA NPs was significantly lower for MCF-7 and E0771 cancer cells (4 and 15 times, respectively) compared with free DOX. Furthermore, DOX-loaded PBCA NPs produced a tumor growth inhibition that was 40% greater than that observed with free DOX, thus reducing DOX toxicity during treatment. These results suggest that DOX-loaded PBCA NPs have great potential for improving the efficacy of DOX therapy against advanced breast cancers.

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

    PubMed

    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.

  18. [Synthesis of 1-furfuryl-indolin-2-one derivatives and preliminary evaluation of their antitumor activities].

    PubMed

    Dong, Xiao-Chun; Zhou, Fu-Sheng; Zheng, Jian-Bin; Wen, Ren

    2008-01-01

    In order to find new indolin-2-one derivatives as antitumor agents, a series of 3-pyrrole substituted 1-(5-formyl-2-furanylmethyl) indolin-2-one derivatives were designed and synthesized. 5-Formyl-2 ,4-dimethyl-lH-pyrrole-3-carboxylic acid ethyl ester was condensed with 5-substituted indolin-2-one 2a-2d to afford 3-[(pyrrol-2-yl) -methylidenyl] indolin-2-ones 3a-3d. Through N-alkylation, 1-(5-formyl-furfuryl) -indolin-2-one 4a-4d were prepared. Compounds 4a-4d were then condensed with indolin-2-one to afford bis-indolin-2-one derivatives 5a-5d. The structures of the synthesized compounds were determined by 1H NMR, MS and element analysis. Antitumor activities of all the synthesized compounds in vitro were tested. All the 12 synthesized compounds possess antitumor activities against SPC-A1 strain. Especially the compounds 5a-5d possess potent antitumor activities better than sunitinib. Their IC50 are all below 5 micromol x L(-1).

  19. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

    PubMed Central

    Demaria, Olivier; De Gassart, Aude; Coso, Sanja; Gestermann, Nicolas; Di Domizio, Jeremy; Flatz, Lukas; Gaide, Olivier; Michielin, Olivier; Hwu, Patrick; Petrova, Tatiana V.; Martinon, Fabio; Modlin, Robert L.; Speiser, Daniel E.; Gilliet, Michel

    2015-01-01

    Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma. PMID:26607445

  20. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.

    PubMed

    Demaria, Olivier; De Gassart, Aude; Coso, Sanja; Gestermann, Nicolas; Di Domizio, Jeremy; Flatz, Lukas; Gaide, Olivier; Michielin, Olivier; Hwu, Patrick; Petrova, Tatiana V; Martinon, Fabio; Modlin, Robert L; Speiser, Daniel E; Gilliet, Michel

    2015-12-15

    Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.

  1. Study of antitumor activity in breast cell lines using silver nanoparticles produced by yeast

    PubMed Central

    Ortega, Francisco G; Fernández-Baldo, Martín A; Fernández, Jorge G; Serrano, María J; Sanz, María I; Diaz-Mochón, Juan J; Lorente, José A; Raba, Julio

    2015-01-01

    In the present article, we describe a study of antitumor activity in breast cell lines using silver nanoparticles (Ag NPs) synthesized by a microbiological method. These Ag NPs were tested for their antitumor activity against MCF7 and T47D cancer cells and MCF10-A normal breast cell line. We analyzed cell viability, apoptosis induction, and endocytosis activity of those cell lines and we observed that the effects of the biosynthesized Ag NPs were directly related with the endocytosis activity. Moreover, Ag NPs had higher inhibition efficacy in tumor lines than in normal lines of breast cells, which is due to the higher endocytic activity of tumor cells compared to normal cells. In this way, we demonstrate that biosynthesized Ag NPs can be an alternative for the treatment of tumors. PMID:25844035

  2. Study of antitumor activity in breast cell lines using silver nanoparticles produced by yeast.

    PubMed

    Ortega, Francisco G; Fernández-Baldo, Martín A; Fernández, Jorge G; Serrano, María J; Sanz, María I; Diaz-Mochón, Juan J; Lorente, José A; Raba, Julio

    2015-01-01

    In the present article, we describe a study of antitumor activity in breast cell lines using silver nanoparticles (Ag NPs) synthesized by a microbiological method. These Ag NPs were tested for their antitumor activity against MCF7 and T47D cancer cells and MCF10-A normal breast cell line. We analyzed cell viability, apoptosis induction, and endocytosis activity of those cell lines and we observed that the effects of the biosynthesized Ag NPs were directly related with the endocytosis activity. Moreover, Ag NPs had higher inhibition efficacy in tumor lines than in normal lines of breast cells, which is due to the higher endocytic activity of tumor cells compared to normal cells. In this way, we demonstrate that biosynthesized Ag NPs can be an alternative for the treatment of tumors.

  3. Alcohol consumption and antitumor immunity: dynamic changes from activation to accelerated deterioration of the immune system.

    PubMed

    Zhang, Hui; Zhu, Zhaohui; Zhang, Faya; Meadows, Gary G

    2015-01-01

    The molecular mechanisms of how alcohol and its metabolites induce cancer have been studied extensively. However, the mechanisms whereby chronic alcohol consumption affects antitumor immunity and host survival have largely been unexplored. We studied the effects of chronic alcohol consumption on the immune system and antitumor immunity in mice inoculated with B16BL6 melanoma and found that alcohol consumption activates the immune system leading to an increase in the proportion of IFN-γ-producing NK, NKT, and T cells in mice not injected with tumors. One outcome associated with enhanced IFN-γ activation is inhibition of melanoma lung metastasis. However, the anti-metastatic effects do not translate into increased survival of mice bearing subcutaneous tumors. Continued growth of the subcutaneous tumors and alcohol consumption accelerates the deterioration of the immune system, which is reflected in the following: (1) inhibition in the expansion of memory CD8+ T cells, (2) accelerated decay of Th1 cytokine-producing cells, (3) increased myeloid-derived suppressor cells, (4) compromised circulation of B cells and T cells, and (5) increased NKT cells that exhibit an IL-4 dominant cytokine profile, which is inhibitory to antitumor immunity. Taken together, the dynamic effects of alcohol consumption on antitumor immunity are in two opposing phases: the first phase associated with immune stimulation is tumor inhibitory and the second phase resulting from the interaction between the effects of alcohol and the tumor leads to immune inhibition and resultant tumor progression.

  4. A NOVEL MITHRAMYCIN ANALOGUE WITH HIGH ANTITUMOR ACTIVITY AND LESS TOXICITY GENERATED BY COMBINATORIAL BIOSYNTHESIS

    PubMed Central

    Núñez, Luz E.; Nybo, Stephen E.; González-Sabín, Javier; Pérez, María; Menéndez, Nuria; Braña, Alfredo F.; He, Min; Morís, Francisco; Salas, José A.; Rohr, Jürgen; Méndez, Carmen

    2012-01-01

    Mithramycin is an antitumor compound produced by Streptomyces argillaceus that has been used for the treatment of several types of tumors and hypercalcaemia processes. However, its use in humans has been limited because its side effects. Using combinatorial biosynthesis approaches, we have generated seven new mithramycin derivatives, which either differ from the parental compound in the sugar profile or in both the sugar profile and the 3-side chain. From these studies three novel derivatives were identified, demycarosyl-3D-β-d-digitoxosyl-mithramycin SK, demycarosyl-mithramycin SDK and demycarosyl-3D-β-d-digitoxosyl-mithramycin SDK, which show high antitumor activity. The first one, which combines two structural features previously found to improve pharmacological behavior, was generated following two different strategies, and it showed less toxicity than mithramycin. Preliminary in vivo evaluation of its antitumor activity through hollow fiber assays, and in subcutaneous colon and melanoma cancers xenografts models, suggests that demycarosyl-3D-β-d-digitoxosyl-mithramycin SK could be a promising antitumor agent, worthy of further investigation. PMID:22578073

  5. The Key Role of Sulfation and Branching on Fucoidan Antitumor Activity.

    PubMed

    Oliveira, Catarina; Ferreira, Andreia S; Novoa-Carballal, Ramon; Nunes, Cláudia; Pashkuleva, Iva; Neves, Nuno M; Coimbra, Manuel A; Reis, Rui L; Martins, Albino; Silva, Tiago H

    2016-12-20

    There is an urgent need for antitumor bioactive agents with minimal or no side effects over normal adjacent cells. Fucoidan is a marine-origin polymer with known antitumor activity. However, there are still some concerns about its application due to the inconsistent experimental results, specifically its toxicity over normal cells and the mechanism behind its action. Herein, three fucoidan extracts (FEs) have been tested over normal and breast cancer cell lines. From cytotoxicity results, only one of the extracts shows selective antitumor behavior (at 0.2 mg mL(-1) ), despite similarities in sulfation degree and carbohydrates composition. Although the three FEs present different molecular weights, depolymerization of selected samples discarded Mw as the key factor in the antitumor activity. Significant differences in sulfates position and branching are observed, presenting FE 2 the higher branching degree. Based on all these experimental data, it is believed that these last two properties are the ones that influence the cytotoxic effects of fucoidan extracts.

  6. Predicting Antitumor Activity of Peptides by Consensus of Regression Models Trained on a Small Data Sample

    PubMed Central

    Radman, Andreja; Gredičak, Matija; Kopriva, Ivica; Jerić, Ivanka

    2011-01-01

    Predicting antitumor activity of compounds using regression models trained on a small number of compounds with measured biological activity is an ill-posed inverse problem. Yet, it occurs very often within the academic community. To counteract, up to some extent, overfitting problems caused by a small training data, we propose to use consensus of six regression models for prediction of biological activity of virtual library of compounds. The QSAR descriptors of 22 compounds related to the opioid growth factor (OGF, Tyr-Gly-Gly-Phe-Met) with known antitumor activity were used to train regression models: the feed-forward artificial neural network, the k-nearest neighbor, sparseness constrained linear regression, the linear and nonlinear (with polynomial and Gaussian kernel) support vector machine. Regression models were applied on a virtual library of 429 compounds that resulted in six lists with candidate compounds ranked by predicted antitumor activity. The highly ranked candidate compounds were synthesized, characterized and tested for an antiproliferative activity. Some of prepared peptides showed more pronounced activity compared with the native OGF; however, they were less active than highly ranked compounds selected previously by the radial basis function support vector machine (RBF SVM) regression model. The ill-posedness of the related inverse problem causes unstable behavior of trained regression models on test data. These results point to high complexity of prediction based on the regression models trained on a small data sample. PMID:22272081

  7. Cytotoxic and anti-tumor activities of lignans from the seeds of Vietnamese nutmeg Myristica fragrans.

    PubMed

    Thuong, Phuong Thien; Hung, Tran Manh; Khoi, Nguyen Minh; Nhung, Hoang Thi My; Chinh, Nguyen Thi; Quy, Nguyen Thi; Jang, Tae Su; Na, Minkyun

    2014-03-01

    Four lignans, meso-dihydroguaiaretic acid (DHGA), macelignan, fragransin A2 and nectandrin B, were isolated from the seeds of Myristica fragrans (Vietnamese nutmeg) and investigated for their cytotoxic activity against eight cancer cell lines. Of these, DHGA exhibited potent cytotoxicity against H358 with IC50 value of 10.1 μM. In addition, DHGA showed antitumor activity in allogeneic tumor-bearing mice model.

  8. Synthesis and antitumor activity of new alkylphospholipids containing modifications of the phosphocholine moiety.

    PubMed

    Ukawa, K; Imamiya, E; Yamamoto, H; Mizuno, K; Tasaka, A; Terashita, Z; Okutani, T; Nomura, H; Kasukabe, T; Hozumi, M

    1989-05-01

    New antitumor alkylglycerophospholipids, in which primarily the phosphocholine moiety of the platelet activating factor (PAF) molecule was modified, were synthesized from 1-alkyl-2-substituted glycerols by introducing polar head phosphoryl groups having methylene bridges of various lengths (from 2 to 14 carbons). They were tested for PAF agonistic activity and antitumor properties. In a series of 1-octadecyl-2-acetoacetylglycerophospholipids (1a-f), an increase in the length of the methylene bridge separating the phosphate and trimethylammonio group in the polar head side chain at position 3 of the glycerol backbone resulted in a progressive decrease in PAF agonistic activity and a characteristic change in antitumor activity against human promyelocytic leukemia cells (HL-60). Maximal potency was obtained with the compound having a decamethylene bridge (1e, IC50 value = 1.5 microgram/ml). Thus, alkylphospholipids possessing a decamethylene bridge and a variety of substituents at position 2 (1g-n) were synthesized. They showed potent inhibitory activity with IC50 values ranging from 0.4 to 1.9 micrograms/ml, depending on the nature of the 2-substituent in the phospholipid molecule. In in vivo tests of the present series of alkylglycerophospholipids (1a--n), using mice bearing sarcoma 180 and mice with mammary carcinoma MM46 (both cells and compounds were given i.p.), 1-octadecyl-2-acetoacetyl-3-glyceryl omega-trimethylammoniodecyl phosphate (1e) showed the most potent life-prolonging effect. The structure-activity relationships are discussed.

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

    PubMed

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

    2011-08-01

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

  10. Synergistic antitumor activity of regorafenib and lapatinib in preclinical models of human colorectal cancer.

    PubMed

    Zhang, Wen-Ji; Li, Yong; Wei, Meng-Ning; Chen, Yao; Qiu, Jian-Ge; Jiang, Qi-Wei; Yang, Yang; Zheng, Di-Wei; Qin, Wu-Ming; Huang, Jia-Rong; Wang, Kun; Zhang, Wen-Juan; Wang, Yi-Jun; Yang, Dong-Hua; Chen, Zhe-Sheng; Shi, Zhi

    2017-02-01

    Regorafenib significantly prolongs overall survival in patients with metastatic colorectal cancer (mCRC), but the overall clinical efficacy of regorafenib remains quite limited. Combination chemotherapy is a potentially promising approach to enhance anticancer activity, overcome drug resistance, and improve disease-free and overall survival. The current study investigates the antitumor activity of regorafenib in combination with lapatinib in preclinical models of human CRC. Our results show improved antitumor efficacy when regorafenib is combined with lapatinib both in vitro and in vivo. Furthermore, pharmacokinetic analyses revealed that regorafenib and lapatinib do not influence on each plasma concentration. The finding that regorafenib in combination with lapatinib have synergistic activity warrants further clinical investigation of this beneficial combination as a potential treatment strategy for CRC patients.

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

    PubMed Central

    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. PMID:24250382

  12. Size effect of se-enriched green tea particles on in vitro antioxidant and antitumor activities.

    PubMed

    Li, Huajia; Li, Feng; Yang, Fangmei; Fang, Yong; Xin, Zhihong; Zhao, Liyan; Hu, Qiuhui

    2008-06-25

    The antioxidant and antitumor activities (in vitro) of superfine regular and Se-enriched green tea particles with different sizes (3.52 microm and 220 nm) were investigated in this paper. The vitamin C and tea polyphenol contents of green tea in different sizes were significantly different, and amino acid and chlorophyll just changed a little. The antioxidant activity of green tea particles was evaluated by DPPH radical scavenging and linoleic acid peroxidation inhibition methods, and the antitumor activity was evaluated by antiproliferation assay on HepG2, A549, and MGC803 cells. The results indicated that enrichment of selenium endowed green tea with higher antioxidant activity and antitumor activity on HepG2 and A549 cells but not on MGC803 cells. The DPPH radical scavenging rates of regular and Se-enriched green tea of 220 nm (67.87% and 69.49%, respectively) were significantly greater than that of 3.52 microm, but the inhibition of linoleic acid peroxidation for green tea of 220 nm was lower. The inhibitory rates of green tea of 220 nm on HepG2, A549, and MGC803 cells achieved 77.35%, 80.76%, and 87.54% for regular green tea, and 82.51%, 88.09%, and 74.48% for Se-enriched green tea at the dose of 100 microg mL (-1), values that were all significantly higher compared to that of 3.52 microm.

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed

    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.

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

    PubMed Central

    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

  16. Antitumor activities and immunomodulatory of rice bran polysaccharides and its sulfates in vitro.

    PubMed

    Wang, Li; Li, Yulin; Zhu, Lidan; Yin, Ran; Wang, Ren; Luo, Xiaohu; Li, Yongfu; Li, Yanan; Chen, Zhengxing

    2016-07-01

    Polysaccharides purified from rice bran show antitumor activity against tumor cells, yet the mechanism of this action remains poorly understood. To address this issue, our study evaluated the effect of rice bran polysaccharides on mouse melanoma cell line B16, and Raw264.7 macrophages. Rice bran polysaccharides (RBP) failed to inhibit B16 cell growth in vitro. However, Raw264.7 macrophages treated by RBP enhancement of cytotoxic effects. The cytotoxicity was confirmed by the stimulation of nitric oxide (NO) production and tumor necrosis factor-α (TNF-α) secretion on Raw264.7 macrophages in a dose-dependent manner. RBP2, a fraction of RBP, notably enhanced the inhibition of B16 cells and boosted the immunepotentiation effect compared with RBP. To further enhance the inhibition of B16 cell growth, sulfated polysaccharides (SRBP) was derived using the chlorosulfonic acid-pyridine method. SRBP2 was found to suppress B16 cell growth, reduce B16 cell survival and stimulate NO and TNF-α production. However, SRBP2 displayed a cytotoxic effect on Raw264.7 macrophages. These results suggest that the antitumor activity of RBP and RBP2 is mediated mainly through the activation of macrophages. SRBP2 exerts its antitumor activity by inducing apoptosis in tumor cells and the secretion of NO and TNF-α.

  17. Anti-tumor activities of peptides corresponding to conserved complementary determining regions from different immunoglobulins.

    PubMed

    Figueiredo, Carlos R; Matsuo, Alisson L; Massaoka, Mariana H; Polonelli, Luciano; Travassos, Luiz R

    2014-09-01

    Short synthetic peptides corresponding to sequences of complementarity-determining regions (CDRs) from different immunoglobulin families have been shown to induce antimicrobial, antiviral and antitumor activities regardless of the specificity of the original monoclonal antibody (mAb). Presently, we studied the in vitro and in vivo antitumor activity of synthetic peptides derived from conserved CDR sequences of different immunoglobulins against human tumor cell lines and murine B16F10-Nex2 melanoma aiming at the discovery of candidate molecules for cancer therapy. Four light- and heavy-chain CDR peptide sequences from different antibodies (C36-L1, HA9-H2, 1-H2 and Mg16-H2) showed cytotoxic activity against murine melanoma and a panel of human tumor cell lineages in vitro. Importantly, they also exerted anti-metastatic activity using a syngeneic melanoma model in mice. Other peptides (D07-H3, MN20v1, MS2-H3) were also protective against metastatic melanoma, without showing significant cytotoxicity against tumor cells in vitro. In this case, we suggest that these peptides may act as immune adjuvants in vivo. As observed, peptides induced nitric oxide production in bone-marrow macrophages showing that innate immune cells can also be modulated by these CDR peptides. The present screening supports the search in immunoglobulins of rather frequent CDR sequences that are endowed with specific antitumor properties and may be candidates to be developed as anti-cancer drugs.

  18. A new cell counting method to evaluate anti-tumor compound activity.

    PubMed

    Wang, Xue-Jian; Zhang, Xiu-Rong; Zhang, Lei; Li, Qing-Hua; Wang, Lin; Shi, Li-Hong; Fang, Chun-Yan

    2014-01-01

    Determining cell quantity is a common problem in cytology research and anti-tumor drug development. A simple and low-cost method was developed to determine monolayer and adherent-growth cell quantities. The cell nucleus is located in the cytoplasm, and is independent. Thus, the nucleus cannot make contact even if the cell density is heavy. This phenomenon is the foundation of accurate cell-nucleus recognition. The cell nucleus is easily recognizable in images after fluorescent staining because it is independent. A one-to-one relationship exists between the nucleus and the cell; therefore, this method can be used to determine the quantity of proliferating cells. Results indicated that the activity of the histone deacetylase inhibitor Z1 was effective after this method was used. The nude-mouse xenograft model also revealed the potent anti-tumor activity of Z1. This research presents a new anti-tumor-drug evaluation method.

  19. Sulfated modification of the polysaccharides obtained from defatted rice bran and their antitumor activities.

    PubMed

    Wang, Li; Li, Xiaoxuan; Chen, Zhengxing

    2009-03-01

    Nine sulfated defatted rice bran polysaccharides (sRBPS), with various degrees of sulfation (DS) and carbohydrate content, were prepared by chlorosulfonic acid-pyridine (CSA-Pyr) method according to orthogonal test. Nine sulfated derivatives sRBPS were obtained and their antitumor activities were compared by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results showed that when DS within the scope of 0.81-1.29, carbohydrate content in the range of 41.41-78.56%, sulfated derivatives exhibit relatively strong antitumor activity in vitro. The optimum modification conditions were reaction temperature of 70 degrees C, the ratio of chlorosulfonic acid to pyridine of 1:4 and the reaction time of 2h.

  20. Allylic isothiouronium salts: The discovery of a novel class of thiourea analogues with antitumor activity.

    PubMed

    Ferreira, Misael; Assunção, Laura Sartori; Silva, Adny Henrique; Filippin-Monteiro, Fabíola Branco; Creczynski-Pasa, Tânia Beatriz; Sá, Marcus Mandolesi

    2017-03-31

    A series of 28 aryl- and alkyl-substituted isothiouronium salts were readily synthesized in high yields through the reaction of allylic bromides with thiourea, N-monosubstituted thioureas or thiosemicarbazide. The S-allylic isothiouronium salts substituted with aliphatic groups were found to be the most effective against leukemia cells. These compounds combine high antitumor activity and low toxicity toward non-tumoral cells, with selectivity index higher than 20 in some cases. Furthermore, the selected isothiouronium salts induced G2/M cell cycle arrest and cell death, possibly by apoptosis. Therefore, these compounds can be considered as a promising class of antitumor agents due to the potent cytostatic activity associated with high selectivity.

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

    PubMed

    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.

  2. [Coordination compounds of Pd(II) with potential antitumor activity].

    PubMed

    González Vílchez, F; García Basallote, M; Benítez Ordóñez, J; Vilaplana Serrano, R

    1982-01-01

    The first results about the anti-neoplastic activity of Pd(II) ion coordinative compounds with complexones of the ethylenediamine-tetraacetic acid type are described. The assays employing Ehrlich ascites cancer of the mouse show that the presence of substitutes in the ethylenediamine skeleton originates important changes of the activity of such compounds.

  3. Pardaxin, a Fish Antimicrobial Peptide, Exhibits Antitumor Activity toward Murine Fibrosarcoma in Vitro and in Vivo

    PubMed Central

    Wu, Shu-Ping; Huang, Tsui-Chin; Lin, Ching-Chun; Hui, Cho-Fat; Lin, Cheng-Hui; Chen, Jyh-Yih

    2012-01-01

    The antitumor activity of pardaxin, a fish antimicrobial peptide, has not been previously examined in in vitro and in vivo systems for treating murine fibrosarcoma. In this study, the antitumor activity of synthetic pardaxin was tested using murine MN-11 tumor cells as the study model. We show that pardaxin inhibits the proliferation of MN-11 cells and reduces colony formation in a soft agar assay. Transmission electron microscopy (TEM) showed that pardaxin altered the membrane structure similar to what a lytic peptide does, and also produced apoptotic features, such as hollow mitochondria, nuclear condensation, and disrupted cell membranes. A qRT-PCR and ELISA showed that pardaxin induced apoptosis, activated caspase-7 and interleukin (IL)-7r, and downregulated caspase-9, ATF 3, SOCS3, STAT3, cathelicidin, p65, and interferon (IFN)-γ suggesting that pardaxin induces apoptosis through the death receptor/nuclear factor (NF)-κB signaling pathway after 14 days of treatment in tumor-bearing mice. An antitumor effect was observed when pardaxin (25 mg/kg; 0.5 mg/day) was used to treat mice for 14 days, which caused significant inhibition of MN-11 cell growth in mice. Overall, these results indicate that pardaxin has the potential to be a novel therapeutic agent to treat fibrosarcomas. PMID:23015777

  4. Antitumor and antimicrobial activities of endophytic fungi from medicinal parts of Aquilaria sinensis.

    PubMed

    Cui, Jin-long; Guo, Shun-xing; Xiao, Pei-gen

    2011-05-01

    The purpose of this study was to isolate and characterize endophytic fungi from the stem tissue which can produce fragrant ingredients in Aquilaria sinensis (also called agarwood) to determine their antitumor and antimicrobial activities. Twenty-eight fungal endophytes were isolated from agarwood by strict sterile sample preparation and were classified into 14 genera and 4 taxonomic classes (Sordariomycetes, Dothideomycetes, Saccharomycetes, and Zygomycetes) based on molecular identification. Of the 28 isolates, 13 (46.4%) showed antimicrobial activity against at least one of the test strains by the agar well diffusion method, and 23 isolates (82.1%) displayed antitumor activity against at least one of five cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The diameters of inhibition zones of YNAS07, YNAS14, HNAS04, HNAS05, HNAS08, and HNAS11 were equal to or higher than 14.0 mm against Staphylococcus aureus, Escherichia coli, Bacillus subtilis, B. subtilis, Aspergillus fumigatus, and B. subtilis, respectively. The inhibition rates of YNAS06, YNAS08, and HNAS06 were not less than 60% to 293-T, 293-T, and SKVO3 cells, respectively. These results suggest that the endophytic fungi associated with agarwood will provide us with not only useful micro-ecological information, but also potential antimicrobial and antitumor agents.

  5. Antitumor and antimicrobial activities of endophytic fungi from medicinal parts of Aquilaria sinensis *

    PubMed Central

    Cui, Jin-long; Guo, Shun-xing; Xiao, Pei-gen

    2011-01-01

    The purpose of this study was to isolate and characterize endophytic fungi from the stem tissue which can produce fragrant ingredients in Aquilaria sinensis (also called agarwood) to determine their antitumor and antimicrobial activities. Twenty-eight fungal endophytes were isolated from agarwood by strict sterile sample preparation and were classified into 14 genera and 4 taxonomic classes (Sordariomycetes, Dothideomycetes, Saccharomycetes, and Zygomycetes) based on molecular identification. Of the 28 isolates, 13 (46.4%) showed antimicrobial activity against at least one of the test strains by the agar well diffusion method, and 23 isolates (82.1%) displayed antitumor activity against at least one of five cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The diameters of inhibition zones of YNAS07, YNAS14, HNAS04, HNAS05, HNAS08, and HNAS11 were equal to or higher than 14.0 mm against Staphylococcus aureus, Escherichia coli, Bacillus subtilis, B. subtilis, Aspergillus fumigatus, and B. subtilis, respectively. The inhibition rates of YNAS06, YNAS08, and HNAS06 were not less than 60% to 293-T, 293-T, and SKVO3 cells, respectively. These results suggest that the endophytic fungi associated with agarwood will provide us with not only useful micro-ecological information, but also potential antimicrobial and antitumor agents. PMID:21528493

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

    PubMed Central

    Han, Wei; Wang, Shengpeng; Liang, Rixin; Wang, Lan; Chen, Meiwan; Li, Hui; Wang, Yitao

    2013-01-01

    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. PMID:23807847

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

    PubMed

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

    1999-11-01

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

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

    PubMed

    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.

  9. Antimicrobial and antitumor activities of chitosan from shiitake stipes, compared to commercial chitosan from crab shells.

    PubMed

    Chien, Rao-Chi; Yen, Ming-Tsung; Mau, Jeng-Leun

    2016-03-15

    Chitosan was prepared by alkaline N-deacetylation of chitin obtained from shiitake stipes and crab shells and its antimicrobial and antitumor activities were studied. Chitosan from shiitake stipes and crab shells exhibited excellent antimicrobial activities against eight species of Gram positive and negative pathogenic bacteria with inhibition zones of 11.4-26.8mm at 0.5mg/ml. Among chitosan samples, shiitake chitosan C120 was the most effective with inhibition zones of 16.4-26.8mm at 0.5mg/ml. In addition, shiitake and crab chitosan showed a moderate anti-proliferative effect on IMR 32 and Hep G2 cells. At 5mg/ml, the viability of IMR 32 cells incubated with chitosan was 68.8-85.0% whereas that of Hep G2 cells with chitosan was 60.4-82.9%. Overall, shiitake chitosan showed slightly better antimicrobial and antitumor activities than crab chitosan. Based on the results obtained, shiitake and crab chitosan were strong antimicrobial agents and moderate antitumor agents.

  10. Antitumor and antiparasitic activity of novel ruthenium compounds with polycyclic aromatic ligands.

    PubMed

    Miserachs, Helena Guiset; Cipriani, Micaella; Grau, Jordi; Vilaseca, Marta; Lorenzo, Julia; Medeiros, Andrea; Comini, Marcelo A; Gambino, Dinorah; Otero, Lucía; Moreno, Virtudes

    2015-09-01

    Five novel ruthenium(II)-arene complexes with polycyclic aromatic ligands were synthesized, comprising three compounds of the formula [RuCl(η(6)-p-cym)(L)][PF6], where p-cym = 1-isopropyl-4-methylbenzene and L are the bidentate aromatic ligands 1,10-phenanthroline-5,6-dione, 1, 5-amine-1,10-phenanthroline, 4, or 5,6-epoxy-5,6-dihydro-phenanthroline, 5. In the other two complexes [RuCl2(η(6)-p-cym)(L')], the metal is coordinated to a monodentate ligand L', where L' is phenanthridine, 2, or 9-carbonylanthracene, 3. All compounds were fully characterized by mass spectrometry and elemental analysis, as well as NMR and IR spectroscopic techniques. Obtained ruthenium compounds as well as their respective ligands were tested for their antiparasitic and antitumoral activities. Even though all compounds showed lower Trypanosoma brucei activity than the free ligands, they also resulted less toxic on mammalian cells. Cytotoxicity assays on HL60 cells showed a moderate antitumoral activity for all ruthenium compounds. Compound 1 was the most potent antitumoral (IC50 = 1.26±0.78 μM) and antiparasitic (IC50 = 0.19 ± 0.05 μM) agent, showing high selectivity towards the parasites (selectivity index >100). As complex 1 was the most promising antitumoral compound, its interaction with ubiquitin as potential target was also studied. In addition, obtained ruthenium compounds were found to bind DNA, and they are thought to interact with this macromolecule mainly through intercalation of the aromatic ligand.

  11. Rottlerin exerts its anti-tumor activity through inhibition of Skp2 in breast cancer cells

    PubMed Central

    Hou, Yingying; Wang, Lixia; Ye, Xiantao; Zhao, Zhe; Zhou, Xiuxia; Li, Yali; Wang, Zhiwei

    2016-01-01

    Studies have investigated the tumor suppressive role of rottlerin in carcinogenesis. However, the molecular mechanisms of rottlerin-induced anti-tumor activity are largely unclear. Skp2 (S-phase kinase associated protein 2) has been validated to play an oncogenic role in a variety of human malignancies. Therefore, inactivation of Skp2 could be helpful for the treatment of human cancers. In the current study, we explore whether rottlerin could inhibit Skp2 expression, leading to inhibition of cell growth, migration and invasion in breast cancer cells. We found that rottlerin treatment inhibited cell growth, induced apoptosis and cell cycle arrest. We also revealed that rottlerin suppressed cell migration and invasion in breast cancer cells. Mechanically, we observed that rottlerin significantly down-regulated the expression of Skp2 in breast cancer cells. Importantly, overexpression of Skp2 abrogated rottlerin-mediated tumor suppressive activity, whereas down-regulation of Skp2 enhanced rottlerin-triggered anti-tumor function. Strikingly, we identified that rottlerin exhibited its anti-tumor potential partly through inactivation of Skp2 in breast cancer. Our findings indicate that rottlerin could be a potential safe agent for the treatment of breast cancer. PMID:27582552

  12. Optimization, characterization, sulfation and antitumor activity of neutral polysaccharides from the fruit of Borojoa sorbilis cuter.

    PubMed

    Xu, Fangfang; Liao, Kangsheng; Wu, Yunshan; Pan, Qi; Wu, Lilan; Jiao, Hong; Guo, Dean; Li, Ben; Liu, Bo

    2016-10-20

    Extraction optimization, purification, characterization, sulfation and antitumor activity of polysaccharides from the fruit body of Borojoa sorbilis cuter were investigated in present study. The optimal Ultrahigh Pressure extraction condition was determined as: extraction once with the solid-liquid ratio of 1:10 in 30°C and 1500Mpa for crude polysaccharide (BP) and experimental yield was 8.28%. Four water-soluble polysaccharides named as BP1-1, BP1-2, BP1-3 and BP1-4, with molecular weight of 35.8, 32.4, 30.1 and 27.7kDa, were purified by DEAE Sepharose and Superdex 200 chromatography. On the basis of chemical and spectroscopic analyses, BP1-1-BP1-4 were found to be neutral β-d-galactan containing a (1→4)-linked backbone. S-BP1s with the DSS of 1.18, was sulfated by chloro-sulfonic acid-pyridine method. Furthermore, S-BP1s exhibited significant in vitro antitumor activity against liver cancer HepG2 and lung cancer A549 cells in a dose-dependent manner. The results indicated that S-BP1s could be potentially developed as functional antitumor drug.

  13. Protecting cisplatin-induced nephrotoxicity with cimetidine does not affect antitumor activity.

    PubMed

    Katsuda, Hiromu; Yamashita, Mariko; Katsura, Hideyuki; Yu, Jia; Waki, Yoshihiro; Nagata, Naoto; Sai, Yoshimichi; Miyamoto, Ken-Ichi

    2010-01-01

    The present study examined the influence of cimetidine on the nephrotoxicity and antitumor effects of cisplatin in vitro and in vivo. When the serum concentration of cimetidine was maintained over 20 µg/ml for 4 h by bolus and continuous intravenous infusion, cimetidine prevented nephrotoxicity of cisplatin without influencing antitumor activity. Cimetidine and the antioxidant N-acetylcysteine (NAC) significantly inhibited the in vitro growth inhibition of cisplatin in cells originating from the kidney, but not in SOSN2 osteosarcoma cells. Cimetidine (1 mM) also did not influence platinum concentration in the cells, regardless of whether the organic cation transporter 2 (OCT2) was expressed. Cisplatin did induce reactive oxygen species (ROS) in the KN41 kidney cell line and cimetidine and NAC significantly reduced ROS production. However, cisplatin did not produce ROS in osteosarcoma cells. From these results, cimetidine clearly inhibits nephrotoxicity induced by cisplatin without any influence on the antitumor activity of cisplatin on osteosarcoma in vitro and in vivo.

  14. Colloidally stable surface-modified iron oxide nanoparticles: Preparation, characterization and anti-tumor activity

    NASA Astrophysics Data System (ADS)

    Macková, Hana; Horák, Daniel; Donchenko, Georgiy Viktorovich; Andriyaka, Vadim Ivanovich; Palyvoda, Olga Mikhailovna; Chernishov, Vladimir Ivanovich; Chekhun, Vasyl Fedorovich; Todor, Igor Nikolaevich; Kuzmenko, Oleksandr Ivanovich

    2015-04-01

    Maghemite (γ-Fe2O3) nanoparticles were obtained by co-precipitation of Fe(II) and Fe(III) chlorides and subsequent oxidation with sodium hypochlorite and coated with poly(N,N-dimethylacrylamide-co-acrylic acid) [P(DMAAm-AA)]. They were characterized by a range of methods including transmission electron microscopy (TEM), elemental analysis, dynamic light scattering (DLS) and zeta potential measurements. The effect of superparamagnetic P(DMAAm-AA)-γ-Fe2O3 nanoparticles on oxidation of blood lipids, glutathione and proteins in blood serum was detected using 2-thiobarbituric acid and the ThioGlo fluorophore. Finally, mice received magnetic nanoparticles administered per os and the antitumor activity of the particles was tested on Lewis lung carcinoma (LLC) in male mice line C57BL/6 as an experimental in vivo metastatic tumor model; the tumor size was measured and the number of metastases in lungs was determined. Surface-modified γ-Fe2O3 nanoparticles showed higher antitumor and antimetastatic activities than commercial CuFe2O4 particles and the conventional antitumor agent cisplatin.

  15. Synthesis and antitumor activity of some substituted indazole derivatives.

    PubMed

    Abbassi, Najat; Rakib, El Mostapha; Chicha, Hakima; Bouissane, Latifa; Hannioui, Abdellah; Aiello, Cinzia; Gangemi, Rosaria; Castagnola, Patrizio; Rosano, Camillo; Viale, Maurizio

    2014-06-01

    Some new N-[6-indazolyl]arylsulfonamides and N-[alkoxy-6-indazolyl]arylsulfonamides were prepared by the reduction of 2-alkyl-6-nitroindazoles with SnCl2 in different alcohols, followed by coupling the corresponding amine with arylsulfonyl chlorides in pyridine. The newly synthesized compounds were evaluated for their antiproliferative and apoptotic activities against two human tumor cell lines: A2780 (ovarian carcinoma) and A549 (lung adenocarcinoma). Preliminary in vitro pharmacological studies revealed that N-(2-allyl-2H-indazol-6-yl)-4-methoxybenzenesulfonamide 4 and N-[7-ethoxy-2-(4-methyl-benzyl)-2H-indazol-6-yl]-4-methyl-benzenesulfonamide 9 exhibited significant antiproliferative activity against the A2780 and A549 cell lines with IC50 values in the range from 4.21 to 18.6 µM, and also that they trigger apoptosis in a dose-dependent manner. Furthermore, both active compounds were able to cause an arrest of cells in the G2/M phase of the cell cycle, typical but not exclusive of tubulin interacting agents, although only infrequent interactions with the microtubule network were observed by immunofluorescence microscopy, while docking analysis showed a possible different behavior between the two active compounds.

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

    SciTech Connect

    Peters, Diane E.; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A.; Leppla, Stephen H.; Bugge, Thomas H.

    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

  17. An efficient synthesis method targeted to marine alkaloids marinacarbolines A-D and their antitumor activities.

    PubMed

    Li, Jun; Tang, Yang; Jin, Hui-Juan; Cui, Yi-Di; Zhang, Li-Juan; Jiang, Tao

    2015-01-01

    Marinacarbolines A-D are a series of marine β-carboline alkaloids isolated from actinomycete Marinactinospora thermotolerans of the deep South China Sea with antiplasmodial activities. In inhibition assays of in vitro growth of Plasmodium falciparum, marinacarbolines exhibited antiplasmodial activity against drug-sensitive line 3D7 and drug-resistant line Dd2 of P. falciparum. However, approaches for the synthesis of such useful compounds are very limited. In this work, we reported a simple, efficient, and versatile process to synthesize marinacarbolines A-D (1-4). On the basis of that, the antitumor activities of marinacarbolines in a structure-dependent manner were allowed to be unveiled.

  18. Increased antitumor activity of tumor-specific peptide modified thymopentin.

    PubMed

    Lao, Xingzhen; Li, Bin; Liu, Meng; Chen, Jiao; Gao, Xiangdong; Zheng, Heng

    2014-12-01

    Thymopoietin pentapeptide (thymopentin, TP5), an immunomodulatory peptide, has been successfully used as an immune system enhancer for treating immune deficiency, cancer, and infectious diseases. However, poor penetration into tumors remains a key limitation to the efficacy and application of TP5. iRGD (CRGDK/RGPD/EC) has been introduced to certain anticancer agents, and increased specific tumor penetrability of drugs and cell internalization have been observed. In the present study, we fused this iRGD fragment with the C-terminal of TP5 to yield a new product, TP5-iRGD. Cell attachment assay showed that TP5-iRGD exhibits more extensive attachment to the melanoma cell line B16F10 than wild-type TP5. Tumor cell viability assay showed that iRGD conjugation with the TP5 C-terminus increases the basal antiproliferative activity of the pentapeptide against the melanoma cell line B16F10, the human lung cancer cell line H460, and the human breast cancer cell line MCF-7. Subsequent injections of TP5-iRGD inhibited in vivo melanoma progression more efficiently than the native TP5. Murine spleen lymphocyte proliferation assay also showed that TP5-iRGD and the parent pentapeptide feature nearly identical spleen lymphocyte proliferation activities. We built an integrin αvβ3 and TP5-iRGD computational binding model to investigate the mechanism by which TP5-iRGD promotes increased activity further. Conjugation with iRGD promotes binding to integrin αvβ3, thereby increasing the tumor-homing efficiency of the resultant peptide. These experimental and computational observations of increased TP5-iRGD activity help broaden the usage of TP5 and reflect the great application potential of the peptide as an anticancer agent.

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

    PubMed

    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.

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

    PubMed

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

    2014-05-01

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

  1. Synthesis and Antitumor Activity of New Thiazole Nortopsentin Analogs

    PubMed Central

    Spanò, Virginia; Attanzio, Alessandro; Cascioferro, Stella; Carbone, Anna; Montalbano, Alessandra; Barraja, Paola; Tesoriere, Luisa; Cirrincione, Girolamo; Diana, Patrizia; Parrino, Barbara

    2016-01-01

    New thiazole nortopsentin analogs in which one of the two indole units was replaced by a naphthyl and/or 7-azaindolyl portion, were conveniently synthesized. Among these, three derivatives showed good antiproliferative activity, in particular against MCF7 cell line, with GI50 values in the micromolar range. Their cytotoxic effect on MCF7 cells was further investigated in order to elucidate their mode of action. Results showed that the three compounds act as pro-apoptotic agents inducing a clear shift of viable cells towards early apoptosis, while not exerting necrotic effects. They also caused cell cycle perturbation with significant decrease in the percentage of cells in the G0/G1 and S phases, accompanied by a concomitant percentage increase of cells in the G2/M phase, and appearance of a subG1-cell population. PMID:27983614

  2. Synthesis and Antitumor Activity of New Thiazole Nortopsentin Analogs.

    PubMed

    Spanò, Virginia; Attanzio, Alessandro; Cascioferro, Stella; Carbone, Anna; Montalbano, Alessandra; Barraja, Paola; Tesoriere, Luisa; Cirrincione, Girolamo; Diana, Patrizia; Parrino, Barbara

    2016-12-14

    New thiazole nortopsentin analogs in which one of the two indole units was replaced by a naphthyl and/or 7-azaindolyl portion, were conveniently synthesized. Among these, three derivatives showed good antiproliferative activity, in particular against MCF7 cell line, with GI50 values in the micromolar range. Their cytotoxic effect on MCF7 cells was further investigated in order to elucidate their mode of action. Results showed that the three compounds act as pro-apoptotic agents inducing a clear shift of viable cells towards early apoptosis, while not exerting necrotic effects. They also caused cell cycle perturbation with significant decrease in the percentage of cells in the G0/G1 and S phases, accompanied by a concomitant percentage increase of cells in the G2/M phase, and appearance of a subG1-cell population.

  3. Anti-tumor activity of calcitriol: pre-clinical and clinical studies.

    PubMed

    Trump, Donald L; Hershberger, Pamela A; Bernardi, Ronald J; Ahmed, Sharmilla; Muindi, Josephia; Fakih, Marwan; Yu, Wei-Dong; Johnson, Candace S

    2004-05-01

    1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.

  4. Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

    PubMed Central

    Covre, A; Coral, S; Nicolay, H; Parisi, G; Fazio, C; Colizzi, F; Fratta, E; Di Giacomo, A M; Sigalotti, L; Natali, P G; Maio, M

    2015-01-01

    The multifaceted immunomodulatory activity of DNA hypomethylating agents improves immunogenicity and immune recognition of neoplastic cells; thus, we predicted they could be utilized to design new immunotherapeutic combinations in cancer. Testing this hypothesis, the antitumor efficacy of the DNA hypomethylating agent 5-aza-2′-deoxycytidine (5-AZA-CdR) combined with the anti-CTLA-4 monoclonal antibody (mAb) 9H10 in syngeneic transplantable murine models was investigated. Murine mammary carcinoma TS/A or mesothelioma AB1 cells were injected in BALB/c, athymic nude, and SCID/Beige mice that were treated with 5-AZA-CdR, mAb 9H10, or their combination. Tumor volumes were captured at different time-points; molecular and immunohistochemical assays investigated changes in neoplastic and normal tissues. A significant antitumor effect of 5-AZA-CdR combined with mAb 9H10 was found: compared to controls, a 77% (p < 0.01), 54% (p < 0.01) and 33% (p = 0.2) decrease in TS/A tumor growth was induced by 5-AZA-CdR combined with mAb 9H10, 5-AZA-CdR or mAb 9H10, respectively. These antitumor activities were confirmed utilizing the AB1 model. 5-AZA-CdR-based regimens induced a promoter-demethylation-sustained tumor expression of cancer testis antigens. MHC class I expression was up-regulated by 5-AZA-CdR. Antitumor efficacy of 5-AZA-CdR in athymic nude and SCID/Beige mice was not increased by mAb 9H10. In BALB/c mice, combined treatment induced the highest tumor infiltration by CD3+ lymphocytes, which included both CD8+ and CD4+ T cells; no such infiltrates were observed in normal tissues. This significant immune-related antitumor activity of 5-AZA-CdR combined with CTLA-4 blockade, demonstrated in highly aggressive mouse tumor models, provides a strong scientific rationale to implement epigenetically-based immunotherapies in cancer patients. PMID:26405573

  5. Antitumor activity of dobutamine on human osteosarcoma cells

    PubMed Central

    YIN, JUN; DONG, QIRONG; ZHENG, MINQIAN; XU, XIAOZU; ZOU, GUOYOU; MA, GUOLIN; LI, KEFENG

    2016-01-01

    Dobutamine has been widely used for the treatment of heart failure and cardiogenic shock since the 1970s. Osteosarcoma is the most commonly observed malignant bone tumor in children. Currently, there are no effective drugs for the treatment of osteosarcoma. In the present study, the potential anticancer activity of dobutamine on human osteosarcoma cells was examined. Human osteosarcoma MG-63 cells were treated with dobutamine at various concentrations and for various incubation times. The inhibition of cell growth by dobutamine was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry was utilized to evaluate the effect of dobutamine on cell apoptosis and the cell cycle. Furthermore, the expression levels of caspase-3 and caspase-9 were assessed by western blot analysis. The influence of dobutamine on cancer cell migration and invasion was additionally evaluated using wound-healing assay and the Boyden Chamber migration method. Dobutamine significantly inhibited the growth of MG-63 cells at a concentration of 10 µM or higher when incubated for 12 h or longer (P=0.023). Dobutamine augmented cell apoptosis and arrested the cell cycle in the G2/M phase. Western blot analysis revealed that dobutamine induces expression of caspase-3 and caspase-9. In addition, the invasiveness and migration of MG-63 cells was inhibited by dobutamine in a concentration-dependent manner. The results of the present study may lead to novel applications for dobutamine in the treatment of osteosarcoma. PMID:27284371

  6. The pH dependence of violaxanthin deepoxidation in isolated pea chloroplasts

    SciTech Connect

    Pfuendel, E.E.; Dilley, R.A. )

    1993-01-01

    The absorbance change at 505 nm was used to monitor the kinetics of violaxanthin deepoxidation in isolated pea (Pisum sativum) chloroplasts under dark conditions at various pH values. In long-term measurements (65 min) a fast and a slow exponential component of the 505-nm absorbance change could be resolved. The fast rate constant was up to 10 times higher than the slow rate constant. The asymptote value of the fast kinetic component was twice that of the slow component. The pH dependency of the parameters of the fast kinetic component was analyzed from pH 5.2 to pH 7.0. It was found that the asymptote value dropped slightly with increasing pH. The rate constant was zero at pH values greater than 6.3 and showed maximum values at pH values less than 5.8. Hill plot analysis revealed a strong positive cooperativity for the pH dependency of the fast rate constant (Hill coefficient n[sub H] = 5.3). The results are discussed with respect to published activity curves of violaxanthin deepoxidation. 23 refs., 6 figs., 1 tab.

  7. Anti-tumor activity of lipophilic imidazolium salts on select NSCLC cell lines.

    PubMed

    Wright, Brian D; Deblock, Michael C; Wagers, Patrick O; Duah, Ernest; Robishaw, Nikki K; Shelton, Kerri L; Southerland, Marie R; DeBord, Michael A; Kersten, Kortney M; McDonald, Lucas J; Stiel, Jason A; Panzner, Matthew J; Tessier, Claire A; Paruchuri, Sailaja; Youngs, Wiley J

    2015-07-01

    The anti-tumor activity of imidazolium salts is highly dependent upon the substituents on the nitrogen atoms of the imidazolium cation. We have synthesized and characterized a series of naphthalene-substituted imidazolium salts and tested them against a variety of non-smallcell lung cancer cell lines. Several of these complexes displayed anticancer activity comparable to cisplatin. These compounds induced apoptosis in the NCI-H460 cell line as determined by Annexin V staining, caspase-3, and PARP cleavage. These results strongly suggest that this class of compounds can serve as potent chemotherapeutic agents.

  8. Resveratrol Enhances Antitumor Activity of TRAIL in Prostate Cancer Xenografts through Activation of FOXO Transcription Factor

    PubMed Central

    Ganapathy, Suthakar; Chen, Qinghe; Singh, Karan P.; Shankar, Sharmila; Srivastava, Rakesh K.

    2010-01-01

    Background Resveratrol (3, 4′, 5 tri-hydroxystilbene), a naturally occurring polyphenol, exhibits anti-inflammatory, antioxidant, cardioprotective and antitumor activities. We have recently shown that resveratrol can enhance the apoptosis-inducing potential of TRAIL in prostate cancer cells through multiple mechanisms in vitro. Therefore, the present study was designed to validate whether resveratrol can enhance the apoptosis-inducing potential of TRAIL in a xenograft model of prostate cancer. Methodology/Principal Findings Resveratrol and TRAIL alone inhibited growth of PC-3 xenografts in nude mice by inhibiting tumor cell proliferation (PCNA and Ki67 staining) and inducing apoptosis (TUNEL staining). The combination of resveratrol and TRAIL was more effective in inhibiting tumor growth than single agent alone. In xenografted tumors, resveratrol upregulated the expressions of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax and p27/K IP1, and inhibited the expression of Bcl-2 and cyclin D1. Treatment of mice with resveratrol and TRAIL alone inhibited angiogenesis (as demonstrated by reduced number of blood vessels, and VEGF and VEGFR2 positive cells) and markers of metastasis (MMP-2 and MMP-9). The combination of resveratrol with TRAIL further inhibited number of blood vessels in tumors, and circulating endothelial growth factor receptor 2-positive endothelial cells than single agent alone. Furthermore, resveratrol inhibited the cytoplasmic phosphorylation of FKHRL1 resulting in its enhanced activation as demonstrated by increased DNA binding activity. Conclusions/Significance These data suggest that resveratrol can enhance the apoptosis-inducing potential of TRAIL by activating FKHRL1 and its target genes. The ability of resveratrol to inhibit tumor growth, metastasis and angiogenesis, and enhance the therapeutic potential of TRAIL suggests that resveratrol alone or in combination with TRAIL can be used for the management of prostate cancer. PMID:21209944

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

    PubMed Central

    Jing, Siqun; Zhang, Xiaoming

    2015-01-01

    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. PMID:25628774

  10. Anti-tumor activity and mechanism of action for a cyanoaziridine-derivative, AMP423

    PubMed Central

    Wisner, Lee; Samulitis, Betty K.; Landowski, Terry H.; Remers, William A.

    2012-01-01

    Purpose Preclinical studies evaluated the anti-tumor activity and mechanism of action of AMP423, a naphthyl derivative of 2-cyanoaziridine-1-carboxamide with structural similarity to the pro-oxidant anti-tumor agent imexon. Methods The cytotoxic potency was evaluated in vitro against a variety of human cancer cell lines. Mechanism-of-action studies were performed in the human 8226/S myeloma cell line and its imexon-resistant variant, 8226/IM10. In vivo activity was evaluated against human myeloma and lymphoma xenografts in SCID mice. Pharmacokinetics and toxicology were investigated in non-tumor-bearing mice. Results The 72-h IC50s for all cell types ranged from 2 to 36 μM, across a wide variety of human cancer cell lines. AMP423 was active in SCID mice bearing 8226/S myeloma and SU-DHL-6 B-cell lymphoma tumors, with a median tumor growth delay (T–C) of 21 days (P = 0.0002) and 5 days (P = 0.004), respectively, and a median tumor growth inhibition (T/C) of 33.3% (P = 0.03) and 82% (P = 0.01), respectively. In non-tumor-bearing mice, AMP423 was not myelosuppressive. Mechanistic studies show that AMP423’s mode of cell death is a mixture of necrosis and apoptosis, with generation of reactive oxygen species, inhibition of protein synthesis, and a decrease in reduced sulfhydryl levels, but no alkylation of nucleophiles. Unlike its structural analog imexon, which causes cell cycle arrest in G2/M, AMP423 induces the accumulation of cells in S-phase. Conclusions AMP423 has pro-oxidant effects similar to imexon, has greater cytotoxic potency in vitro, and has anti-tumor activity in hematologic tumors in vivo. PMID:22186884

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

    PubMed

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

    2007-11-01

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

  12. Non-thermal atmospheric pressure plasma activates lactate in Ringer's solution for anti-tumor effects.

    PubMed

    Tanaka, Hiromasa; Nakamura, Kae; Mizuno, Masaaki; Ishikawa, Kenji; Takeda, Keigo; Kajiyama, Hiroaki; Utsumi, Fumi; Kikkawa, Fumitaka; Hori, Masaru

    2016-11-08

    Non-thermal atmospheric pressure plasma is a novel approach for wound healing, blood coagulation, and cancer therapy. A recent discovery in the field of plasma medicine is that non-thermal atmospheric pressure plasma not only directly but also indirectly affects cells via plasma-treated liquids. This discovery has led to the use of non-thermal atmospheric pressure plasma as a novel chemotherapy. We refer to these plasma-treated liquids as plasma-activated liquids. We chose Ringer's solutions to produce plasma-activated liquids for clinical applications. In vitro and in vivo experiments demonstrated that plasma-activated Ringer's lactate solution has anti-tumor effects, but of the four components in Ringer's lactate solution, only lactate exhibited anti-tumor effects through activation by non-thermal plasma. Nuclear magnetic resonance analyses indicate that plasma irradiation generates acetyl and pyruvic acid-like groups in Ringer's lactate solution. Overall, these results suggest that plasma-activated Ringer's lactate solution is promising for chemotherapy.

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

    PubMed Central

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

    2015-01-01

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

  14. CpG-based immunotherapy impairs antitumor activity of BRAF inhibitors in a B-cell-dependent manner.

    PubMed

    Huang, L; Wang, Z; Liu, C; Xu, C; Mbofung, R M; McKenzie, J A; Khong, H; Hwu, P; Peng, W

    2017-03-06

    Combining immunotherapy with targeted therapy has increasingly become an appealing therapeutic paradigm for cancer treatment due to its great potential for generating durable and synergistic antitumor response. In this study, however, we unexpectedly found that two types of CpG-based tumor peptide vaccine treatments consistently negated the antitumor activity of a selective BRAF inhibitor in tumors with BRAF mutation rather than showing a synergistic antitumor effect. Our further studies demonstrated that CpG alone was sufficient to dampen BRAF inhibitor-induced antitumor responses, suggesting that the impaired antitumor activity of the BRAF inhibitor observed in mice receiving CpG-based peptide vaccine is mainly dependent upon the use of CpG. Mechanistically, CpG increased the number of circulating B cells, which produced elevated amounts of tumor necrosis factor-α (TNFα) that contributed to the increased tumor resistance to BRAF inhibitors. More importantly, B-cell depletion or TNFα neutralization can restore the antitumor effect of BRAF inhibition in mice receiving CpG treatment, indicating that TNFα-secreting B cells play an indispensable role in BRAF inhibitor resistance induced by CpG. Taken together, our results strongly suggest that precautions must be implemented when designing combinatorial approaches for cancer treatment, because distinct regimens, despite their respective therapeutic benefit as monotherapy, may together provide antagonistic clinical outcomes.Oncogene advance online publication, 6 March 2017; doi:10.1038/onc.2017.35.

  15. The antitumor activity study of ginsenosides and metabolites in lung cancer cell

    PubMed Central

    Xu, Feng-Yuan; Shang, Wen-Qing; Yu, Jia-Jun; Sun, Qian; Li, Ming-Qing; Sun, Jian-Song

    2016-01-01

    Ginseng and its components exert various biological effects, including antioxidant, anti-carcinogenic, anti-mutagenic, and antitumor activity. Ginsenosides are the main biological components of ginseng. Protopanaxadiol (PPD) and protopanaxatriol (PPT) are two metabolites of ginsenosides. However, the difference between these compounds in anti-lung cancer is unclear. The present study aimed to evaluate the antitumor activity of PPD, PPT, Ginsenosides-Rg3 (G-Rg3) and Ginsenosides-Rh2 (G-Rh2) in lung cancer cell. After treatment with cisplatin, PPD, PPT, G-Rg3 or G-Rh2, the viability, apoptosis level and invasiveness of lung cell lines (A549 cell, a lung adenocarcinoma cell line and SK-MES-1 cell, a lung squamous cell line) in vitro were analyzed by Cell Counting Kit-8 (CCK8), Annexin V/PI apoptosis and Matrigel invasion assays, respectively. Here we found that all these compounds led to significant decreases of viability and invasiveness and an obvious increase of apoptosis of A549 and SK-MES-1 cells. Among these, the viability of SK-MES-1 cell treated with PPT was decreased to 66.8%, and this effect was closest to Cisplatin. G-Rg3 had the highest stimulatory effect on apoptosis, and PTT had the highest inhibitory effect on cell invasiveness in A549 and SK-MES-1 cells. These results indicate that both ginsenosides and two metabolites have antitumor activity on lung cancer cell in vitro. However, PPT is more powerful for inhibiting the viability and invasiveness of lung cancer cell, especially lung squamous cell. G-Rg3 has the best pro-apoptosis effects. This study provides a scientific basis for potential therapeutic strategies targeted to lung cancer by further structure modification. PMID:27186294

  16. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma

    PubMed Central

    Hu-Lieskovan, Siwen; Mok, Stephen; Moreno, Blanca Homet; Tsoi, Jennifer; Faja, Lidia Robert; Goedert, Lucas; Pinheiro, Elaine M.; Koya, Richard C.; Graeber, Thomas; Comin-Anduix, Begoña; Ribas, Antoni

    2016-01-01

    Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA-4 antibody ipilimumab was terminated early due to substantial liver toxicities. MEK inhibitors can potentiate the MAPK inhibition in BRAF mutant cells, while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAFV600E driven melanoma, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors and improved in vivo cytotoxicity. Single agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and MHC expression, and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested combination of dabrafenib, trametinib with anti-PD1 therapy in SM1 tumors, and observed superior anti-tumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAFV600E mutant metastatic melanoma. PMID:25787767

  17. Encapsulation of trans-dehydrocrotonin in liposomes: an enhancement of the antitumor activity.

    PubMed

    Lapenda, T L S; Morais, W A; Almeida, F J F; Ferraz, M S; Lira, M C B; Santos, N P S; Maciel, M A M; Santos-Magalhães, N S

    2013-03-01

    The aim of this study was the encapsulation of trans-dehydrocrotonin (t-DCTN) and its inclusion complexes with hydropropyl-beta-cyclodextrin (HP-beta-CD) in liposomes to improve t-DCTN antitumor activity. The in vitro kinetic profiles of t-DCTN-loaded liposomes (LD) and t-DCTN:HP-beta-CD-loaded liposomes (LC) were evaluated using the dialysis technique. The antitumor activity of LD and LC were investigated against Sarcoma 180 in Swiss mice. Histopathological and hematological analyses were carried out. The amounts of t-DCTN and t-DCTN:HP-beta-CD inclusion complex encapsulated in liposomes were equivalent to 1 mg of t-DCTN. The encapsulation efficiencies of LD and LC were 95.0 +/- 3.8% and 91.1 +/- 5.6%, respectively. In relation to kinetics, the drug release profiles of t-DCTN are in substantial agreement with the Fickian model. The treatment of animals with LD and LC produced tumor inhibitions of 79.4 +/- 9.6% and 63.5 +/- 5.5%, respectively. The liposomal encapsulation of t-DCTN by entrapment in the phospholipid bilayer increased at twice the antitumor activity. Moreover, the liposomal formulations reduced the hepatotoxicity effect of the drug and no significant hematological toxicity was observed in the treated animals. However, the counting of platelets was slightly decreased. Thus, the results show that the development of liposomal formulations containing t-DCTN or t-DCTN:HP-beta-CD is an important advance for enabling this drug to be use in therapy.

  18. Evaluation of cytotoxic and anti-tumor activity of partially purified serine protease isolate from the Indian earthworm Pheretima posthuma

    PubMed Central

    Verma, Mahendra Kumar; Xavier, Francies; Verma, Yogendra Kumar; Sobha, Kota

    2013-01-01

    Objective To isolate, partially purify and evaluate the cytotoxic and antitumor activity of a serine protease from the chosen Indian earthworm Pheretima posthuma. Methods Whole animal extract was prepared and purified its protein constituents by size and charge based chromatographic separation techniques using Sephadex G-50 and DEAE-Cellulose resin respectively. Average molecular weight of the protein isolate was determined and analyzed for its cytotoxic property against Vero cells in different dilutions (1: 20 and 1: 40) and anti-tumor activity by MTT assay (a colorimetric assay) using breast cancer cell line MCF-7, with tamoxifen as standard. Results One of the protein constituents after purification was characterized as serine protease by Caseinolytic plate diffusion assay. Average molecular weight of this purified isolate was determined, by SDS-PAGE analysis with standard protein ladder, as of 15 kDa. The performed tests suggested that the 15kDa fraction has potent cytotoxic activity and satisfactory antitumor activity as well in vitro. Conclusions Exact molecular mechanism of the cytotoxic and antitumor activities is yet to be explored and currently we are working on ultra-purification and biophysical characterization of this fraction. Further investigation into the mechanism(s) of cytotoxic and antitumor activities at molecular level would be useful in treatment of various classes of cancer and viral infections in future.

  19. Peritonitis-induced antitumor activity of peritoneal macrophages from uremic patients.

    PubMed

    Turyna, Bohdan; Jurek, Aleksandra; Gotfryd, Kamil; Siaśkiewicz, Agnieszka; Kubit, Piotr; Klein, Andrzej

    2004-01-01

    The macrophages belong to the effector cells of both nonspecific and specific immune response. These cells generally express little cytotoxicity unless activated. The present work was intended to determine if peritoneal macrophages collected from patients on Continuous Ambulatory Peritoneal Dialysis (CAPD) during episodes of peritonitis were active against human tumor cell lines without further in vitro stimulation. We also compared macrophage antitumor potential with effectiveness of drugs used in cancer therapy (taxol and suramin). Conditioned medium (CM) of macrophages collected during inflammation-free periods did not exhibit cytostatic and cytotoxic activity against both tumor (A549 and HTB44) and non-transformed (BEAS-2B and CRL2190) cells. Exposure of tumor cells to CM of macrophages harvested during peritonitis resulted in significant suppression of proliferation, impairment of viability and induction of apoptosis, in contrast to non-transformed cells, which remained unaffected. The efficacy of CM of inflammatory macrophages as an antitumor agent appeared to be comparable to cytostatic and cytotoxic potency of taxol and suramin or, in the case of HTB44 cells, even higher. The results obtained suggest that activated human macrophages might represent a useful tool for cancer immunotherapy.

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

    PubMed

    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.

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

    PubMed Central

    Wang, Saiqi; Shi, Hongge; Wang, Junwei; Wang, Ran; Li, Yongmei; Dou, Yinhui; Liu, Ying; Hou, Guiqin; Ke, Yu; Liu, Hongmin

    2015-01-01

    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. PMID:26103161

  2. Screening for in vitro and in vivo antitumor activities of the mushroom Agaricus blazei.

    PubMed

    Ziliotto, Liane; Pinheiro, Fabriciano; Barbisan, Luís Fernando; Rodrigues, Maria Aparecida Marchesan

    2009-01-01

    We have investigated the in vitro antitumor activity of the mushroom Agaricus blazei Murill on human cancer cell lines as well as its potential anticancer activity in a model of rat colon carcinogenesis. The in vitro anticancer analysis was performed using 9 human cancer cell lines incubated with organic and aqueous extracts of A. blazei. Antitumor activity was observed with the dichloromethane/methanol and hexanic extracts of A. blazei at 250 mu g/ml for all cancer cell lines tested. No antiproliferative/cytotoxic activities were detected for the aqueous, methanol, ethyl acetate, or n-butanolic extracts. In the in vivo analysis, crude A. blazei was given orally after carcinogen treatment in a rat medium-term study (20 weeks) of colon carcinogenesis using aberrant crypt foci (ACF) as biomarker. Male Wistar rats were given dimethylhydrazine (DMH) and then were fed A. blazei at 5% in the diet until Week 20. ACF were scored for number and crypt multiplicity. A. blazei intake did not suppress ACF development or crypt multiplicity induced by DMH. No differences in tumor incidence in the colon were observed among the DMH-treated groups. Our results indicate that employing A. blazei in the diet does not have a suppressive effect on colon carcinogenesis.

  3. Antimicrobial, antibiofilm and antitumor activities of essential oil of Agastache rugosa from Xinjiang, China.

    PubMed

    Haiyan, Gong; Lijuan, He; Shaoyu, Li; Chen, Zhang; Ashraf, Muhammad Aqeel

    2016-07-01

    In the study, we evaluated chemical composition and antimicrobial, antibiofilm, and antitumor activities of essential oils from dried leaf essential oil of leaf and flower of Agastache rugosa for the first time. Essential oil of leaf and flower was evaluated with GC and GC-MS methods, and the essential oil of flower revealed the presence of 21 components, whose major compounds were pulegone (34.1%), estragole (29.5%), and p-Menthan-3-one (19.2%). 26 components from essential oil of leaf were identified, the major compounds were p-Menthan-3-one (48.8%) and estragole (20.8%). At the same time, essential oil of leaf, there is a very effective antimicrobial activity with MIC ranging from 9.4 to 42 μg ml(-1) and potential antibiofilm, antitumor activities for essential oils of flower and leaf essential oil of leaf. The study highlighted the diversity in two different parts of A. rugosa grown in Xinjiang region and other places, which have different active constituents. Our results showed that this native plant may be a good candidate for further biological and pharmacological investigations.

  4. Apigenin sensitizes colon cancer cells to anti-tumor activity of ABT-263

    PubMed Central

    Shao, Huanjie; Jing, Kai; Mahmoud, Esraa; Huang, Haihong; Fang, Xianjun; Yu, Chunrong

    2013-01-01

    Apigenin is an edible plant-derived flavonoid that shows modest anti-tumor activities in vitro and in vivo. Apigenin treatment resulted in cell growth arrest and apoptosis in various types of tumors by modulating several signaling pathways. In the present study, we evaluated interactions between apigenin and ABT-263 in colon cancer cells. We observed a synergistic effect between apigenin and ABT-263 on apoptosis of colon cancer cells. ABT-263 alone induced limited cell death while upregulating expression of Mcl-1, a potential mechanism for the acquired resistance to ABT-263. The presence of apigenin antagonized ABT-263-induced Mcl-1 upregulation and dramatically enhanced ABT-263-induced cell death. Meanwhile, apigenin suppressed AKT and ERK activation. Inactivation of either AKT or ERK by lentivirus-transduced shRNA or treatment with specific small molecule inhibitors of these pathways enhanced ABT-263-induced cell death, mirroring the effect of apigenin. Moreover, the combination response was associated with upregulation of Bim and activation of Bax. Downregulation of Bax eliminated the synergistic effect of apigenin and ABT-263 on cell death. Xenograft studies in SCID mice showed that the combined treatment with apigenin and ABT-263 inhibited tumor growth by up to 70% without obvious adverse effects, while either agent only inhibited around 30%. Our results demonstrate a novel strategy to enhance ABT-263 induced anti-tumor activity in human colon cancer cells by apigenin via inhibition of the Mcl-1, AKT and ERK pro-survival regulators. PMID:24126433

  5. In vitro antitumor activity of silybin nanosuspension in PC-3 cells.

    PubMed

    Zheng, Dandan; Wang, Yancai; Zhang, Dianrui; Liu, Zhaoping; Duan, Cunxian; Jia, Lejiao; Wang, Feihu; Liu, Yue; Liu, Guangpu; Hao, Leilei; Zhang, Qiang

    2011-08-28

    The present study aims to evaluate the antitumor activity of silybin nanosuspension on human prostatic carcinoma PC-3 cell line in vitro. Silybin nanosuspension was prepared by the high pressure homogenization (HPH) method. MTT assay, observation of morphological changes and apoptotic body showed that silybin nanosuspension could significantly enhance the in vitro cytotoxicity against PC-3 cells compared to the silybin solution. Flow cytometric (FCM) analysis demonstrated that silybin nanosuspension induced G1 cycle arrest and apoptosis in PC-3 cells. Thereby, the overall results suggest that the silybin nanosuspension represents a potential source of medicine for the treatment of human prostate cancer.

  6. Necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy

    PubMed Central

    Wu, Zhi-Qiang; Shi, Yang-Yang; Zaorsky, Nicholas G.; Deng, Lei; Yuan, Zhi-Yong; Lu, You; Wang, Ping

    2016-01-01

    While the mechanisms underlying apoptosis and autophagy have been well characterized over recent decades, another regulated cell death event, necroptosis, remains poorly understood. Elucidating the signaling networks involved in the regulation of necroptosis may allow this form of regulated cell death to be exploited for diagnosis and treatment of cancer, and will contribute to the understanding of the complex tumor microenvironment. In this review, we have summarized the mechanisms and regulation of necroptosis, the converging and diverging features of necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy, as well as attempts to exploit this newly gained knowledge to provide therapeutics for cancer. PMID:27429198

  7. Anti-tumor activity of arginine deiminase via arginine deprivation in retinoblastoma.

    PubMed

    Kim, Jeong Hun; Kim, Jin Hyoung; Yu, Young Suk; Kim, Dong Hun; Min, Bon-Hong; Kim, Kyu-Won

    2007-12-01

    In spite of recent advances in the treatment of retinoblastoma, chemotherapy is still challenging in high-stage intraocular retinoblastoma or metastatic retinoblastoma. Here, we investigated whether arginine deprivation via arginine deiminase (ADI) could be a new anti-tumor therapy in retinoblastoma cells. Expression of argininosuccinate synthetase (ASS) was detected in human retinoblastoma tissues. Even with a high expression of ASS, ADI effectively inhibited the proliferation of retinoblastoma cells and induced retinoblastoma cell death in a dose-dependent manner. These results indicate that arginine deprivation via ADI could be another treatment option for retinoblastoma due to low ASS activity in retinoblastoma cells.

  8. Synthesis of novel psoralen analogues and their in vitro antitumor activity.

    PubMed

    Francisco, Carla S; Rodrigues, Lígia R; Cerqueira, Nuno M F S A; Oliveira-Campos, Ana M F; Rodrigues, Lígia M; Esteves, Ana P

    2013-09-01

    New tetracyclic benzofurocoumarin (benzopsoralen) analogues were synthesized and their inhibitory effect on the growth of tumor cell lines was evaluated. The human tumor cell lines used were MDA MB231 (breast adenocarcinoma), HeLa (cervix adenocarcinoma) and TCC-SUP (bladder transitional cell carcinoma). The in vitro antitumor activity of the new benzopsoralens was discussed in terms of structure-activity relationship. Molecular docking studies with human-CYP2A6 enzymes were also carried out with the synthesized compounds in order to evaluate the potential of these compounds to interact with the heme group of the enzymes. The results have demonstrated that the linear compounds have the most pronounced activity against tumor cell lines and this might be related to the better accessibility that these compounds have to the active site in relation to the angular ones that have shown in the majority of the cases multiple binding poses in the active site of CYP2A6.

  9. Tumor-Specific Peptide, Selected from a Phage Peptide Library, Enhances Antitumor Activity of Lactaptin

    PubMed Central

    Makartsova, Anna A.; Fomin, Alexandr S.; Nushtaeva, Anna A.; Koval, Olga A.

    2016-01-01

    A recombinant analogue of lactaptin (RL2), a new potential anticancer molecule, induces apoptosis in cultured tumor cells. The tumor suppression efficacy of RL2 was shown against mouse hepatoma-1 cells and MDA-MB-231 human breast adenocarcinoma cells. The RL2-based therapeutic drug lactaptin is distributed evenly throughout the organism, which reduces its antitumor efficacy. In the current study, we obtained a genetic construct that allows production of the recombinant fusion protein T3-RL2, consisting of RL2 and T3 peptide (YTYDPWLIFPAN), in E. coli cells. T3 peptide was selected from a phage peptide library as a result of two screenings: in vitro using MDA-MB-231 cell culture and in vivo using a mouse xenograft model of breast cancer MDA-MB-231. It was shown that the displayed peptide T3 provides binding and internalization of phage particles by MDA-MB-231 cells and their specific accumulation in MDA-MB-231 tumor tissue. In addition, based on the nucleotide sequences coding RL2 and the known tumor-targeting peptide iRGD, we obtained genetic constructs that provide synthesis of fusion proteins RL2-iRGD and RL-iRGD-His. We studied the cytotoxic activity of fusion proteins T3-RL2, RL2-iRGD and RL-iRGD-His in vitro using MDA-MB-231 and MCF-7 human adenocarcinoma cells. The in vitro results showed that the fusion proteins inhibit proliferation of both cell cultures, and their cytotoxic activity is higher than that of RL2. In vivo experiments on the study of the antitumor efficacy of the obtained fusion proteins demonstrated that T3-RL2 protein significantly inhibits MDA-MB-231 tumor growth in a xenograft model compared with RL2, while the antitumor effect of RL2-iRGD and RL-iRGD-His proteins is comparable to the effect of RL2. PMID:27513518

  10. Preclinical antitumor activity of SST0116CL1: a novel heat shock protein 90 inhibitor.

    PubMed

    Vesci, Loredana; Milazzo, Ferdinando Maria; Carollo, Valeria; Pace, Silvia; Giannini, Giuseppe

    2014-10-01

    4-Amino substituted resorcino-isoxazole (SST0116CL1) (property of Sigma-Tau Research Switzerland S.A.) is a potent, second generation, small-molecule heat shock protein 90 inhibitor (Hsp90i). SST0116CL1 binds to the ATP binding pocket of Hsp90, and interferes with Hsp90 chaperone function thus resulting in client protein degradation and tumor growth inhibition. The aim of the study was to assess SST0116CL1 in various solid and haematological tumors. The antitumor properties of SST0116CL1 were assessed using in vitro cell proliferation and client protein degradation assays and in vivo different tumor xenograft models. Pharmacokinetic (PK) data were also generated in tumor-bearing mice to gain an understanding of optimal dosing schedules and regimens. SST0116CL1 was shown to inhibit recombinant Hsp90α and to induce the destabilization of different client proteins, often overexpressed and constitutively activated in different types of hematological or solid human tumors. In preclinical in vivo studies, it was revealed to induce antitumor effects in murine models of leukemia and of gastric and ovarian carcinoma. A modulation of PD biomarkers in terms of downregulation of Hsp90 client proteins in tumor-bearing mice was found. SST0116CL1 is a new clinical candidate for cancer therapy. The antitumor property of SST0116CL1, likely due to direct inhibition of the Hsp90 enzymatic activity, may prove to be a critical attribute as the compound enters phase I clinical trials.

  11. Biodegradable nanoassemblies of piperlongumine display enhanced anti-angiogenesis and anti-tumor activities

    NASA Astrophysics Data System (ADS)

    Liu, Yuanyuan; Chang, Ying; Yang, Chao; Sang, Zitai; Yang, Tao; Ang, Wei; Ye, Weiwei; Wei, Yuquan; Gong, Changyang; Luo, Youfu

    2014-03-01

    Piperlongumine (PL) shows an inhibitory effect on tumor growth; however, lipophilicity has restricted its further applications. Nanotechnology provides an effective method to overcome the poor water solubility of lipophilic drugs. Polymeric micelles with small particle size can passively target tumors by the enhanced permeability and retention (EPR) effect, thus improving their anti-tumor effects. In this study, to improve the water solubility and anti-tumor activity of PL, PL encapsulated polymeric micelles (PL micelles) were prepared by a solid dispersion method. The prepared PL micelles showed a small particle size and high encapsulation efficiency, which could be lyophilized into powder, and the re-dissolved PL micelles are homogenous and stable in water. In addition, a sustained release behavior of PL micelles was observed in vitro. Encapsulation of PL into polymeric micelles could increase the cytotoxicity, cellular uptake, reactive oxygen species (ROS) and oxidized glutathione (GSSG), and reduce glutathione (GSH) levels in vitro. Encapsulation of PL into polymeric micelles enhanced its inhibitory effect on neovascularization both in vitro and in vivo. Compared with free PL, PL micelles showed a stronger inhibitory effect on the proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). Additionally, in a transgenic zebrafish model, embryonic angiogenesis was inhibited by PL micelles. Furthermore, PL micelles were more effective in inhibiting tumor growth and prolonging survival in a subcutaneous CT-26 murine tumor model in vivo. Therefore, our data revealed that the encapsulation of PL into biodegradable polymeric micelles enhanced its anti-angiogenesis and anti-tumor activities both in vitro and in vivo.

  12. In vitro and in vivo antitumor activity of scutebarbatine A on human lung carcinoma A549 cell lines.

    PubMed

    Yang, Xiao-Kun; Xu, Ming-Yuan; Xu, Gui-Sen; Zhang, Yu-Lan; Xu, Zhao-Xia

    2014-06-25

    During our systematic study on the anticancer activities of Scutellaria barbata, scutebarbatine A (SBT-A), one of the major alkaloids in S. barbata, was found to have antitumor effects on A549 cells. Thus, we designed the present study to investigate in detail the antitumor effects of SBT-A. The cytotoxic effect of SBT-A on A549 in vitro were determined by an MTT assay and evaluated by IC50 values. Furthermore, results of Hoechst 33258 and Annexin V/PI staining assays demonstrated that SBT-A had significant antitumor effects on A549 cells via apoptosis, in a concentration-dependent manner. What's more, the mechanism was explored by western blotting, and our study revealed that SBT-A can up-regulate the expressions of cytochrome c, caspase-3 and 9, and down-regulate the levels of Bcl-2 in A549 cells. Finally, the antitumor effects of SBT-A were evaluated in vivo by using transplanted tumor nude mice, and the results confirmed that SBT-A has a notable antitumor effect on A549 cancer via mitochondria-mediated apoptosis. Collectively, our results demonstrated that SBT-A showed significant antitumor effects on A549 cells in vivo and in vitro via mitochondria-mediated apoptosis by up-regulating expressions of caspase-3 and 9, and down-regulating Bcl-2.

  13. Purification, characterization, and antitumor activity of a novel glucan from the fruiting bodies of Coriolus Versicolor

    PubMed Central

    Awadasseid, Annoor; Hou, Jie; Gamallat, Yaser; Xueqi, Shang; Eugene, Kuugbee D.; Musa Hago, Ahmed; Bamba, Djibril; Meyiah, Abdo; Gift, Chiwala; Xin, Yi

    2017-01-01

    Cancer is one of the most common causes of deaths worldwide. Herein, we report an efficient natural anticancer glucan (CVG) extracted from Coriolus Versicolar (CV). CVG was extracted by the hot water extraction method followed by ethanol precipitation and purified using gas exclusion chromatography. Structural analysis revealed that CVG has a linear α-glucan chain composed of only (1→ 6)-α-D-Glcp. The antitumor activity of CVG on Sarcoma-180 cells was investigated in vitro and in vivo. Mice were treated with three doses of CVG (40, 100, 200 mg/kg body weight) for 9 days. Tumor weight, relative spleen, thymus weight, and lymphocyte proliferation were studied. A significant increase (P< 0.01) in relative spleen and thymus weight and a decrease (P< 0.01) in tumor weight at the doses of 100 and 200 mg/kg were observed. The results obtained demonstrate CVG has antitumor activity towards Sarcoma-180 cells by its immunomodulation activity. PMID:28178285

  14. Antitumor Activity of Garcinol in Human Prostate Cancer Cells and Xenograft Mice.

    PubMed

    Wang, Yu; Tsai, Mei-Ling; Chiou, Li-Yu; Ho, Chi-Tang; Pan, Min-Hsiung

    2015-10-21

    Garcinol, which is isolated from fruit rinds of Garcinia indica, is a polyisoprenylated benzophenone. It has been studied for its antitumor activity by inducing apoptosis and inhibiting autophagy in human prostate cancer cells. The Bax/Bcl-2 ratio increased when garcinol was applied to PC-3 cells indicating a presence of apoptosis. Meanwhile, procaspases-9 and -3 were suppressed with attenuating PARP and DFF-45. Autophagy was inhibited through activating p-mTOR and p-PI3 Kinase/AKT by garcinol, which as a result induced the cells to apoptosis directly. In addition, the apoptosis effect of garcinol in a xenograft mouse model was also tested, suggesting a consistent result with PC-3 cell model. The tumor size was reduced more than 80 percent after the mouse accepted the garcinol treatment. Garcinol was demonstrated to have a strong antitumor activity through inhibiting autophagy and inducing apoptosis, which was discovered for the first time. Based on these findings, our data suggests that garcinol deserves further investigation as a potent chemopreventive agent.

  15. A natural diterpenoid kamebacetal A with anti-tumor activity: Theoretical and experimental study

    NASA Astrophysics Data System (ADS)

    Wang, Tao; Tang, Fu-ming; Zhang, Yi-Heng; Chen, Zhong

    2010-06-01

    Kamebacetal A ( 1) is an ent-kaurane diterpenoid isolated from Isodon racemosa (Hemsl) Hara. This natural product exhibits significant cytotoxicity against human Bel-7402 and HO-8910 tumor cells. The geometrical conformation of 1 has been optimized at the B3LYP/6-311+G(d) level of theory. The results indicated that the calculated geometric parameters are close to the X-ray crystal structure. The theoretical 13C NMR chemical shifts of 1 were also calculated at the GIAO-B3LYP level of theory with different basis sets. The calculated NMR chemical shifts are in closer agreement with the experimental results. A molecular electrostatic potential (MEP) map was used in an attempt to identify key features of the kamebacetal A to account for its anti-tumor activity. MEP investigations reveal that compound 1, which shows anti-tumor activity, possesses electron-rich regions that extend over the hydroxyl and carbonyl groups of compound 1. The data generated in this study is valuable as it provides an insight into kamebacetal A molecular and structure-activity relationships.

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

    NASA Astrophysics Data System (ADS)

    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.

  17. Characterization, antioxidant and antitumor activities of polysaccharides from purple sweet potato.

    PubMed

    Wu, Qiongying; Qu, Hongsen; Jia, Junqiang; Kuang, Cong; Wen, Yan; Yan, Hui; Gui, Zhongzheng

    2015-11-05

    Three polysaccharides, PSPP1-1, PSPP2-1 and PSPP3-1, were isolated from purple sweet potato. The three polysaccharides belonged to β-type polysaccharides and contained low proportions of proteins and uronic acids. PSPP1-1 and PSPP3-1 with molecular weights of 33.3 and 75.3 kDa, respectively, were composed of rhamnose, xylose, glucose and galactose, whereas PSPP2-1 with molecular weight of 17.8 kDa was composed of rhamnose and galactose. The three polysaccharides possessed in vitro antioxidant (scavenging DPPH radicals, chelating ferrous ions and reducing power) and antitumor activities (against SGC7901 and SW620 cells) in a dose-dependent manner. Among the three polysaccharides, PSPP2-1 exhibited the strongest reducing power, scavenging activity on DPPH radicals and chelating capability on ferrous ions. PSPP1-1 showed the strongest inhibitory activities on the growth of SGC7901 and SW620 cells. In addition, flow cytometry results showed that PSPP1-1 could induce apoptosis in SGC7901 and SW620 cells. These results suggest that polysaccharides from purple sweet potato are potential natural antioxidant and antitumor agents that can be used as drugs or functional food ingredients.

  18. Selenium-dependent antitumor immunomodulating activity of polysaccharides from roots of A. membranaceus.

    PubMed

    Li, Shuang; Bian, Fuling; Yue, Ling; Jin, Hua; Hong, Zongguo; Shu, Guangwen

    2014-08-01

    Roots of Astragalus membranaceus (Fish.) Bge. var. mongholicus (Bge.) Hsiao (A. membranaceus) have been long used as an auxiliary reagent supporting cancer treatment. Here, we compared the chemical composition and antitumor immunomodulating activity of polysaccharides from roots of A. membranaceus (PAMs) from five major habitats in Inner Mongolia, PR China. We revealed that compositions of monosaccharides and amino acids were comparable among PAMs from different habitats. However, amounts of selenium varied widely in roots of A. membranaceus and PAMs. PAMs selenium-dependently repressed the in vivo proliferation of transplanted H22 ascitic hepatoma and S180 sarcoma cells with low toxic impacts on tumor-bearing mice. Selenium-containing PAMs ameliorated host CD4+ T cell apoptosis and serum cytokine dysregulation induced by tumor transplantation, leading to the enhancement of cytotoxic activities of natural killer and CD8+ T cells. Moreover, PAMs also selenium-dependently improved the phagocytotic function of intra-abdominal macrophages and suppressed M2-like polarization of tumor-associated macrophages. These data suggested that the selenium content varies in the roots of A. membranaceus and PAMs from different geographical origins dramatically and selenium is an important contributor to the antitumor immunomodulation activities of PAMs.

  19. Antitumoral activity of snake venom proteins: new trends in cancer therapy.

    PubMed

    Calderon, Leonardo A; Sobrinho, Juliana C; Zaqueo, Kayena D; de Moura, Andrea A; Grabner, Amy N; Mazzi, Maurício V; Marcussi, Silvana; Nomizo, Auro; Fernandes, Carla F C; Zuliani, Juliana P; Carvalho, Bruna M A; da Silva, Saulo L; Stábeli, Rodrigo G; Soares, Andreimar M

    2014-01-01

    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.

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

    PubMed Central

    Calderon, Leonardo A.; Sobrinho, Juliana C.; Zaqueo, Kayena D.; de Moura, Andrea A.; Grabner, Amy N.; Mazzi, Maurício V.; Marcussi, Silvana; Fernandes, Carla F. C.; Zuliani, Juliana P.; Carvalho, Bruna M. A.; da Silva, Saulo L.; Stábeli, Rodrigo G.; Soares, Andreimar M.

    2014-01-01

    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. PMID:24683541

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

    PubMed

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

    2016-09-01

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

  2. Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities.

    PubMed

    Yoon, Yeong Keng; Ali, Mohamed Ashraf; Wei, Ang Chee; Choon, Tan Soo; Osman, Hasnah; Parang, Keykavous; Shirazi, Amir Nasrolahi

    2014-01-15

    A total of 15 novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. All compounds showed better inhibition on SIRT2 as compared to SIRT1. Among these, compound 5j displayed the best inhibitory activity for SIRT1 (IC50=58.43μM) as well as for SIRT2 (IC50=45.12μM). Cell cytotoxicity assays also showed that compound 5j possesses good antitumor activity against two different cancer cell lines derived from breast cancer (MCF-7 and MDA-MB-468). A simple structure-activity-relationship (SAR) study of the newly synthesized benzimidazole derivatives was also discussed.

  3. Role of chitosan co-formulation in enhancing interleukin-12 delivery and antitumor activity

    PubMed Central

    Yang, Lirong; Zaharoff, David A.

    2013-01-01

    Local delivery systems that provide sustained, high concentrations of antitumor cytokines in the tumor microenvironment while minimizing systemic dissemination are needed to realize the potential of cytokine-based immunotherapies. Recently, co-formulations of cytokines with chitosan solutions have been shown to increase local cytokine retention and bioactivity. In particular, intratumoral (i.t.) injections of chitosan/IL-12 can eliminate established tumors and generate tumor-specific immune responses. In the present study, we explored the mechanisms by which chitosan potentiated IL-12’s antitumor activity. The location of chitosan/IL-12 injection was found to be critical for optimal cytokine delivery. I.t. injections eliminated 9 of 10 MC38 adenocarcinomas while contralateral and peritumoral injections delayed tumor growth but could not eliminate tumors. Microdosing studies demonstrated that IL-12 depots, simulated through daily i.t. injections with IL-12 alone, were not as effective as weekly i.t. chitosan/IL-12. 50–75% of mice receiving daily IL-12 microdoses and 87.5% of mice receiving weekly chitosan/IL-12 were cured of MC38 tumors. Chitosan was found to increase IL-12-mediated leukocytic expansion in tumors and tumor-draining lymph nodes (TDLNs) by 40% and 100%, respectively. Immunophenotyping studies demonstrated that chitosan co-formulation amplified IL-12-induced increases in important effector populations, such as CD8+IFN-γ+ and NKT cells, in tumors and dendritic cell populations in TDLNs. Remarkable increases in Gr-1+CD11b+ tumor infiltrates were also observed in mice receiving chitosan or chitosan/IL-12. This population does not appear be suppressive and may facilitate the local antitumor response. Presented data suggest that chitosan-mediated depot formation and enhanced local cytokine retention is significantly, but not entirely, responsible for increased cytokine bioactivity. PMID:23453060

  4. Irradiation enhances dendritic cell potential antitumor activity by inducing tumor cell expressing TNF-α.

    PubMed

    Chang, Lijia; Zhang, Zhengzheng; Chen, Fang; Zhang, Wen; Song, Shuang; Song, Shuxia

    2017-03-01

    Dendritic cells (DCs)-based tumor vaccines have shown to be the promising methods for inducing therapeutic antitumor response. However, DCs alone rarely carry curative antitumor activity, and the immunosuppressive microenvironment may contribute to this defect of DC vaccinal function. Irradiation in combination with DCs has been shown to promote immune-mediated tumor destruction in preclinical studies. However, little is known about how irradiation alters the tumor microenvironment, and what host pathways modulate the activity of administrated DCs. In this study, BALB/c mice and the 4T1 breast cancer cell line were used in a tumor-bearing model. The tumor-bearing mice were irradiated locally up to 10 Gy for 3 consecutive days or a single dose of 30 Gy using a cesium source. Studies of dynamic change of the tumor microenvironment in irradiated versus untreated tumors revealed that there was no obvious change on IL-10, IL-6 and TGF-β expression or production, whereas increased TNF-α level within the first 2 weeks of irradiation. The increased TNF-α level is exactly right timing window for DCs injection, corresponding to the significant elevation of intratumoral CD8(+) T infiltration and the regression of tumor size. With attention to scheduling, combination X-ray with DCs i.t. injection may offer a practical strategy to improve treatment outcomes.

  5. Dual subcellular compartment delivery of doxorubicin to overcome drug resistant and enhance antitumor activity

    PubMed Central

    Song, Yan-feng; Liu, Dao-zhou; Cheng, Ying; Liu, Miao; Ye, Wei-liang; Zhang, Bang-le; Liu, Xin-you; Zhou, Si-yuan

    2015-01-01

    In order to overcome drug resistant and enhance antitumor activity of DOX, a new pH-sensitive micelle (DOX/DQA-DOX@DSPE-hyd-PEG-AA) was prepared to simultaneously deliver DOX to nucleus and mitochondria. Drug released from DOX/DQA-DOX@DSPE-hyd-PEG-AA showed a pH-dependent manner. DOX/DQA-DOX@DSPE-hyd-PEG-AA induced the depolarization of mitochondria and apoptosis in MDA-MB-231/ADR cells and A549 cells, which resulted in the high cytotoxicity of DOX/DQA-DOX@DSPE-hyd-PEG-AA against MDA-MB-231/ADR cells and A549 cells. Confocal microscopy confirmed that DOX/DQA-DOX@DSPE-hyd-PEG-AA simultaneously delivered DQA-DOX and DOX to the mitochondria and nucleus of tumor cell. After DOX/DQA-DOX@DSPE-hyd-PEG-AA was injected to the tumor-bearing nude mice by the tail vein, DOX was mainly found in tumor tissue. But DOX was widely distributed in the whole body after the administration of free DOX. Compared with free DOX, the same dose of DOX/DQA-DOX@DSPE-hyd-PEG-AA significantly inhibited the growth of DOX-resistant tumor in tumor-bearing mice without obvious systemic toxicity. Therefore, dual subcellular compartment delivery of DOX greatly enhanced the antitumor activity of DOX on DOX-resistant tumor. DOX/DQA-DOX@DSPE-hyd-PEG-AA has the potential in target therapy for DOX-resistant tumor. PMID:26530454

  6. Negative Impact of Total Body Irradiation on the Antitumor Activity of Rhenium-(I)-diselenoether.

    PubMed

    Collery, Philippe; Santoni, Francois; Mohsen, Ahmed; Mignard, Caroline; Desmaele, Didier

    2016-11-01

    It has been shown that a rhenium-(I)-diselenoether complex had significant antitumor activity in MDA-MB231 tumor-bearing mice after repeated oral or intraperitoneal administrations for 4 weeks at safe doses of 10 mg/kg/day. It has also been suggested that lower doses could be as effective as this dose. We, thus, tested two doses (5 and 10 mg/kg). The drug was orally administered daily by gavage for 4 weeks and for a further 2 weeks with or without 15 mg/kg paclitaxel treatment (intravenously, once a week). This experiment was performed in MDA-MB 231 tumor-bearing mice, as a model of resistant breast tumor. However, in contrast to previous studies, the mice were pretreated with total body irradiation to increase the tumor growth. These two doses were safe, even in combination with paclitaxel. The expected tumor regression was not observed with the rhenium-(I)-diselenoether complex, and there was even a significant increase of the tumor volume in mice treated with 10 mg/kg versus controls. No synergism was observed with paclitaxel. We comment on the possible negative impact of radiotherapy on the antitumor activity of the drug. Plasma and tumor rhenium and selenium concentrations are also reported.

  7. The effect of N-acetylcysteine on the antitumor activity of ifosfamide.

    PubMed

    Chen, Nancy; Hanly, Lauren; Rieder, Michael; Yeger, Herman; Koren, Gideon

    2011-05-01

    Ifosfamide-induced nephrotoxicity is a serious adverse effect in children undergoing chemotherapy. Our previous cell and rodent models have shown that the antioxidant N-acetylcysteine (NAC), used extensively as an antidote for acetaminophen poisoning, protects renal tubular cells from ifosfamide-induced nephrotoxicity at a clinically relevant concentration. For the use of NAC to be clinically relevant in preventing ifosfamide nephrotoxicity, we must ensure there is no effect of NAC on the antitumor activity of ifosfamide. Common pediatric tumors that are sensitive to ifosfamide, human neuroblastoma SK-N-BE(2) and rhabdomyosarcoma RD114-B cells, received either no pretreatment or pretreatment with 400 µmol/L of NAC, followed by concurrent treatment with NAC and either ifosfamide or the active agent ifosfamide mustard. Ifosfamide mustard significantly decreased the growth of both cancer cell lines in a dose-dependent manner (p < 0.001). The different combined treatments of NAC alone, sodium 2-mercaptoethanesulfonate alone, or NAC plus sodium 2-mercaptoethanesulfonate did not significantly interfere with the tumor cytotoxic effect of ifosfamide mustard. These observations suggest that NAC may improve the risk/benefit ratio of ifosfamide by decreasing ifosfamide-induced nephrotoxicity without interfering with its antitumor effect in cancer cells clinically treated with ifosfamide.

  8. Gemcitabine-loaded PEGylated unilamellar liposomes vs GEMZAR: biodistribution, pharmacokinetic features and in vivo antitumor activity.

    PubMed

    Paolino, Donatella; Cosco, Donato; Racanicchi, Leda; Trapasso, Elena; Celia, Christian; Iannone, Michelangelo; Puxeddu, Efisio; Costante, Giuseppe; Filetti, Sebastiano; Russo, Diego; Fresta, Massimo

    2010-06-01

    The systemic efficacy of the chemotherapeutic agents presently used to treat solid tumors is limited by their low therapeutic index. Previously, our research group improved the in vitro antitumoral activity of gemcitabine, an anticancer agent rapidly deaminated to the inactive metabolite 2',2'-difluorodeoxyuridine, entrapping it into unilamellar pegylated liposomes made up of 1,2-dipalmitoyl-snglycero-3-phosphocholine monohydrate/cholesterol/N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (6:3:1 molar ratio). In this work, we investigated the in vivo efficiency of the gemcitabine liposomal formulation (5mg/kg) with respect to the antitumoral commercial product GEMZAR (50mg/kg) on an anaplastic thyroid carcinoma xenograft model obtaining similar effects in terms of inhibition of tumor mass proliferation after 4weeks of treatment. The investigation of the carrier biodistribution and the drug pharmacokinetic profile furnished the rationalization of the efficacy of the vesicular system containing the active compound 10-fold less concentrated; in fact, liposomes promoted the concentration of the drug inside the tumor and they increased its plasmatic half-life. In addition, no signs of blood toxicity were observed when vesicular devices of effective doses of the drug were used.

  9. Antitumor activity of TNF-α after intratumoral injection using an in situ thermosensitive hydrogel.

    PubMed

    Xu, Yourui; Shen, Yan; Ouahab, Ammar; Li, Chang; Xiong, Yerong; Tu, Jiasheng

    2015-03-01

    Local drug delivery strategies based on nanoparticles, gels, polymeric films, rods and wafers are increasingly used in cancer chemotherapy in order to enhance therapeutic effect and reduce systemic toxicity. Herein, a biodegradable and biocompatible in situ thermosensitive hydrogel was designed and employed to deliver tumor necrosis factor-α (TNF-α) locally by intratumoral injection. The triblock copolymer was synthesized by ring-opening polymerization (ROP) of β-butyrolactone (β-BL) and lactide (LA) in bulk using polyethylene glycol (PEG) as an initiator and Sn(Oct)2 as the catalyst, the polymer was characterized by NMR, gel permeation chromatography and differential scanning calorimetry. Blood and tumor pharmacokinetics and in vivo antitumor activity of TNF-α after intratumoral administration in hydrogel or solution with the same dose were evaluated on S180 tumor-bearing mice. Compared with TNF-α solution, TNF-α hydrogel exhibited a longer T1/2 (4-fold) and higher AUCtumor (19-fold), but Cmax was lower (0.5-fold), which means that the hydrogel formulation improved the efficacy with a lower systhemic exposure than the solution formation. In addition, TNF-α hydrogel improved the antitumor activity and survival due to lower systemic exposure than the solution. These results demonstrate that the in situ thermosensitive hydrogel-based local delivery system by intratumoral injection is well suited for the administration of TNF-α.

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

    PubMed

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

    2004-12-01

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

  11. Antitumor and antioxidant activity of protocatechualdehyde produced from Streptomyces lincolnensis M-20.

    PubMed

    Kim, Kyoung-Ja; Kim, Mi-Ae; Jung, Jee-Hyung

    2008-12-01

    We characterized the biological functions of protocatechualdehyde (PA) isolated from the butanol extract of culture supernatant from Streptomyces lincolnensis M-20. Following butanol extraction, it was purified by silica gel and Sephadex LH-20 column chromatography. PA was analyzed by Furier Transform Infrared Spectroscopy (FT-IR), Gas chromatograph-Mass Spectrometer (GC-MS), and Nuclear Magnetic Resonance (NMR). PA had potent antioxidant activity, as measured by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity. Antitumor activity against MCF-7 human breast cancer cells was evaluated by the 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyl tetrazolium-bromide (MTT) assay. PA treatment (0 approximately 150 muM) dose-dependently blocked apoptosis, as shown by improved cell viability and inter-nucleosomal DNA fragmentation. Our findings suggest that Streptomyces lincolnensis M-20, a lincomycin producer, also produces protocatechualdehyde.

  12. Antitumor activity of palmitic acid found as a selective cytotoxic substance in a marine red alga.

    PubMed

    Harada, Hideki; Yamashita, Uki; Kurihara, Hideyuki; Fukushi, Eri; Kawabata, Jun; Kamei, Yuto

    2002-01-01

    In a previous report, we discussed an extract from a marine red alga, Amphiroa zonata, which shows selective cytotoxic activity to human leukemic cells, but no cytotoxicity to normal human dermal fibroblast (HDF) cells in vitro. In this study, we identified palmitic acid, a selective cytotoxic substance from the marine algal extract, and investigated its biological activities. At concentrations ranging from 12.5 to 50 micrograms/ml, palmitic acid shows selective cytotoxicity to human leukemic cells, but no cytotoxicity to normal HDF cells. Furthermore, palmitic acid induces apoptosis in the human leukemic cell line MOLT-4 at 50 micrograms/ml. Palmitic acid also shows in vivo antitumor activity in mice. One molecular target of palmitic acid in tumor cells is DNA topoisomerase I, however, interestingly, it does not affect DNA topoisomerase II, suggesting that palmitic acid may be a lead compound of anticancer drugs.

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

    PubMed

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

    2015-12-01

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

  14. Synthesis of 1-substituted 3-aryl-5-aryl(hetaryl)-2-pyrazolines and study of their antitumor activity.

    PubMed

    Insuasty, Braulio; Chamizo, Leidy; Muñoz, Jhon; Tigreros, Alexis; Quiroga, Jairo; Abonía, Rodrigo; Nogueras, Manuel; Cobo, Justo

    2012-04-01

    Three series of novel 1,3,5-trisubstituted 2-pyrazoline derivatives containing thiophene and benzodioxol moieties as potential antitumor agents were synthesized. The in vitro antitumor activity of the obtained compounds was determined at the National Cancer Institute (NCI). The 5-(benzo[d][1,3]dioxol-5-yl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (9a) is the most prominent of the compounds due to its remarkable activity toward leukemia (RPMI-8226), renal cancer (UO-31) and prostate cancer (DU-145) cell lines with GI(50) values of 1.88, 1.91 and 1.94 µM, respectively.

  15. Antibody Complementarity-Determining Regions (CDRs) Can Display Differential Antimicrobial, Antiviral and Antitumor Activities

    PubMed Central

    Polonelli, Luciano; Pontón, José; Elguezabal, Natalia; Moragues, María Dolores; Casoli, Claudio; Pilotti, Elisabetta; Ronzi, Paola; Dobroff, Andrey S.; Rodrigues, Elaine G.; Juliano, Maria A.; Maffei, Domenico Leonardo; Magliani, Walter; Conti, Stefania; Travassos, Luiz R.

    2008-01-01

    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 sized synthetic

  16. Antitumor activity of opiorphin, sialorphin and their conjugates with a peptide klaklakklaklak.

    PubMed

    Kamysz, Elżbieta; Smolarczyk, Ryszard; Cichoń, Tomasz; Jarosz-Biej, Magdalena; Sikorska, Emilia; Sobocińska, Małgorzata; Jaśkiewicz, Maciej; Kamysz, Wojciech

    2016-11-01

    This is the study on the effect of opiorphin, sialorphin and their analogs on antitumor activity. We demonstrated that conjugation of opiorphin and sialorphin with a proapoptotic, antimicrobial peptide klak (klaklakklaklak) led to compounds (opio-klak and sialo-klak) that were cytotoxic against cancer cells (LN18, PC3, A549, HCT116 and B10-F16) in the MTT test. The conjugated analogs were designed to increase the effectiveness of the peptide. The opio-klak derivative was the most effective in the in vitro assays and led to a decrease in viability of cancer cells over time as compared with that of untreated controls. In contrast, treatment with either the untargeted klak peptide or opiorphin as a negative control led to a negligible loss in viability. Antitumor effect of the opio-klak was also observed in vivo in murine melanoma tumor-bearing mice. Cessation of peptide administration resulted in tumor regrowth. Our results are seemingly valuable for the development of opiorphin analogs with potential clinical applications. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  17. Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity

    NASA Astrophysics Data System (ADS)

    Chiang, Po-Chang; Gould, Stephen; Nannini, Michelle; Qin, Ann; Deng, Yuzhong; Arrazate, Alfonso; Kam, Kimberly R.; Ran, Yingqing; Wong, Harvey

    2014-04-01

    Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.

  18. Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity.

    PubMed

    Chiang, Po-Chang; Gould, Stephen; Nannini, Michelle; Qin, Ann; Deng, Yuzhong; Arrazate, Alfonso; Kam, Kimberly R; Ran, Yingqing; Wong, Harvey

    2014-04-01

    Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.

  19. Antitumor efficacy of radiation plus immunotherapy depends upon dendritic cell activation of effector CDS+ T cells

    PubMed Central

    Dovedi, Simon J.; Lipowska-Bhalla, Grazyna; Beers, Stephen A.; Cheadle, Eleanor J.; Mu, Lijun; Glennie, Martin J.

    2017-01-01

    Tumor cells dying after cytotoxic therapy are a potential source of antigen for T-cell priming. Antigen-presenting cells (APCs) can cross-present MHC I–restricted peptides after the uptake of dying cells. Depending on the nature of the surrounding environmental signals, APCs then orchestrate a spectrum of responses ranging from immune activation to inhibition. Previously, we had demonstrated that combining radiation with either agonistic monoclonal antibody (mAb) to CD40 or a systemically administered TLR7 agonist could enhance CD8 T-cell–dependent protection against syngeneic murine lymphoma models. However, it remains unknown how individual APC populations impact on this antitumor immune response. Using APC depletion models, we now show that dendritic cells (DCs), but not macrophages or B cells, were responsible for the generation of long-term immunological protection following combination therapy with radiotherapy and either agonistic CD40 mAb or systemic TLR7 agonist therapy. Novel immunotherapeutic approaches that augment antigen uptake and presentation by DCs may further enhance the generation of therapeutic antitumor immune responses, leading to improved outcomes after radiotherapy. PMID:27241845

  20. Structural characterization, sulfation and antitumor activity of a polysaccharide fraction from Cyclina sinensis.

    PubMed

    Jiang, Changxing; Xiong, Qingping; Li, Songlin; Zhao, Xirong; Zeng, Xiaoxiong

    2015-01-22

    In the present study, we investigated the preliminary structure, sulfation and antitumor activity of a polysaccharide fraction from Cyclina sinensis (CSPS-1). Results of structural characterization showed that the backbone chain of CSPS-1 was composed of glucose linked by α-(1→4) glycosidic bond, and the branch chain was attached to backbone chain by (1→6) glycosidic bond. CSPS-1 was sulfated by chlorosulfonic acid-pyridine method under different modification conditions according to the orthogonal test L9(3(4)), affording nine sulfated polysaccharides (CSPS-1-S). The optimal sulfation conditions for CSPS-1 were reaction temperature of 65°C, reaction time of 2h and chlorosulfonic acid-pyridine ratio of 1:4. Structural analysis revealed that sulfation had occurred at position of C-6 in CSPS-1. In addition, CSPS-1-S exhibited significantly higher inhibitory activity in vitro against human gastric cancer BGC-823 cells.

  1. A tumor-penetrating peptide modification enhances the antitumor activity of endostatin in vivo.

    PubMed

    Hai-Tao, Zhang; Hui-Cheng, Li; Zheng-Wu, Li; Chang-Hong, Guo

    2011-06-01

    Many antitumor drugs have a limited ability to penetrate more than a few cell diameters from blood vessels into solid tumors, which limits their effectiveness. In this study, we investigated whether the biological activity of endostatin can be enhanced by the addition of an integrin-targeting and permeability-enhancing sequence. The internalization RGD (CRGDKGPDC; iRGD) sequence was added at the carboxyl terminus of endostatin. Modification of endostatin with the iRGD motif showed specific and increased binding to endothelial cells; the increased binding correlated with an improved antiangiogenic property. iRGD-modified endostatin was more effective than human endostatin in inhibiting liver cancer growth in athymic mice. The finding indicates that addition of a vascular targeting and permeability sequence can enhance the biological activity of an antiangiogenic molecule and tumor targeting.

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

    PubMed

    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.

  3. Synthesis and antitumor activities of novel 1,4-disubstituted phthalazine derivatives.

    PubMed

    Zhang, Shulan; Zhao, Yanfang; Liu, Yajing; Chen, Dong; Lan, Weihuan; Zhao, Qiaoling; Dong, Chengcheng; Xia, Lin; Gong, Ping

    2010-08-01

    In an attempt to develop potent and selective antitumor agents, a series of novel 1,4-disubstituted phthalazine derivatives was designed and synthesized. All the prepared compounds were screened for their cytotoxic activities against A549, HT-29 and MDA-MB-231 cell lines in vitro. Among them, seven compounds (7a-7e, 7j and 7i) displayed excellent selectivity for MDA-MB-231 cells with IC(50) values in the nM range, a desirable range for pharmacological testing. The most promising compound, 7a (IC(50) = 3.79 microM, 2.32 microM, 0.84 nM), was 5.6-, 10.8- and 6.9 x 10(4)- times more active than PTK-787 (IC(50) = 21.16 microM, 22.11 microM, 57.72 microM), respectively.

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

    PubMed Central

    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. PMID:26599335

  5. PH-dependent forms of red wine anthocyanins as antioxidants.

    PubMed

    Lapidot, T; Harel, S; Akiri, B; Granit, R; Kanner, J

    1999-01-01

    Anthocyanins are one of the main classes of flavonoids in red wines, and they appear to contribute significantly to the powerful antioxidant properties of the flavonoids. In grapes and wines the anthocyanins are in the flavylium form. However, during digestion they may reach higher pH values, forming the carbinol pseudo-base, quinoidal-base, or the chalcone, and these compounds appear to be absorbed from the gut into the blood system. The antioxidant activity of these compounds, in several metal-catalyzed lipid oxidation model systems, was evaluated in comparison with other antioxidants. The pseudo-base and quinoidal-base malvidin 3-glucoside significantly inhibited the peroxidation of linoleate by myoglobin. Both compounds were found to work better than catechin, a well-known antioxidant. In a membrane lipid peroxidation system, the effectiveness of the antioxidant was dependent on the catalyst: In the presence of H(2)O(2)-activated myoglobin, the inhibition efficiency of the antioxidant was malvidin 3-glucoside > catechin > malvidin > resveratrol. However, in the presence of an iron redox cycle catalyzer, the order of effectiveness was resveratrol > malvidin 3-glucoside = malvidin > catechin. The pH-transformed forms of the anthocyanins remained effective antioxidants in these systems, and their I(50) values were between 0.5 and 6.2 microM.

  6. Histidine oxidation photosensitized by pterin: pH dependent mechanism.

    PubMed

    Castaño, Carolina; Oliveros, Esther; Thomas, Andrés H; Lorente, Carolina

    2015-12-01

    Aromatic pterins accumulate in the skin of patients suffering from vitiligo, a chronic depigmentation disorder, due to the oxidation of tetrahydrobiopterin, the biologically active form of pterins. In this work, we have investigated the ability of pterin, the parent compound of aromatic pterins, to photosensitize the oxidation of histidine in aqueous solutions under UV-A irradiation. Histidine is an α-amino acid with an imidazole functional group, and is frequently present at the active sites of enzymes. The results highlight the role of the pH in controlling the competition between energy and electron transfer mechanisms. It has been previously demonstrated that pterins participate as sensitizers in photosensitized oxidations, both by type I (electron-transfer) and type II mechanisms (singlet oxygen ((1)O2)). By combining different analytical techniques, we could establish that a type I photooxidation was the prevailing mechanism at acidic pH, although a type II mechanism is also present, but it is more important in alkaline solutions.

  7. Anti-tumor activity and the mechanism of SIP-S: A sulfated polysaccharide with anti-metastatic effect.

    PubMed

    Zong, Aizhen; Liu, Yuhong; Zhang, Yan; Song, Xinlei; Shi, Yikang; Cao, Hongzhi; Liu, Chunhui; Cheng, Yanna; Jiang, Wenjie; Du, Fangling; Wang, Fengshan

    2015-09-20

    Our previous studies demonstrated that SIP-S had anti-metastatic activity and inhibited the growth of metastatic foci. Here we report the anti-tumor and immunoregulatory potential of SIP-S. SIP-S could significantly inhibit tumor growth in S180-bearing mice, and the inhibition rates was 43.7% at 30 mg/kg d. Besides, SIP-S could improve the thymus and spleen indices of S180-bearing mice and the mice treated with CTX. The combination of SIP-S (15 mg/kg d) with CTX (12.5 mg/kg d) showed higher anti-tumor potency than CTX (25 mg/kg d) alone. These results indicated that SIP-S had immunoenhancing and anticancer activity, and the immunoenhancing activity might be one mechanism for its anti-tumor activity. Flow cytometry results showed that SIP-S could induce tumor cells apoptosis. Western blot analysis indicated that SIP-S could upregulate the expression of pro-apoptotic proteins, caspase-3, -8, -9 and Bax, and downregulate the expression of anti-apoptotic protein PARP-1 in tumor cells in a dose-dependent manner. In summary, SIP-S has anti-tumor activity, which may be associated with its immunostimulating and pro-apoptotic activity.

  8. Identification of anti-CD98 antibody mimotopes for inducing antibodies with antitumor activity by mimotope immunization

    PubMed Central

    Saito, Misa; Kondo, Masahiro; Ohshima, Motohiro; Deguchi, Kazuki; Hayashi, Hideki; Inoue, Kazuyuki; Tsuji, Daiki; Masuko, Takashi; Itoh, Kunihiko

    2014-01-01

    A mimotope is an antibody-epitope-mimicking peptide retrieved from a phage display random peptide library. Immunization with antitumor antibody-derived mimotopes is promising for inducing antitumor immunity in hosts. In this study, we isolated linear and constrained mimotopes from HBJ127, a tumor-suppressing anti-CD98 heavy chain mAb, and determined their abilities for induction of antitumor activity equal to that of the parent antibody. We detected elevated levels of antipeptide responses, but failed to detect reactivity against native CD98-expressing HeLa cells in sera of immunized mice. Phage display panning and selection of mimotope-immunized mouse spleen-derived antibody Fab library showed that HeLa cell-reactive Fabs were successfully retrieved from the library. This finding indicates that native antigen-reactive Fab clones represented an undetectable minor population in mimotope-induced antibody repertoire. Functional and structural analysis of retrieved Fab clones revealed that they were almost identical to the parent antibody. From these results, we confirmed that mimotope immunization was promising for retrieving antitumor antibodies equivalent to the parent antibody, although the co-administration of adjuvant compounds such as T-cell epitope peptides and Toll-like receptor 4 agonist peptides is likely to be necessary for inducing stronger antitumor immunity than mimotope injection alone. PMID:24484217

  9. Identification of anti-CD98 antibody mimotopes for inducing antibodies with antitumor activity by mimotope immunization.

    PubMed

    Saito, Misa; Kondo, Masahiro; Ohshima, Motohiro; Deguchi, Kazuki; Hayashi, Hideki; Inoue, Kazuyuki; Tsuji, Daiki; Masuko, Takashi; Itoh, Kunihiko

    2014-04-01

    A mimotope is an antibody-epitope-mimicking peptide retrieved from a phage display random peptide library. Immunization with antitumor antibody-derived mimotopes is promising for inducing antitumor immunity in hosts. In this study, we isolated linear and constrained mimotopes from HBJ127, a tumor-suppressing anti-CD98 heavy chain mAb, and determined their abilities for induction of antitumor activity equal to that of the parent antibody. We detected elevated levels of antipeptide responses, but failed to detect reactivity against native CD98-expressing HeLa cells in sera of immunized mice. Phage display panning and selection of mimotope-immunized mouse spleen-derived antibody Fab library showed that HeLa cell-reactive Fabs were successfully retrieved from the library. This finding indicates that native antigen-reactive Fab clones represented an undetectable minor population in mimotope-induced antibody repertoire. Functional and structural analysis of retrieved Fab clones revealed that they were almost identical to the parent antibody. From these results, we confirmed that mimotope immunization was promising for retrieving antitumor antibodies equivalent to the parent antibody, although the co-administration of adjuvant compounds such as T-cell epitope peptides and Toll-like receptor 4 agonist peptides is likely to be necessary for inducing stronger antitumor immunity than mimotope injection alone.

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

    PubMed Central

    Meng, Fa-Yan; Ning, Yuan-Ling; Qi, Jia; He, Zhou; Jie, Jiang; Lin, Juan-Juan; Huang, Yan-Jun; Li, Fu-Sen; Li, Xue-Hua

    2014-01-01

    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. PMID:24663085

  11. Deglycosylated bleomycin has the antitumor activity of bleomycin without pulmonary toxicity.

    PubMed

    Burgy, Olivier; Wettstein, Guillaume; Bellaye, Pierre S; Decologne, Nathalie; Racoeur, Cindy; Goirand, Françoise; Beltramo, Guillaume; Hernandez, Jean-François; Kenani, Abderraouf; Camus, Philippe; Bettaieb, Ali; Garrido, Carmen; Bonniaud, Philippe

    2016-02-17

    Bleomycin (BLM) is a potent anticancer drug used to treat different malignancies, mainly lymphomas, germ cell tumors, and melanomas. Unfortunately, BLM has major, dose-dependent, pulmonary toxicity that affects 20% of treated individuals. The most severe form of BLM-induced pulmonary toxicity is lung fibrosis. Deglyco-BLM is a molecule derived from BLM in which the sugar residue d-mannosyl-l-glucose disaccharide has been deleted. The objective of this study was to assess the anticancer activity and lung toxicity of deglyco-BLM. We compared the antitumor activity and pulmonary toxicity of intraperitoneally administrated deglyco-BLM and BLM in three rodent models. Pulmonary toxicity was examined in depth after intratracheal administration of both chemotherapeutic agents. The effect of both drugs was further studied in epithelial alveolar cells in vitro. We demonstrated in rodent cancer models, including a human Hodgkin's lymphoma xenograft and a syngeneic melanoma model, that intraperitoneal deglyco-BLM is as effective as BLM in inducing tumor regression. Whereas the antitumor effect of BLM was accompanied by a loss of body weight and the development of pulmonary toxicity, deglyco-BLM did not affect body weight and did not engender lung injury. Both molecules induced lung epithelial cell apoptosis after intratracheal administration, but deglyco-BLM lost the ability to induce caspase-1 activation and the production of ROS (reactive oxygen species), transforming growth factor-β1, and other profibrotic and inflammatory cytokines in the lungs of mice and in vitro. Deglyco-BLM should be considered for clinical testing as a less toxic alternative to BLM in cancer therapy.

  12. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma.

    PubMed

    Ligresti, Alessia; Moriello, Aniello Schiano; Starowicz, Katarzyna; Matias, Isabel; Pisanti, Simona; De Petrocellis, Luciano; Laezza, Chiara; Portella, Giuseppe; Bifulco, Maurizio; Di Marzo, Vincenzo

    2006-09-01

    Delta(9)-Tetrahydrocannabinol (THC) exhibits antitumor effects on various cancer cell types, but its use in chemotherapy is limited by its psychotropic activity. We investigated the antitumor activities of other plant cannabinoids, i.e., cannabidiol, cannabigerol, cannabichromene, cannabidiol acid and THC acid, and assessed whether there is any advantage in using Cannabis extracts (enriched in either cannabidiol or THC) over pure cannabinoids. Results obtained in a panel of tumor cell lines clearly indicate that, of the five natural compounds tested, cannabidiol is the most potent inhibitor of cancer cell growth (IC(50) between 6.0 and 10.6 microM), with significantly lower potency in noncancer cells. The cannabidiol-rich extract was equipotent to cannabidiol, whereas cannabigerol and cannabichromene followed in the rank of potency. Both cannabidiol and the cannabidiol-rich extract inhibited the growth of xenograft tumors obtained by s.c. injection into athymic mice of human MDA-MB-231 breast carcinoma or rat v-K-ras-transformed thyroid epithelial cells and reduced lung metastases deriving from intrapaw injection of MDA-MB-231 cells. Judging from several experiments on its possible cellular and molecular mechanisms of action, we propose that cannabidiol lacks a unique mode of action in the cell lines investigated. At least for MDA-MB-231 cells, however, our experiments indicate that cannabidiol effect is due to its capability of inducing apoptosis via: direct or indirect activation of cannabinoid CB(2) and vanilloid transient receptor potential vanilloid type-1 receptors and cannabinoid/vanilloid receptor-independent elevation of intracellular Ca(2+) and reactive oxygen species. Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer.

  13. VP22 mediates intercellular trafficking and enhances the in vitro antitumor activity of PTEN.

    PubMed

    Yu, Xian; Xu, Zhengmin; Lei, Jun; Li, Tingting; Wang, Yan

    2015-07-01

    PTEN acts as a phosphatidylinositol phosphatase with a possible role in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Mutations in PTEN are frequent and their presence is associated with poor prognosis in breast cancer, which is the most common type of non-cutaneous malignancy in females. Delivery of the tumor suppressor PTEN gene represents a powerful strategy for breast cancer therapy, but a present limitation of gene therapy is the ability to deliver sufficient quantities of active proteins to target cells. The capacity of HSV-1VP22 fusion proteins to spread from the primary transduced cell to surrounding cells could improve gene therapeutics, particularly in cancer. To assess the potential efficacy of VP22 as a gene therapy for breast cancer, expression vectors for N- and C-terminal PTEN-VP22 fusion proteins were constructed. VP22‑mediated intercellular transport and antitumor efficacy in BT549 (PTEN-null) breast tumor cells were investigated. The results showed that PTEN-VP22 has the same spreading abilities as VP22. In cell proliferation and apoptosis assays, PTEN-VP22 gene transfer induces a stronger anti-proliferative effect and apoptotic activity compared with PTEN gene transfer alone. In addition, VP22 enhanced the PTEN‑mediated decrease in the level of phosphorylated AKT. The results show that PTEN-VP22 can spread in vitro and PTEN-VP22 gene induces significantly greater antitumor activity than the PTEN gene alone. This study confirms the utility of VP22-mediated delivery in vitro and suggests that PTEN-VP22 may have applications in breast cancer gene therapy.

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

    PubMed

    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.

  15. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity.

    PubMed

    Atkins, Charity; Liu, Qi; Minthorn, Elisabeth; Zhang, Shu-Yun; Figueroa, David J; Moss, Katherine; Stanley, Thomas B; Sanders, Brent; Goetz, Aaron; Gaul, Nathan; Choudhry, Anthony E; Alsaid, Hasan; Jucker, Beat M; Axten, Jeffrey M; Kumar, Rakesh

    2013-03-15

    The unfolded protein response (UPR) is a signal transduction pathway that coordinates cellular adaptation to microenvironmental stresses that include hypoxia, nutrient deprivation, and change in redox status. These stress stimuli are common in many tumors and thus targeting components of the UPR signaling is an attractive therapeutic approach. We have identified a first-in-class, small molecule inhibitor of the eukaryotic initiation factor 2-alpha kinase 3 (EIF2AK3) or PERK, one of the three mediators of UPR signaling. GSK2656157 is an ATP-competitive inhibitor of PERK enzyme activity with an IC(50) of 0.9 nmol/L. It is highly selective for PERK with IC(50) values >100 nmol/L against a panel of 300 kinases. GSK2656157 inhibits PERK activity in cells with an IC(50) in the range of 10-30 nmol/L as shown by inhibition of stress-induced PERK autophosphorylation, eIF2α substrate phosphorylation, together with corresponding decreases in ATF4 and CAAT/enhancer binding protein homologous protein (CHOP) in multiple cell lines. Oral administration of GSK2656157 to mice shows a dose- and time-dependent pharmacodynamic response in pancreas as measured by PERK autophosphorylation. Twice daily dosing of GSK2656157 results in dose-dependent inhibition of multiple human tumor xenografts growth in mice. Altered amino acid metabolism, decreased blood vessel density, and vascular perfusion are potential mechanisms for the observed antitumor effect. However, despite its antitumor activity, given the on-target pharmacologic effects of PERK inhibition on pancreatic function, development of any PERK inhibitor in human subjects would need to be cautiously pursued in cancer patients.

  16. pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents.

    PubMed

    Malik, Erum; Dennison, Sarah R; Harris, Frederick; Phoenix, David A

    2016-11-01

    Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel

  17. pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

    PubMed Central

    Malik, Erum; Dennison, Sarah R.; Harris, Frederick; Phoenix, David A.

    2016-01-01

    Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel

  18. Antitumor and Antioxidant Activities of the Extracts from Fruiting Body of Phellinus linteus

    PubMed Central

    Lee, June Woo; Baek, Seong Jin; Bae, Woo Chul; Park, Jeong Min

    2006-01-01

    Fruiting bodies of Phellinus linteus were extracted by hot water and alkali methods. Sugar contents of PL-H (hot water extract) and PL-A (alkali water extract) were 81.1%, 37.4% and protein contents were 6.2%, 21.8%, respectively. Amino acid pattern showed that two extracts contained large amount of aspartic acid and alanine. Two extracts showed characteristic IR absorption pattern for glycosidic bond at 890 cm-1. PL-H was divided two fractions by gel filtration chromatography and the molecular weights of each fraction were estimated to be about 10 kD and 225 kD, respectively and also PL-A was estimated 10 kD. Two extracts showed strong antitumor, immunomodulating and antioxidant activities, and were compared with commercialized glycopeptide anticancer drugs. PMID:24039504

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

    PubMed Central

    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. PMID:24281104

  20. Coumarin derivatives as potential antitumor agents: Growth inhibition, apoptosis induction and multidrug resistance reverting activity.

    PubMed

    Bisi, Alessandra; Cappadone, Concettina; Rampa, Angela; Farruggia, Giovanna; Sargenti, Azzurra; Belluti, Federica; Di Martino, Rita M C; Malucelli, Emil; Meluzzi, Alessia; Iotti, Stefano; Gobbi, Silvia

    2017-02-15

    A small library of coumarins, carrying butynyl-amino chains, was synthesized continuing our studies in the field of MDR reverting ageEnts and in order to obtain multipotent agents to combat malignancies. In particular, the reported anticancer and chemopreventive natural product 7-isopentenyloxycoumarin was linked to different terminal amines, selected on the basis of our previously reported results. The anticancer behaviour and the MDR reverting ability of the new compounds were evaluated on human colon cancer cells, particularly prone to develop the MDR phenotype. Some of the new derivatives showed promising effects, directly acting as cytotoxic compounds and/or counteracting MDR phenomenon. Compound 1e emerged as the most interesting of this series, showing a multipotent biological profile and suggesting that conjugation of an appropriate coumarin core with a properly selected butynyl-amino chain allows to obtain novel hybrid molecules endowed with improved in vitro antitumor activity.

  1. CD8+ T Cell-Independent Immune-Mediated Mechanisms of Anti-Tumor Activity

    PubMed Central

    Pluhar, G. Elizabeth; Pennell, Christopher A.; Olin, Michael R.

    2016-01-01

    Despite the growing number of preclinical and clinical trials focused on immunotherapy for the treatment of malignant gliomas, the prognosis for this disease remains grim. Cancer immunotherapy seeks to recruit an effective immune response to eliminate tumor cells. To date, cancer vaccines have shown only limited effectiveness because of our incomplete understanding of the necessary effector cells and mechanisms that yield efficient tumor clearance. CD8+ T cell cytotoxic activity has long been proposed as the primary effector function necessary for tumor regression. However, there is increasing evidence that indicates that components of the immune system other than CD8+ T cells play important roles in tumor eradication and control. The following review should provide an understanding of the mechanisms involved in an effective antitumor response to guide future therapeutic designs. The information provided suggests an alternate means of effective tumor clearance in malignant glioma to the canonical CD8+ cytotoxic T cell mechanism. PMID:26351148

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

    El-Naa, Mona Mohamed; Othman, Mohamed; Younes, Sheren

    2016-01-01

    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 analysis revealed that sildenafil was capable of improving the category of tumor activity from moderate to low proliferative. Sildenafil induced necrosis in the tumor. Moreover, the drug of interest showed cytotoxic activity against MCF-7 in vitro as well as potentiated cisplatin antitumor activity in vivo and in vitro. These findings shed light on the antitumor activity of sildenafil and its possible impact on potentiating the antitumor effect of conventional chemotherapeutic agents such as cisplatin. These effects might be related to antiangiogenic

  4. Anti-microorganism, anti-tumor, and immune activities of a novel polysaccharide isolated from Tricholoma matsutake

    PubMed Central

    Hou, Yiling; Ding, Xiang; Hou, Wanru; Zhong, Jie; Zhu, Hongqing; Ma, Binxiang; Xu, Ting; Li, Junhua

    2013-01-01

    Background: Many more fungal polysaccharides have been reported to exhibit a variety of biological activities, including anti-tumor, immunostimulation, anti-oxidation, and so on. The non-starch polysaccharides have emerged as an important class of bioactive natural products. Objective: To investigate the anti-microorganism, anti-tumor, and immune activities of a novel polysaccharide (TMP-A) isolated from Tricholoma matsutake. Materials and Methods: The anti-microorganism activity of purified polysaccharides (TMP-A) was evaluated by the inhibition zone diameter, the anti-tumor activity was evaluated by the S180 tumor cells that were implanted subcutaneously into the Kunming strain male mice in vivo, and the immune activity was evaluated by lymphocyte proliferation and macrophage stimulation, respectively. Results: In this study, the most susceptible bacteria of TMP-A at a concentration of 20 mg/ml was Micrococcus lysodeikticus (inhibition zone diameter 24.38 ± 1.19 mm) and the TMP-A did not show any antifungal activity for the tested stains of the fungi. In addition, the inhibitory rate in mice treated with 80 mg/kg TMP-A could reach 68.422%, being the highest in the three doses, which might be comparable to mannatide. The anti-tumor activity of the TMP-A was usually believed to be a consequence of the stimulation of the cell-mediated immune response, because it could significantly promote the lymphocyte and macrophage cells in the dose range of 50–200 μg/mL and in the dose range of 100 – 400 μg/mL in vitro, respectively. Discussion and Conclusion: The results obtained in the present study indicate that the purification polysaccharide of Tricholoma matsutake is a potential source of natural broad-spectrum, anti-microorganism, anti-tumor, and immunomodulation. PMID:23930009

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

    SciTech Connect

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

    1981-03-09

    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/sup 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.

  6. Antioxidant and antitumor activities of Capparis spinosa L. and the related mechanisms.

    PubMed

    Yu, Lei; Yang, Jinghui; Wang, Xin; Jiang, Bo; Sun, Yongxue; Ji, Yubin

    2017-01-01

    The 'ethnodrug' Capparis spinosa L. has several pharmacological activities. First, it was found in previous experiments that an ethyl acetate extract of Capparis spinosa L. (CSE) exhibited antioxidant activity. In order to further research this finding, the present study investigate the blood biochemical indices, injury, energy metabolism, oxidative damage and mitochondrial membrane potential (Δψm) level of cardiac cells to study the effect of CSE on doxorubicin-induced cardiac toxicity. CSE had protective effects on the cardiac toxic effect of doxorubicin, and decreased the activity of lactic dehydrogenase (LDH) and creatine kinase (CK). CSE increased the ability of myocardial tissue to scavenge free radicals, inhibited lipid peroxidation, increased recovery activity of antioxidant enzymes, adjusted the energy metabolism of myocardial tissue, inhibited the generation of a large number of ROS in the cells, raised the level of Δψm, and improved the metabolism of free radicals. CSE demonstrated protective effects on doxorubicin-induced myocardial damage. Second, the quaternary ammonium hydroxide of Capparis spinosa L. (CSQAH) was found to possess antitumor activity, such as antiproliferative and apoptosis-induced effects on HepG2 cells. We investigated the regulatory mechanism of HepG2 apoptosis induced by CSQAH. Laser scanning confocal microscope and Fluo-3/AM staining were utilized to detect the Ca2+ concentration in the HepG2 cells. A microplate reader was used to measure the changes in Ca2+-Mg2+-ATP enzyme. Then, flow cytometry was applied to analyze the activity of ROS and the expression levels of Bcl-2 and Bax. As a result, different concentrations of CSQAH increased the concentration of Ca2+ in the cytoplasm in a dosage-dependent manner. CSQAH decreased the Ca2+‑Mg2+‑ATPase activity in the HepG2 cells. The levels of ROS in the CSQAH groups were significantly higher than the level in the control group. Flow cytometric analysis showed that the Bcl-2

  7. Cremophor-free intravenous self-microemulsions for teniposide: Safety, antitumor activity in vitro and in vivo.

    PubMed

    He, Suna; Cui, Zheng; Wang, Xueqing; Zhang, Hua; Dai, Wenbing; Zhang, Qiang

    2015-11-10

    The study was designed to identify the safety and antitumor activity of teniposide self-microemulsified drug delivery system (TEN-SMEDDS) previously developed, and to provide evidence for the feasibility and effectiveness of TEN-SMEDDS for application in clinic. The TEN-SMEDDS could form fine emulsion with mean diameter of 279 ± 19 nm, Zeta potential of -6.9 ± 1.4 mV, drug loading of 0.04 ± 0.001% and entrapment efficiency of 98.7 ± 1.6% after dilution with 5% glucose, respectively. The safety, including hemolysis, hypersensitivity, vein irritation and toxicity in vivo, and antitumor activity were assessed, VUNON as a reference. Sulforhodamine B assays demonstrated that the IC50 of TEN-SMEDDS against C6 and U87MG cells were higher than that of VUMON. But the effect of TEN-SMEDDS on the cell cycle distribution and cell apoptotic rate was similar to that of VUMON as observed by flow cytometry. Likewise, the antitumor activity of TEN-SMEDDS was considerable to that of VUMON. Finally, the TEN-SMEDDS exhibited less body weight loss, lower hemolysis and lower myelosuppression as compared with VUMON. In conclusion, promising TEN-SMEDDS retained the antitumor activity of teniposide and was less likely to cause some side effects compared to VUMON. It may be favorable for the application in clinic.

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

    PubMed

    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.

  9. In Vivo Anti-Tumor Activity of Polypeptide HM-3 Modified by Different Polyethylene Glycols (PEG)

    PubMed Central

    Liu, Zhendong; Ren, Yinling; Pan, Li; Xu, Han-Mei

    2011-01-01

    HM-3, designed by our laboratory, is a polypeptide composed of 18 amino acids. Pharmacodynamic studies in vivo and in vitro indicated that HM-3 could inhibit endothelial cell migration and angiogenesis, thereby inhibiting tumor growth. However, the half-life of HM-3 is short. In this study, we modified HM-3 with different polyethylene glycols (PEG) in order to reduce the plasma clearance rate, extend the half-life in the body, maintain a high concentration of HM-3 in the blood and increase the therapeutic efficiency. HM-3 was modified with four different types of PEG with different molecular weights (ALD-mPEG5k, ALD-mPEG10k, SC-mPEG10k and SC-mPEG20k), resulting in four modified products (ALD-mPEG5k-HM-3, ALD-mPEG10k-HM-3, SC-mPEG10k-HM-3 and SC-mPEG20k-HM-3, respectively). Anti-tumor activity of these four modified HM-3 was determined in BALB/c mice with Taxol as a positive control and normal saline as a negative control. Tumor weight inhibition rates of mice treated with Taxol, HM-3, ALD-mPEG5k-HM-3, ALD-mPEG10k-HM-3, SC-mPEG10k-HM-3 and SC-mPEG20k-HM-3 were 44.50%, 43.92%, 37.95%, 31.64%, 20.27% and 50.23%, respectively. Tumor inhibition rates in the Taxol, HM-3 and SC-mPEG20k-HM-3 groups were significantly higher than that in the negative control group. The efficiency of tumor inhibition in the SC-mPEG20k-HM-3 group (drug treatment frequency: once per two days) was better than that in the HM-3 group (drug treatment frequency: twice per day). In addition, tumor inhibition rate in the SC-mPEG20k-HM-3 group was higher than that in the taxol group. We conclude that SC-mPEG20k-HM-3 had a low plasma clearance rate and long half-life, resulting in high anti-tumor therapeutic efficacy in vivo. Therefore, SC-mPEG20k-HM-3 could be potentially developed as new anti-tumor drugs. PMID:21731464

  10. Nucleolus and c-Myc: potential targets of cardenolide-mediated antitumor activity.

    PubMed

    Mijatovic, Tatjana; De Nève, Nancy; Gailly, Philippe; Mathieu, Véronique; Haibe-Kains, Benjamin; Bontempi, Gianluca; Lapeira, Javier; Decaestecker, Christine; Facchini, Vincenzo; Kiss, Robert

    2008-05-01

    The use of cardenolides like ouabain, digitoxin, or oleandrin has been reported previously many times as a means of potentially combating human refractory prostate cancer by inducing apoptosis through an increase in intracellular calcium concentrations. The aims of the current study were to investigate if part of the antitumor effects mediated by cardenolides concerned disorganization of nucleolar structure and whether this was further associated with a marked decrease in c-Myc expression. Accordingly, the antitumor activity of a novel hemisynthetic cardenolide [1R,3aS,3bR,5aS,6aR,7aS,9R,12aR,13aR,15aR]-3a,11a-dihydroxy-13a-(hydroxymethyl)-9,15a-dimethyl-1-(5-oxo-2,5-dihydrofuran-3-yl)icosahydro-1H,4'H-spiro[cyclopenta [7,8]phenanthro[2,3-b]pyrano[3,2-e][1,4]dioxine-11,2'-[1,3]thiazolidin]-4'-one (UNBS1450)] was compared with that of classic cardenolides and reference anticancer agents in prostate cancer cell lines in vitro and in vivo following s.c. and orthotopic prostate cancer cell grafting into mice. The present study indicates that UNBS1450 markedly decreases the in vitro viability/proliferation of human prostate cancer cell lines but not of normal cells. The induced effects are not linked to an increase in intracellular calcium concentrations and subsequent induction of apoptosis. Rather, they appear to relate to the compound's capacity to disorganize nucleolar structure and function (through an impairment of cyclin-dependent kinase and c-Myc expression and related signaling pathways; paralleled by the disorganization of cancer cell-specific perinucleolar bodies as revealed by disruption of Sam68). This nonapoptotic cancer cell death mediated by severe nucleolar targeting and down-regulation of c-Myc expression is a completely new cardenolide-induced mechanism of antitumor action.

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

    PubMed Central

    Ma, Mingshu; Hao, Yanli; Liu, Nan; Yin, Zhe; Wang, Lan; Liang, Xingjie; Zhang, Xiaoning

    2012-01-01

    Purpose 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 curve(0–6 hour) levels of docetaxel in blood and tumors were significantly higher in the M-DOC group (15.9 ± 3.2 μg/mL−1, 601.1 ± 194.5 μg/g−1) than in the I-DOC group (7.2 ± 1.7 μg/mL−1, 357.8 ± 86.2 μg/g−1). The fluorescent dye 1,1-dioctadecyl-3,3,3,3

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

    PubMed

    Peters, Diane E; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A; Leppla, Stephen H; Bugge, Thomas H

    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.

  13. Monocyte-Derived Dendritic Cells Are Essential for CD8+ T Cell Activation and Antitumor Responses After Local Immunotherapy

    PubMed Central

    Kuhn, Sabine; Yang, Jianping; Ronchese, Franca

    2015-01-01

    Tumors harbor several populations of dendritic cells (DCs) 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 antitumor immune responses and is associated with the appearance of a population of monocyte-derived DCs (moDCs) in the tumor and tumor-draining lymph node (dLN). Here, we use depletion of DCs or monocytes and monocyte transfer to show that these moDCs are critical to the activation of antitumor immune responses. Treatment with the immunostimulatory agents monosodium urate crystals and Mycobacterium smegmatis induced the accumulation of monocytes in the dLN, 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 moDCs, the infiltration of tumor-specific T cells into the tumor, and antitumor 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 antitumor immunity. PMID:26635798

  14. Quercetin nanoparticles display antitumor activity via proliferation inhibition and apoptosis induction in liver cancer cells.

    PubMed

    Ren, Ke-Wei; Li, Ya-Hua; Wu, Gang; Ren, Jian-Zhuang; Lu, Hui-Bin; Li, Zong-Ming; Han, Xin-Wei

    2017-04-01

    Quercetin is a potent cancer therapeutic agent and dietary antioxidant present in fruit and vegetables. Quercetin prevents tumor proliferation by inducing cell cycle arrest and is a well known cancer therapeutic agent and autophagy mediator. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, gold-quercetin into poly(DL-lactide-co-glycolide) nanoparticles was examined. In this study, we explored the role and possible underlying mechanisms of quercetin nanoparticle in regulation of antitumor activity in liver cancer cells. Treatment with quercetin nanoparticle effectively inhibited the liver cancer cell proliferation, cell migration and colony formation, thus suppressing liver cancer progression. Quercetin nanoparticle also upregulated apoptosis markedly. Further study suggested that quercetin nanoparticle accelerated the cleavage of caspase-9, caspase-3, and induced the up-releasing of cytochrome c (Cyto-c), contributing to apoptosis in liver cancer cells. Quercetin nanoparticles also promoted telomerase reverse transcriptase (hTERT) inhibition through reducing AP-2β expression and decreasing its binding to hTERT promoter. In addition, quercetin nanoparticle had an inhibitory role in cyclooxygenase 2 (COX-2) via suppressing the NF-κB nuclear translocation and its binding to COX-2 promoter. Quercetin nanoparticle also inactivated Akt and ERK1/2 signaling pathway. Taken together, our results suggested that quercetin nanoparticle had an antitumor effect by inactivating caspase/Cyto-c pathway, suppressing AP-2β/hTERT, inhibiting NF-κB/COX-2 and impeding Akt/ERK1/2 signaling pathways. Our results provided new mechanistic basis for further investigation of quercetin nanoparticles to find potential therapeutic strategies and possible targets for liver cancer inhibition.

  15. Macrophage immunomodulating and antitumor activities of polysaccharides isolated from Agaricus bisporus white button mushrooms.

    PubMed

    Jeong, Sang Chul; Koyyalamudi, Sundar Rao; Jeong, Yong Tae; Song, Chi Hyun; Pang, Gerald

    2012-01-01

    Agaricus bisporus white button mushroom (WBM) is widely consumed in most countries for its culinary properties. Recently, its dietary intake has been shown to protect against breast cancer. Mushroom polysaccharides are known for their immunomodulating and antitumor properties; however, little is known regarding the properties of A. bisporus polysaccharides. Using size-exclusion chromatography to fractionate the crude extract of A. bisporus, two polysaccharide fractions (designated as ABP-1 and ABP-2) were obtained. The estimated molecular masses of ABP-1 and ABP-2 were 2,000 kDa and 40-70 kDa, respectively, and their sugar compositions consisted mainly of glucose, mannose, xylose, and fructose. Analysis of the effects of the polysaccharides on murine macrophages demonstrated that both fractions stimulated the production of nitric oxide, interleukin-6, and tumor necrosis factor-α. Modulation of macrophage function by A. bisporus polysaccharides was mediated in part through activation of nuclear factor-κB with the production p50/105 heterodimers. Both ABP-1 and ABP-2 had the ability to inhibit the growth of human breast cancer MCF-7 cells but had little effect on the growth of human colon, prostate, gastric cancer, and murine Sarcoma 180 cells as assessed by a tetrazolium dye [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]-based assay. However, when murine Sarcoma 180 cells exposed to ABP-1 or ABP-2 were implanted subcutaneously into mice, a reduction in tumor growth was observed compared with that observed in control mice. Taken together, our data provide a molecular basis to explain in part the reported beneficial therapeutic effects of A. bisporus WBM intake and suggest that macrophages likely contribute to the antitumor effects of Agaricus polysaccharides.

  16. Sweet antibiotics - the role of glycosidic residues in antibiotic and antitumor activity and their randomization.

    PubMed

    Kren, Vladimír; Rezanka, Tomás

    2008-08-01

    A large number of antibiotics are glycosides. In numerous cases the glycosidic residues are crucial to their activity; sometimes, glycosylation only improves their pharmacokinetic parameters. Recent developments in molecular glycobiology have improved our understanding of aglycone vs. glycoside activities and made it possible to develop new, more active or more effective glycodrugs based on these findings - a very illustrative recent example is vancomycin. The majority of attention has been devoted to glycosidic antibiotics including their past, present, and probably future position in antimicrobial therapy. The role of the glycosidic residue in the biological activity of glycosidic antibiotics, and the attendant targeting and antibiotic selectivity mediated by glycone and aglycone in antibiotics some antitumor agents is discussed here in detail. Chemical and enzymatic modifications of aglycones in antibiotics, including their synthesis, are demonstrated on various examples, with particular emphasis on the role of specific and mutant glycosyltransferases and glycorandomization in the preparation of these compounds. The last section of this review describes and explains the interactions of the glycone moiety of the antibiotics with DNA and especially the design and structure-activity relationship of glycosidic antibiotics, including their classification based on their aglycone and glycosidic moiety. The new enzymatic methodology 'glycorandomization' enabled the preparation of glycoside libraries and opened up new ways to prepare optimized or entirely novel glycoside antibiotics.

  17. The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids.

    PubMed

    McAllister, Sean D; Soroceanu, Liliana; Desprez, Pierre-Yves

    2015-06-01

    As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ(9)-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment.

  18. Antitumor activity of jujuboside B and the underlying mechanism via induction of apoptosis and autophagy.

    PubMed

    Xu, Mei-Ying; Lee, So Young; Kang, Sam Sik; Kim, Yeong Shik

    2014-02-28

    Jujuboside B (1) is one of the saponins isolated from the seeds of Zizyphus jujuba var. spinosa, which are used as a well-known traditional medicine for the treatment of insomnia and anxiety in East Asian countries. This is the first study to investigate the antitumor mechanism of 1 in vivo and in vitro. The results showed that 1 induced apoptosis and autophagy in AGS and HCT 116 human cancer cells and also effectively suppressed tumor growth in a nude mouse xenograft model bearing HCT 116 cells. The apoptosis-inducing effect of 1 was characterized by annexin V/propidium iodide staining, sub-G1 phase increase, and caspase-3 activation. Mechanistic studies showed that 1-induced apoptosis is associated with the extrinsic pathway through an increase in FasL and caspase-8 activation. Moreover, 1 activated p38/c-Jun N-terminal kinase (JNK), and the extrinsic pathway-mediated apoptosis was attenuated by both SB202190 (a p38 inhibitor) and SP600125 (a JNK inhibitor). The autophagy-inducing effect was indicated by the formation of cytoplasmic vacuoles and microtubule-associated protein 1 light chain-3 II (LC3-II) conversion. The autophagy inhibitor bafilomycin A1 (BaF) decreased 1-induced cell viability and increased pp38, pJNK, FasL, caspase-8 activation, and caspase-3 activation. Taken together, these results demonstrate that 1 induced protective autophagy to retard extrinsic pathway-mediated apoptosis.

  19. The antitumor activity of plant-derived non-psychoactive cannabinoids

    PubMed Central

    McAllister, Sean D.; Soroceanu, Liliana; Desprez, Pierre-Yves

    2015-01-01

    As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ9-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer stem cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment. PMID:25916739

  20. Inhibition of antibacterial activity of himastatin, a new antitumor antibiotic from Streptomyces hygroscopicus, by fatty acid sodium salts.

    PubMed Central

    Mamber, S W; Brookshire, K W; Dean, B J; Firestone, R A; Leet, J E; Matson, J A; Forenza, S

    1994-01-01

    Himastatin, a cyclohexadepsipeptide antibiotic, had in vivo antitumor activity against localized P388 leukemia and B16 melanoma but had no distal site antitumor activity. An in vitro Bacillus subtilis well-agar diffusion assay was employed to test the hypothesis that himastatin was enzymatically inactivated. The activity of himastatin against B. subtilis was inhibited when himastatin was mixed with mouse liver S9 fraction and microsomes. However, subsequent investigations demonstrated that the markedly decreased antibacterial activity was not enzymatic in nature but was related to the presence of certain fatty acid salts. Saturated fatty acid sodium salts with a carbon chain number of 8 or more reduced the antimicrobial activity of himastatin 50 to 100 times. If antibiotics such as ampicillin, bacitracin, chloramphenicol, and tunicamycin were used in place of himastatin, no meaningful reduction in antibacterial activity occurred. However, the antibacterial activity of the membrane-active peptide antibiotic polymyxin B, but not that of polymyxin E (colistin), was reduced in a manner similar to that of himastatin. Importantly, the activity of himastatin against HCT-116 colon adenocarcinoma cells in soft agar was markedly reduced in the presence of sodium palmitate as the reference fatty acid salt. The data indicate that himastatin may be trapped in micelles in vitro. It may be speculated that the lack of distal site antitumor activity resulted from similar complex formation between himastatin and lipids in vivo. The results also suggest that the cancer cytotoxic and antimicrobial effects of himastatin may result from interactions with the cell membrane. PMID:7872760

  1. Antitumor Activity of KW-2450 Against Triple-Negative Breast Cancer by Inhibiting Aurora A and B Kinases

    PubMed Central

    Kai, Kazuharu; Kondo, Kimie; Wang, Xiaoping; Xie, Xuemei; Pitner, Mary K.; Reyes, Monica E.; Torres-Adorno, Angie M.; Masuda, Hiroko; Hortobagyi, Gabriel N.; Bartholomeusz, Chandra; Saya, Hideyuki; Tripathy, Debu; Sen, Subrata; Ueno, Naoto T.

    2015-01-01

    Currently, no targeted drug is available for triple-negative breast cancer (TNBC), an aggressive breast cancer that does not express estrogen receptor, progesterone receptor, or HER2. TNBC has high mitotic activity, and since Aurora A and B mitotic kinases drive cell division and are overexpressed in tumors with a high mitotic index, we hypothesized that inhibiting Aurora A and B produces a significant antitumor effect in TNBC. We tested this hypothesis by determining the antitumor effects of KW-2450, a multikinase inhibitor of both Aurora A and B kinases. We observed significant inhibitory activities of KW-2450 on cell viability, apoptosis, colony formation in agar, and mammosphere formation in TNBC cells. The growth of TNBC xenografts was significantly inhibited with KW-2450. In cell cycle analysis, KW-2450 induced tetraploid accumulation followed by apoptosis or surviving octaploid (8N) cells, depending on dose. These phenotypes resembled those of Aurora B knockdown and complete pharmaceutical inhibition of Aurora A. We demonstrated that 8N cells resulting from KW-2450 treatment depended on the activation of mitogen-activated protein kinase kinase (MEK) for their survival. When treated with the MEK inhibitor selumetinib combined with KW-2450, compared with KW-2450 alone, the 8N cell population was significantly reduced and apoptosis was increased. Indeed this combination showed synergistic antitumor effect in SUM149 TNBC xenografts. Collectively, Aurora A and B inhibition had a significant antitumor effect against TNBC, and this antitumor effect was maximized by the combination of selumetinib with Aurora A and B inhibition. PMID:26443806

  2. Antitumor Activity of KW-2450 against Triple-Negative Breast Cancer by Inhibiting Aurora A and B Kinases.

    PubMed

    Kai, Kazuharu; Kondo, Kimie; Wang, Xiaoping; Xie, Xuemei; Pitner, Mary K; Reyes, Monica E; Torres-Adorno, Angie M; Masuda, Hiroko; Hortobagyi, Gabriel N; Bartholomeusz, Chandra; Saya, Hideyuki; Tripathy, Debu; Sen, Subrata; Ueno, Naoto T

    2015-12-01

    Currently, no targeted drug is available for triple-negative breast cancer (TNBC), an aggressive breast cancer that does not express estrogen receptor, progesterone receptor, or HER2. TNBC has high mitotic activity, and, because Aurora A and B mitotic kinases drive cell division and are overexpressed in tumors with a high mitotic index, we hypothesized that inhibiting Aurora A and B produces a significant antitumor effect in TNBC. We tested this hypothesis by determining the antitumor effects of KW-2450, a multikinase inhibitor of both Aurora A and B kinases. We observed significant inhibitory activities of KW-2450 on cell viability, apoptosis, colony formation in agar, and mammosphere formation in TNBC cells. The growth of TNBC xenografts was significantly inhibited with KW-2450. In cell-cycle analysis, KW-2450 induced tetraploid accumulation followed by apoptosis or surviving octaploid (8N) cells, depending on dose. These phenotypes resembled those of Aurora B knockdown and complete pharmaceutical inhibition of Aurora A. We demonstrated that 8N cells resulting from KW-2450 treatment depended on the activation of mitogen-activated protein kinase kinase (MEK) for their survival. When treated with the MEK inhibitor selumetinib combined with KW-2450, compared with KW-2450 alone, the 8N cell population was significantly reduced and apoptosis was increased. Indeed, this combination showed synergistic antitumor effect in SUM149 TNBC xenografts. Collectively, Aurora A and B inhibition had a significant antitumor effect against TNBC, and this antitumor effect was maximized by the combination of selumetinib with Aurora A and B inhibition.

  3. Targeting of Tumor Growth and Angiogenesis Underlies the Enhanced Antitumor Activity of Lenvatinib in Combination with Everolimus.

    PubMed

    Matsuki, Masahiro; Adachi, Yusuke; Ozawa, Yoichi; Kimura, Takayuki; Hoshi, Taisuke; Okamoto, Kiyoshi; Tohyama, Osamu; Mitsuhashi, Kaoru; Yamaguchi, Atsumi; Matsui, Junji; Funahashi, Yasuhiro

    2017-01-20

    The combination of lenvatinib-a multiple receptor tyrosine kinase (RTK) inhibitor-plus everolimus-a mammalian target of rapamycin (mTOR) inhibitor-significantly improved clinical outcomes versus everolimus monotherapy in a phase 2 clinical study of metastatic renal cell carcinoma (RCC). Here, we investigated potential mechanisms underlying the antitumor activity of the combination treatment in preclinical RCC models. Lenvatinib plus everolimus showed greater antitumor activity than either monotherapy in 3 human RCC xenograft mouse models (A-498, Caki-1, and Caki-2). In particular, the combination led to tumor regression in the A-498 and Caki-1 models. In the A-498 model, everolimus demonstrated antiproliferative activity, whereas lenvatinib showed antiangiogenic effects. The antiangiogenic activity was potentiated by the lenvatinib plus everolimus combination in Caki-1 xenografts, where FGF-driven angiogenesis may contribute to tumor growth. The combination showed mostly additive activity in VEGF-activated, and synergistic activity against FGF-activated endothelial cells in cell proliferation and tube formation assays, as well as strongly suppressed mTOR-S6K-S6 signaling. Enhanced antitumor activities of the combination versus each monotherapy were also observed in mice bearing human pancreatic KP-1 xenografts overexpressing VEGF or FGF. Our results indicated that simultaneous targeting tumor cell growth and angiogenesis by lenvatinib plus everolimus resulted in enhanced antitumor activity. The enhanced inhibition of both VEGF- and FGF-signaling pathways by the combination underlies its superior antiangiogenic activity in human RCC xenograft models. This article is protected by copyright. All rights reserved.

  4. Antitumor and antifungal activities of organic extracts of seacucumber Holothuria atra from the southeast coast of India

    NASA Astrophysics Data System (ADS)

    Dhinakaran, Devaraj Isaac; Lipton, Aaron Premnath

    2015-02-01

    In phylum Echinodermata, the family Holothuridae is distinguished by its capacity of bioactive compounds. Sea cucumber Holothuria atra is commonly known as the lollyfish. The antifungal activity was detected using agar well diffusion method against the various fungal strains such as Trichoderma viride, Aspergillus niger, Aspergillus flavis, Candida albicans and Penicillium chrysogenum. Relatively high antifungal activity was seen against Candida albicans at 100 μL-1 concentration of extracts. Zone of inhibition was measured at 18 mm of diameter. The anti-tumor activities were detected against the Vero and Hep2 cell lines using MTT assay. The cells were treated with H. atra extract at concentrations 0.078-10mg mL-1. The extract showed high proliferative activity against the Hep2 cells. The body wall extracts of sea cucumber ( H. atra) showed effective antifungal and antitumor activities. All these findings suggest that the extracts could be used for the development of drugs.

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

    PubMed Central

    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. Synthesis and evaluation of antibacterial and antitumor activities of new galactopyranosylated amino alcohols.

    PubMed

    de Souza Fernandes, Fábio; Fernandes, Tayrine Silva; da Silveira, Lígia Souza; Caneschi, Wiliam; Lourenço, Maria Cristina S; Diniz, Claudio G; de Oliveira, Pollyanna Francielli; Martins, Sabrina de Paula Lima; Pereira, Daiane Eleutério; Tavares, Denise Crispim; Le Hyaric, Mireille; de Almeida, Mauro V; Couri, Mara Rubia C

    2016-01-27

    Three series of d-galactose derivatives linked to a lipophilic aminoalcohol moiety were synthesized and their antibacterial activity was evaluated against Mycobacterium tuberculosis and representative species of Gram positive and Gram negative bacteria. Five out of the thirteen tested compounds displayed activity against M. tuberculosis, with a minimal inhibitory concentration (MIC) of 12.5 μg/mL and seven compounds were active against the four bacterial strains tested. The best results were obtained for amino alcohols 10 and 11 against Staphylococcus epidermidis (MIC = 2 μg/mL). The antitumor activity was evaluated against three tumor cell lines (MCF-7, HeLa and MO59J) and compared to the normal cell line GM07492A. The results showed that the lowest IC50 values were observed for the amino alcohol 16 against MCF-7 (11.9 μM) and MO59J (10.0 μM).

  7. Synthesis and Antitumor Properties of BQC-Glucuronide, a Camptothecin Prodrug for Selective Tumor Activation.

    PubMed

    Prijovich, Zeljko M; Burnouf, Pierre-Alain; Chou, Hua-Cheng; Huang, Ping-Ting; Chen, Kai-Chuan; Cheng, Tian-Lu; Leu, Yu-Lin; Roffler, Steve R

    2016-04-04

    Major limitations of camptothecin anticancer drugs (toxicity, nonselectivity, water insolubility, inactivation by human serum albumin) may be improved by creating glucuronide prodrugs that rely on beta-glucuronidase for their activation. We found that the camptothecin derivative 5,6-dihydro-4H-benzo[de]quinoline-camptothecin (BQC) displays greater cytotoxicity against cancer cells than the clinically used camptothecin derivatives SN-38 and topotecan even in the presence of human serum albumin. We synthesized the prodrug BQC-glucuronide (BQC-G), which was 4000 times more water soluble and 20-40 times less cytotoxic than BQC. Importantly, even in the presence of human serum albumin, BQC-G was efficiently hydrolyzed by beta-glucuronidase and produced greater cytotoxicity (IC50 = 13 nM) than camptothecin, 9-aminocamptothecin, SN-38, or topotecan (IC50 > 3000, 1370, 48, and 28 nM, respectively). BQC-G treatment of mice bearing human colon cancer xenografts with naturally or artificially elevated beta-glucuronidase activity produced significant antitumor activity, showing that BQC-G is a potent prodrug suitable for selective intratumoral drug activation.

  8. Ganoderma lucidum polysaccharide exerts anti-tumor activity via MAPK pathways in HL-60 acute leukemia cells.

    PubMed

    Yang, Guohua; Yang, Lei; Zhuang, Yun; Qian, Xifeng; Shen, Yunfeng

    2016-01-01

    In this study, we investigated the anti-tumor activity both in vitro and in vivo of a polysaccharide obtained from Ganoderma lucidum on HL-60 acute myeloid leukemia cells, and focused on its targeting effect on mitogen-activated protein kinase (MAPK) pathways. It was found by the methods such as western blot and flow cytometry (FCM), that G. lucidum polysaccharide (GLP) blocked the extracellular signal-regulated kinase/MAPK signaling pathway, simultaneously activated p38 and JNK MAPK pathways, and therefore regulated their downstream genes and proteins, including p53, c-myc, c-fos, c-jun, Bcl-2, Bax, cleaved caspase-3 and cyclin D1. As a result, cycle arrest and apoptosis of HL-60 cells were induced. Therefore, GLP exerted anti-tumor activity via MAPK pathways in HL-60 acute leukemia cells.

  9. Antitumor immunomodulatory activity of allogenic bone marrow cells on TiNi scaffold

    NASA Astrophysics Data System (ADS)

    Kokorev, O. V.; Hodorenko, V. N.; Cherdyntseva, N. V.; Gunther, V. E.

    2016-08-01

    The present study was undertaken to evaluate the feasibility of modulation of anti-tumor response by allogenic bone marrow cell transplantation into porous TiNi-based scaffold. Transplantation of bone marrow cells into porous TiNi-based scaffold leads to antitumor (35%) and antimetastatic (55%) effects. The lifetime of tumor-bearing animals and implanted allogenic bone marrow cells in incubator of TiNi increases up to 60%. The possible mechanisms of the effect of allogenic cells on tumor process are the stimulation of endogenous effectors of antitumor immunity.

  10. Identification of triterpene hydroxycinnamates with in vitro antitumor activity from whole cranberry fruit (Vaccinium macrocarpon).

    PubMed

    Murphy, Brian T; MacKinnon, Shawna L; Yan, Xiaojun; Hammond, Gerald B; Vaisberg, Abraham J; Neto, Catherine C

    2003-06-04

    Bioactivity-guided fractionation of cranberry fruit was used to determine the identity of triterpenoid esters from Vaccinium macrocarpon, which inhibit tumor cell growth and may play a role in cancer prevention. In our previous study, a fraction from whole fruit exhibited tumor cell growth inhibition in vitro. The major components of this fraction were isolated by chromatographic separation of ethyl acetate extracts, purified by semipreparative HPLC, and identified by NMR as cis- (1) and trans- (2) isomers of 3-O-p-hydroxycinnamoyl ursolic acid. These triterpenoid esters have not been previously reported in Vaccinium fruit. Bioassay of the purified triterpene cinnamates in tumor cell lines in vitro showed slightly greater activity of compound 1 in most cell lines, with GI(50) values of approximately 20 microM in MCF-7 breast, ME180 cervical and PC3 prostate tumor cell lines. Quercetin was slightly less active than 1, while cyanidin-3-galactoside exhibited much lower cytotoxicity, with GI(50) greater than 250 microM in all cell lines. Phenylboronic acid (3) was also isolated from the fruit but showed insignificant antitumor activity.

  11. Characterization, antioxidant and antitumor activities of polysaccharides from Salvia miltiorrhiza Bunge.

    PubMed

    Jiang, Yuan-yuan; Wang, Long; Zhang, Li; Wang, Tao; Yu, Lin; Ding, Chun-bang; Yang, Rui-wu; Wang, Xiao-li; Zhou, Yong-hong

    2014-09-01

    Polysaccharides were extracted from Salvia miltiorrhiza Bunge using response surface methodology (RSM) with ultrasonication. A Box-Behnken design was used to optimize the extraction parameters to maximize the polysaccharide extraction yield. The polysaccharide SMP-U1 was isolated and characterized; then the antioxidant and antiproliferation activities were evaluated in vitro. The modified optimal conditions were an ultrasonic power of 180 W, an extraction temperature of 54°C, and an extraction time of 32 min, achieving an extraction yield of 40.54±0.25%. The results indicate that SMP-U1 has significant antioxidant activity, scavenging the free radical 2,2-diphenyl-1-picrylhydrazyl. It has also exhibited effect on the proliferation of human breast carcinoma cells Bcap-37 and human esophageal carcinoma cells Eca-109, especially at a concentration of 0.30 mg/mL. In conclusion, SMP-U1 has remarkable in vitro antioxidant and antiproliferation activity, and has potential for application as a natural antioxidant or antitumor agent.

  12. Synthesis and antitumor activity of novel N-substituted carbazole imidazolium salt derivatives

    PubMed Central

    Liu, Lan-Xiang; Wang, Xue-Quan; Zhou, Bei; Yang, Li-Juan; Li, Yan; Zhang, Hong-Bin; Yang, Xiao-Dong

    2015-01-01

    A series of novel N-substituted carbazole imidazolium salt derivatives has been prepared and investigated for their cytotoxic activity against five human tumor cell lines by MTS assay. The results indicated that the existence of 5,6-dimethyl-benzimidazole ring, substitution of the imidazolyl-3-position with a 2-bromobenzyl or naphthylacyl group, as well as alkyl chain length between carbazole and imidazole ring were important for the antitumor activity. Compound 61, bearing a 2-bromobenzyl substituent at position-3 of the 5,6-dimethyl-benzimidazole, showed powerful inhibitory activities and was more selective to HL-60, SMMC-7721, MCF-7 and SW480 cell lines with IC50 values 0.51–2.48 μM. Mechanism of action studies revealed that this new compound could remarkably induce cell cycle arrest and apoptosis in SMMC-7721 cells. This work provides alternative novel way for future drug development based on carbazole and imidazolium salt scaffolds. PMID:26287982

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

    PubMed

    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.

  14. Influence of fucoidans and their derivatives on antitumor and phagocytic activity of human blood leucocytes.

    PubMed

    Anisimova, N Yu; Ustyuzhanina, N E; Donenko, F V; Bilan, M I; Ushakova, N A; Usov, A I; Nifantiev, N E; Kiselevskiy, M V

    2015-07-01

    The immunotropic activity of structurally different fucoidans and their derivatives towards isolated immune blood cells, effectors of innate immune system, was studied. The most potent effect was observed for high molecular weight fucoidan CF from the alga Chordaria flagelliformis, whose backbone is built of (1→3)-linked units of α-L-fucopyranose, and branches included residues of α-D-glucuronic acid and α-L-fucofuranose. This compound at the concentration of 0.05 mg/ml potentiated phagocytosis of Saccharomyces cerevisiae and Lactobacillus acidophilus by neutrophils, increasing relative quantity of phagocytes as well as their effectiveness. Along with this, 14% increase in the concentration of membrane-bound integrin CD11c molecules was observed. The systemic effect of CF at the dose of 0.01 mg/mouse i.p. led to potentiation of cytotoxic activity of spleen mononuclear leucocytes towards melanoma cells of line B16 by 1.9-fold and towards chronic myelogenous leukemia cells of line K-562 by 1.7-fold. These results indicate that fucoidan CF can stimulate anti-infective and antitumor activity of effectors of the innate immune system via CD11c integrins.

  15. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T-lymphocytes

    PubMed Central

    Caruana, Ignazio; Savoldo, Barbara; Hoyos, Valentina; Weber, Gerrit; Liu, Hao; Kim, Eugene S.; Ittmann, Michael M.; Marchetti, Dario; Dotti, Gianpietro

    2015-01-01

    Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking effects in solid tumors1–3 than in lymphoid malignancies4, 5. Although active tumor-mediated immunosuppression may play a role in limiting efficacy6, functional changes in T lymphocytes following their ex vivo manipulation may also account for cultured CAR-T cells’ reduced ability to penetrate stroma-rich solid tumors. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE) that degrades heparan sulphate proteoglycans, which are main components of ECM. We found that HPSE mRNA is down regulated in in vitro-expanded T cells, which may be a consequence of p53 binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed improved capacity to degrade ECM, which promoted tumor T-cell infiltration and antitumor activity. Employing this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors. PMID:25849134

  16. In vivo antioxidant, hypoglycemic, and anti-tumor activities of anthocyanin extracts from purple sweet potato

    PubMed Central

    Zhao, Jin-Ge; Yan, Qian-Qian; Lu, Li-Zhen

    2013-01-01

    Anthocyanin from purple sweet potato (PSP) extracted by microwave baking (MB) and acidified electrolyzed water (AEW) exhibited antioxidant activity. After further purification by macroporous AB-8 resin, the color value of PSP anthocyanin (PSPA) reached 30.15 with a total flavonoid concentration of 932.5 mg/g. The purified extracts had more potent antioxidant activities than the crude extracts. After continuously administering the PSP extracts to 12-mo-old mice for 1 mo, the anti-aging index of the experimental group was not significantly different from that of 5-mo-old mice. To a certain degree, PSPA was also effective for controlling plasma glucose levels in male Streptozocin (STZ)-treated diabetic mice. In addition, the extracts inhibited Sarcoma S180 cell growth in ICR mice. Mice consuming the PSP extracts formed significantly fewer and smaller sarcomas than mice consuming the control diets. The highest inhibition rate was 69.03%. These results suggest that anthocyanin extracts from PSP not only exert strong antioxidant effects in vitro, but also had anti-aging, anti-hyperglycemic, and anti-tumor activities. PMID:24133614

  17. Antitumor Effects of Fucoidan on Human Colon Cancer Cells via Activation of Akt Signaling.

    PubMed

    Han, Yong-Seok; Lee, Jun Hee; Lee, Sang Hun

    2015-05-01

    We identified a novel Akt signaling mechanism that mediates fucoidan-induced suppression of human colon cancer cell (HT29) proliferation and anticancer effects. Fucoidan treatment significantly inhibited growth, induced G1-phase-associated upregulation of p21WAF1 expression, and suppressed cyclin and cyclin-dependent kinase expression in HT29 colon cancer cells. Additionally, fucoidan treatment activated the Akt signaling pathway, which was inhibited by treatment with an Akt inhibitor. The inhibition of Akt activation reversed the fucoidan-induced decrease in cell proliferation, the induction of G1-phase-associated p21WAF1 expression, and the reduction in cell cycle regulatory protein expression. Intraperitoneal injection of fucoidan reduced tumor volume; this enhanced antitumor efficacy was associated with induction of apoptosis and decreased angiogenesis. These data suggest that the activation of Akt signaling is involved in the growth inhibition of colon cancer cells treated with fucoidan. Thus, fucoidan may serve as a potential therapeutic agent for colon cancer.

  18. The role of NK cells in antitumor activity of dietary fucoidan from Undaria pinnatifida sporophylls (Mekabu).

    PubMed

    Maruyama, Hiroko; Tamauchi, Hidekazu; Iizuka, Mariko; Nakano, Takahisa

    2006-12-01

    Fucoidan from Mekabu (sporophyll of Undaria pinnatifida), a dietary alga, exerts antitumor activity possibly through enhancing the immune response. The present report describes the effects of dietary Mekabu fucoidan on the tumor growth of mouse A20 leukemia cells and on T cell-mediated immune responses in T cell receptor transgenic (DO-11 - 10 - Tg) mice. The animals were fed with a diet containing 1% Mekabu fucoidan (0.034 +/- 0.003 g/mouse/day) for 10 days and subcutaneously (s. c.) inoculated with A20 leukemia cells. Thereafter, the mice were fed with the diet containing fucoidan for 40 days. Mekabu fucoidan inhibited tumors by 65.4 %. We studied how the killer activities of T cell-mediated and natural killer (NK) cells are augmented in DO-11 - 10 mice fed with Mekabu fucoidan. The cytolytic activities of ovalbumin (OVA), which is specific against OVA-transfected A20 (OVA-A20) B lymphoma cells, and NK cells against YAC-1 were significantly enhanced in the mice fed with fucoidan compared with a basic diet. Thus, these findings suggested that Mekabu fucoidan mediates tumor destruction through Th1 cell and NK cell responses.

  19. A Tumor-Penetrating Peptide Modification Enhances the Antitumor Activity of Thymosin Alpha 1

    PubMed Central

    Chen, Jiao; Zheng, Heng

    2013-01-01

    A serious limitation of numerous antitumor drugs is the incapacity to penetrate solid tumors. However, addition of an RGD fragment to peptide drugs might solve this problem. In this study, we explored whether the introduction of a permeability-enhancing sequence, such as iRGD (CRGDK/RGPD/EC) fragments, would enhance the activity of thymosin alpha 1 (Tα1). The modified Tα1 (Tα1-iRGD) was successfully expressed and purified, and the in vitro assay showed that Tα1-iRGD presented a similar activity as Tα1 in promoting proliferation of mouse splenocytes. Meanwhile, cell adhesion analysis revealed that Tα1-iRGD exhibited more specific and greater binding with tumor cells compared with Tα1. Furthermore, the iRGD fragment evidently enhanced the basal ability of Tα1 to inhibit proliferation of cancer cells in vitro, particularly of mouse melanoma cell line B16F10 and human lung cancer cell line H460. Our findings indicated that the addition of an iRGD fragment increased the anti-proliferative activity of Tα1 against cancer cells by improving the ability of Tα1 to penetrate the tumor cells. This study highlighted the important roles of an iRGD sequence in the therapeutic strategy of Tα1-iRGD. Thus, Tα1-iRGD could be a novel drug candidate for cancer treatment. PMID:23977262

  20. A tumor-penetrating peptide modification enhances the antitumor activity of thymosin alpha 1.

    PubMed

    Lao, Xingzhen; Liu, Meng; Chen, Jiao; Zheng, Heng

    2013-01-01

    A serious limitation of numerous antitumor drugs is the incapacity to penetrate solid tumors. However, addition of an RGD fragment to peptide drugs might solve this problem. In this study, we explored whether the introduction of a permeability-enhancing sequence, such as iRGD (CRGDK/RGPD/EC) fragments, would enhance the activity of thymosin alpha 1 (Tα1). The modified Tα1 (Tα1-iRGD) was successfully expressed and purified, and the in vitro assay showed that Tα1-iRGD presented a similar activity as Tα1 in promoting proliferation of mouse splenocytes. Meanwhile, cell adhesion analysis revealed that Tα1-iRGD exhibited more specific and greater binding with tumor cells compared with Tα1. Furthermore, the iRGD fragment evidently enhanced the basal ability of Tα1 to inhibit proliferation of cancer cells in vitro, particularly of mouse melanoma cell line B16F10 and human lung cancer cell line H460. Our findings indicated that the addition of an iRGD fragment increased the anti-proliferative activity of Tα1 against cancer cells by improving the ability of Tα1 to penetrate the tumor cells. This study highlighted the important roles of an iRGD sequence in the therapeutic strategy of Tα1-iRGD. Thus, Tα1-iRGD could be a novel drug candidate for cancer treatment.

  1. Recombinant human tumor necrosis factor-alpha: evidence of an indirect mode of antitumor activity.

    PubMed

    Manda, T; Shimomura, K; Mukumoto, S; Kobayashi, K; Mizota, T; Hirai, O; Matsumoto, S; Oku, T; Nishigaki, F; Mori, J

    1987-07-15

    The antitumor activity of recombinant human tumor necrosis factor (rTNF-alpha) was examined on murine tumors in mice and in cultured cells in vitro. Mice were implanted intradermally with Meth A fibrosarcoma (Meth A) on day 0. rTNF-alpha caused tumor necrosis and inhibited the tumor growth when given i.v. on day 7 or 10, but not when given on day 3. When rTNF-alpha was given i.v. in doses of 0.1-3.2 micrograms/mouse twice a week for 3 weeks beginning on day 7 or 11, the growth of solid Meth A, Colon 26 adenocarcinoma, Colon 38 carcinoma, Sarcoma-180, and M5076 reticulum cell sarcoma tumors implanted s.c. or intradermally was markedly inhibited, and the life of the mice bearing these tumors, except M5076 reticulum cell sarcoma, was prolonged. The growth of Meth A implanted i.m. was also markedly inhibited by rTNF-alpha given i.v. However, the life of mice bearing i.p. Colon 26 adenocarcinoma, MH134 hepatoma, Sarcoma-180, and Ehrlich carcinoma was not prolonged by rTNF-alpha given i.p. nine times (days 1-9) in doses up to 1.0 or 3.2 micrograms/mouse. Only in the case of mice bearing i.p. Meth A, the life was slightly prolonged by i.p. treatment with rTNF-alpha but not by i.v. treatment. In experiments against in vitro cultured cells, rTNF-alpha did not show any direct cytotoxicity against mouse tumor cells: Meth A, Colon 26 adenocarcinoma, Colon 38 carcinoma, and Sarcoma-180, but had a cytotoxic effect against L929 mouse fibroblast. The results suggest that rTNF-alpha is a unique antitumor drug with potent necrotizing activity against solid tumors in mice, and that this activity may derive from indirect mechanisms related to the growth of tumors and not to the direct cytotoxicity of the drug.

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

    PubMed

    Liu, Yi; Piao, Hongyu; Gao, Ying; Xu, Caihong; Tian, Ye; Wang, Lihong; Liu, Jinwen; Tang, Bo; Zou, Meijuan; Cheng, Gang

    2015-01-01

    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-OH)SN38 and chitosan-(C20-OH)SN38) 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-OH)SN38 (CS-(10s)SN38) and chitosan-(C20-OH) SN38 (CS-(20s)SN38) 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 (AUC)0-24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P<0.01). A larger AUC0-24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 (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-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg (P<0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C20-OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.

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

    PubMed

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

    2014-04-01

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

  4. Antitumor effects and molecular mechanisms of ponatinib on endometrial cancer cells harboring activating FGFR2 mutations

    PubMed Central

    Kim, Do-Hee; Kwak, Yeonui; Kim, Nam Doo; Sim, Taebo

    2016-01-01

    ABSTRACT Aberrant mutational activation of FGFR2 is associated with endometrial cancers (ECs). AP24534 (ponatinib) currently undergoing clinical trials has been known to be an orally available multi-targeted tyrosine kinase inhibitor. Our biochemical kinase assay showed that AP24534 is potent against wild-type FGFR1-4 and 5 mutant FGFRs (V561M-FGFR1, N549H-FGFR2, K650E-FGFR3, G697C-FGFR3, N535K-FGFR4) and possesses the strongest kinase-inhibitory activity on N549H-FGFR2 (IC50 of 0.5 nM) among all FGFRs tested. We therefore investigated the effects of AP24534 on endometrial cancer cells harboring activating FGFR2 mutations and explored the underlying molecular mechanisms. AP24534 significantly inhibited the proliferation of endometrial cancer cells bearing activating FGFR2 mutations (N549K, K310R/N549K, S252W) and mainly induced G1/S cell cycle arrest leading to apoptosis. AP24534 also diminished the kinase activity of immunoprecipitated FGFR2 derived from MFE-296 and MFE-280 cells and reduced the phosphorylation of FGFR2 and FRS2 on MFE-296 and AN3CA cells. AP24534 caused substantial reductions in ERK phosphorylation, PLCγ signaling and STAT5 signal transduction on ECs bearing FGFR2 activating mutations. Akt signaling pathway was also deactivated by AP24534. AP24534 causes the chemotherapeutic effect through mainly the blockade of ERK, PLCγ and STAT5 signal transduction on ECs. Moreover, AP24534 inhibited migration and invasion of endometrial cancer cells with FGFR2 mutations. In addition, AP24534 significantly blocked anchorage-independent growth of endometrial cancer cells. We, for the first time, report the molecular mechanisms by which AP24534 exerts antitumor effects on ECs with FGFR2 activating mutations, which would provide mechanistic insight into ongoing clinical investigations of AP24534 for ECs. PMID:26574622

  5. Improved tumor targeting and antitumor activity of camptothecin loaded solid lipid nanoparticles by preinjection of blank solid lipid nanoparticles.

    PubMed

    Jang, Dong-Jin; Moon, Cheol; Oh, Euichaul

    2016-05-01

    This study aimed to enhance the in vivo antitumor effects of camptothecin (CPT), a strong antitumor agent whose delivery is limited by poor aqueous solubility and instability of the active lactone form. CPT was loaded into sterically stabilized, solid lipid nanoparticles (CPT-SLNs) formulated for intravenous administration. The influence of preinjected blank SLNs on the tumor targeting, pharmacokinetics and antitumor activity of CPT-SLNs was investigated. The CPT-SLNs composed of trilaurin-based lipid matrix containing poloxamer188 and pegylated phospholipid as stabilizers were prepared by hot homogenization method and evaluated for in vitro characteristics and in vivo performance. The CPT-SLNs showed an in vitro long-term sustained release pattern and effectively protected the CPT lactone form from hydrolysis under physiological conditions. Notable tumor targeting and tumor growth inhibition were observed after intravenous administration of CPT-SLNs to mice with subcutaneous transplants of CT26 carcinoma cells. In pharmacokinetic studies in rats, CPT-SLNs markedly elevated plasma CPT level and prolonged blood circulation compared to free CPT. Nonetheless, high uptake of CPT-SLNs by reticuloendothelial system (RES)-rich tissues resulted in limited tumor targeting of CPT-SLNs and plasma CPT levels. Preinjection of blank SLNs before administration of CPT-SLNs to tumor-bearing mice substantially reduced the accumulation of CPT-SLNs in RES organs. This led to significantly enhanced tumor targeting, improved pharmacokinetic parameters and increased antitumor efficacy of CPT-SLNs. These results suggested that the in vivo antitumor effects of CPT-SLNs could be further enhanced by preinjection of blank SLNs. Therefore, CPT-SLNs with preinjected blank SLNs could be a potential approach for stable and effective CPT-based cancer therapy.

  6. A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells.

    PubMed

    Chu, B; Liu, F; Li, L; Ding, C; Chen, K; Sun, Q; Shen, Z; Tan, Y; Tan, C; Jiang, Y

    2015-03-12

    Aberrant expression or function of epidermal growth factor receptor (EGFR) or the closely related human epidermal growth factor receptor 2 (HER2) can promote cell proliferation and survival, thereby contributing to tumorigenesis. Specific antibodies and low-molecular-weight tyrosine kinase inhibitors of both proteins are currently in clinical trials for cancer treatment. Benzimidazole derivatives possess diverse biological activities, including antitumor activity. However, the anticancer mechanism of 5a (a 2-aryl benzimidazole compound; 2-chloro-N-(2-p-tolyl-1H-benzo[d]imidazol-5-yl)acetamide, C(16)H(14)ClN(3)O, MW299), a novel 2-aryl benzimidazole derivative, toward breast cancer is largely unknown. Here, we demonstrate that 5a potently inhibited both EGFR and HER2 activity by reducing EGFR and HER2 tyrosine phosphorylation and preventing downstream activation of PI3K/Akt and MEK/Erk pathways in vitro and in vivo. We also show that 5a inhibited the phosphorylation of FOXO and promoted FOXO translocation from the cytoplasm into the nucleus, resulting in the G1-phase cell cycle arrest and apoptosis. Moreover, 5a potently induced apoptosis via the c-Jun N-terminal kinase (JNK)-mediated death receptor 5 upregulation in breast cancer cells. The antitumor activity of 5a was consistent with additional results demonstrating that 5a significantly reduced tumor volume in nude mice in vivo. Analysis of the primary breast cancer cell lines with HER2 overexpression further confirmed that 5a significantly inhibited Akt Ser473 and Bad Ser136 phosphorylation and reduced cyclin D3 expression. On the basis of our findings, further development of this 2-aryl benzimidazole derivative, a new class of multitarget anticancer agents, is warranted and represents a novel strategy for improving breast cancer treatment.

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

    PubMed

    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.

  8. Herbacetin is a novel allosteric inhibitor of ornithine decarboxylase with antitumor activity

    PubMed Central

    Lee, Mee-Hyun; Oi, Naomi; Lim, Do Young; Kim, Myoung Ok; Cho, Young-Yeon; Pugliese, Angelo; Shim, Jung-Hyun; Chen, Hanyong; Cho, Eun Jin; Kim, Jong-Eun; Kang, Sun Chul; Paul, Souren; Kang, Hee Eun; Jung, Ji Won; Lee, Sung-Young; Kim, Sung-Hyun; Reddy, Kanamata; Yeom, Young Il; Bode, Ann M; Dong, Zigang

    2015-01-01

    Ornithine decarboxylase (ODC) is a rate-limiting enzyme in the first step of polyamine biosynthesis that is associated with cell growth and tumor formation. Existing catalytic inhibitors of ODC have lacked efficacy in clinical testing or displayed unacceptable toxicity. In this study, we report the identification of an effective and nontoxic allosteric inhibitor of ODC. Using computer docking simulation and an in vitro ODC enzyme assay, we identified herbacetin, a natural compound found in flax and other plants, as a novel ODC inhibitor. Mechanistic investigations defined aspartate 44 in ODC as critical for binding. Herbacetin exhibited potent anticancer activity in colon cancer cell lines expressing high levels of ODC. Intraperitoneal or oral administration of herbacetin effectively suppressed HCT116 xenograft tumor growth and also reduced the number and size of polyps in a mouse model of APC-driven colon cancer (ApcMin/+). Unlike the well established ODC inhibitor DFMO, herbacetin treatment was not associated with hearing loss. Taken together, our findings defined the natural product herbacetin as an allosteric inhibitor of ODC with chemopreventive and antitumor activity in preclinical models of colon cancer, prompting its further investigation in clinical trials. PMID:26676750

  9. Involvement of autophagy in antitumor activity of folate-appended methyl-β-cyclodextrin.

    PubMed

    Onodera, Risako; Motoyama, Keiichi; Tanaka, Nao; Ohyama, Ayumu; Okamatsu, Ayaka; Higashi, Taishi; Kariya, Ryusho; Okada, Seiji; Arima, Hidetoshi

    2014-03-20

    Autophagy, the major lysosomal pathway for recycling intracellular components including organelles, is emerging as a key process regulating tumorigenesis and cancer therapy. Most recently, we newly synthesized folate-appended methyl-β-cyclodextrin (FA-M-β-CyD), and demonstrated the potential of FA-M-β-CyD as a new antitumor drug. In this study, we investigated whether anticancer activity of FA-M-β-CyD in folate receptor-α (FR-α)-positive tumor cells is involved in autophagy. In contrast to methyl-β-cyclodextrin (M-β-CyD), FA-M-β-CyD entered KB cells (FR-α (+)) through CLIC/GEEC endocytosis. No significant depression in the DNA content was observed in KB cells after treatment with FA-M-β-CyD. Additionally, the transmembrane potential of mitochondria after treatment with FA-M-β-CyD was drastically elevated. Meanwhile, FA-M-β-CyD induced the formation of autophagic vacuoles, which were partially colocalized with mitochondria, in KB cells. Taken together, these results suggest that FR-α-expressing cell-selective cytotoxic activity of FA-M-β-CyD could be mediated by the regulation of autophagy, rather than the induction of apoptosis.

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

    PubMed

    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.

  11. Oncolytic adenovirus expressing interleukin-18 improves antitumor activity of dacarbazine for malignant melanoma

    PubMed Central

    Yang, Chunhua; Cao, Hang; Liu, Ning; Xu, Kai; Ding, Meng; Mao, Li-jun

    2016-01-01

    Conditionally replicating adenoviruses have emerged as novel therapeutic agents for cancer. This study aimed to evaluate synergistic antitumor activity of replication-competent adenovirus armed with interleukin (IL)-18 (ZD55-IL-18) and dacarbazine (DTIC) against melanoma. Melanoma A375 cells or nude mouse tumor xenografts were treated with ZD55-IL-18 alone or together with DTIC. The results showed that ZD55-IL-18 competently replicated in A375 cells and expressed IL-18, and these were not affected by DTIC. ZD55-IL-18 enhanced the cytotoxicity of DTIC accompanied by increased apoptosis. Moreover, ZD55-IL-18 and DTIC synergistically inhibited the growth but promoted the apoptosis of A375 xenografts and inhibited vascular endothelial growth factor expression and lung metastasis in xenografts of nude mice. In conclusion, this is the first study to show synergistic anticancer activity of ZD55-IL-18 and DTIC for malignant melanoma. Our results provide evidence that chemo-gene-viro therapeutic approach has greater potential for malignant cancers than conventional chemotherapy or gene therapy. PMID:27895465

  12. Oncolytic adenovirus expressing interleukin-18 improves antitumor activity of dacarbazine for malignant melanoma.

    PubMed

    Yang, Chunhua; Cao, Hang; Liu, Ning; Xu, Kai; Ding, Meng; Mao, Li-Jun

    2016-01-01

    Conditionally replicating adenoviruses have emerged as novel therapeutic agents for cancer. This study aimed to evaluate synergistic antitumor activity of replication-competent adenovirus armed with interleukin (IL)-18 (ZD55-IL-18) and dacarbazine (DTIC) against melanoma. Melanoma A375 cells or nude mouse tumor xenografts were treated with ZD55-IL-18 alone or together with DTIC. The results showed that ZD55-IL-18 competently replicated in A375 cells and expressed IL-18, and these were not affected by DTIC. ZD55-IL-18 enhanced the cytotoxicity of DTIC accompanied by increased apoptosis. Moreover, ZD55-IL-18 and DTIC synergistically inhibited the growth but promoted the apoptosis of A375 xenografts and inhibited vascular endothelial growth factor expression and lung metastasis in xenografts of nude mice. In conclusion, this is the first study to show synergistic anticancer activity of ZD55-IL-18 and DTIC for malignant melanoma. Our results provide evidence that chemo-gene-viro therapeutic approach has greater potential for malignant cancers than conventional chemotherapy or gene therapy.

  13. Sulfated polysaccharides from brown seaweeds Saccharina japonica and Undaria pinnatifida: isolation, structural characteristics, and antitumor activity.

    PubMed

    Vishchuk, Olesya S; Ermakova, Svetlana P; Zvyagintseva, Tatyana N

    2011-12-13

    During the last decade brown seaweeds attracted much attention as a source of polysaccharides, namely laminarans, alginic acids, and sulfated polysaccharides-fucoidans, with various structures and biological activities. In this study, sulfated polysaccharides were isolated from brown seaweeds Saccharina japonica (formerly named Laminaria) and Undaria pinnatifida and their antitumor activity was tested against human breast cancer T-47D and melanoma SK-MEL-28 cell lines. The sulfated polysaccharide form S. japonica was highly branched partially acetylated sulfated galactofucan, built up of (1→3)-α-L-fucose residues. The sulfated polysaccharide from U. pinnatifida was partially acetylated highly sulfated galactofucan consisting of (1→3)- or (1→3);(1→4)-α-L-fucose residues. Fucoidans from S. japonica and U. pinnatifida distinctly inhibited proliferation and colony formation in both breast cancer and melanoma cell lines in a dose-dependent manner. These results indicated that the use of sulfated polysaccharides from brown seaweeds S. japonica and U. pinnatifida might be a potential approach for cancer treatment.

  14. Purification, antitumor and immunomodulatory activity of polysaccharides from soybean residue fermented with Morchella esculenta.

    PubMed

    Li, Shuhong; Gao, Ang; Dong, Shuang; Chen, Ye; Sun, Shuang; Lei, Zhongfang; Zhang, Zhenya

    2017-03-01

    Crude polysaccharides (MPS) from soybean residue fermented with Morchella esculenta were extracted and purified by DEAE Sephadex A-50 chromatography and Sephadex G-100 size-exclusion chromatography in sequence. Three main fractions MP-1, MP-3 and MP-4 were obtained during the purification steps. The recovery rates based on MPS used were 26.2%, 29.1% and 18.7% for MP-1, MP-3 and MP-4 respectively. The monosaccharide composition, ultraviolet spectrum, infrared spectrum and NMR of the three fractions were analyzed. Furthermore, the influence of polysaccharides fractions upon activation of macrophage cells (RAW 264.7), antitumor activities of the human hepatocellular cell line (HepG-2) and human cervical carcinoma cells (Hela) in vitro were evaluated. The results indicated that the proliferation of MP-3 on RAW 264.7 was 313.57% at 25μg/mL, which is high while MP-1 had a higher growth inhibition effect on HepG-2 cells of 68.01% at concentration of 50μg/mL. The fractions of MP-1, MP-3 and MP-4 induced apoptosis in HepG-2 cells and Hela cells by arresting cell cycle progression at the G0/G1 phase. These findings suggest that the purified polysaccharides fractions may be a potent candidate for human hepatocellular and cervical carcinoma treatment and prevention in functional foods and pharmacological fields.

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

    PubMed Central

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

    2011-01-01

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

  16. Engineered adenovirus fiber shaft fusion homotrimer of soluble TRAIL with enhanced stability and antitumor activity

    PubMed Central

    Yan, J; Wang, L; Wang, Z; Wang, Z; Wang, B; Zhu, R; Bi, J; Wu, J; Zhang, H; Wu, H; Yu, B; Kong, W; Yu, X

    2016-01-01

    Successful cancer therapies aim to induce selective apoptosis in neoplastic cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered an attractive anticancer agent due to its tumor cell-specific cytotoxicity. However, earlier studies with recombinant TRAIL revealed many shortcomings, including a short half-life, off-target toxicity and existence of TRAIL-resistant tumor cells. In this study, we developed a novel engineering strategy for recombinant soluble TRAIL by redesigning its structure with the adenovirus knobless fiber motif to form a stable homotrimer with improved antitumor activity. The result is a highly stable fiber-TRAIL fusion protein that could form homotrimers similar to natural TRAIL. The recombinant fusion TRAIL developed here displayed high specific activity in both cell-based assays in vitro and animal tests in vivo. This construct will serve as a foundation for a new generation of recombinant proteins suitable for use in preclinical and clinical studies and for effective combination therapies to overcome tumor resistance to TRAIL. PMID:27336718

  17. Synthesis, Characterization, Antimicrobial and Antitumor Activities of Sucrose Octa(N-ethyl)carbamate.

    PubMed

    Raposo, Claudia D; Petrova, Krasimira T; Barros, Maria T; Calhelha, Ricardo C; Sokovic, Marina; Ferreira, Isabel C F R

    2016-01-01

    Sucrose octa(N-ethyl)carbamate was synthesized directly from sucrose and ethyl isocyanate, and its structure was confirmed by various analytical methods, such as (1)H and (13)C NMR, FTIR, m.p., MS, and optical rotation. Its antibacterial, antifungal and cytotoxic activities were investigated. It exhibited strong inhibition against all bacteria tested, namely S. aureus (MIC 0.18±0.006), B. cereus (MIC 0.094±0.000), M. flavus (MIC 0.28±0.01), L. monocytogenes (MIC 0.18±0.006), P. aeruginosa (MIC 0.094±0.002), S. typhimurium (MIC 0.094±0.002), E. coli (MIC 0.18±0.006) and E. cloacae (MIC 0.18±0.006) and strong antifungal activity towards T. viride (MIC 0.09 ± 0.006), A. versicolor (MIC 0.18 ± 0.01), A. ochraceus (MIC 0.375 ± 0.01) and P. ochrochloron (MIC 0.375 ± 0.04). Furthermore, it showed moderate antitumor potential against human breast (GI50 357.20±14.12), colon (GI50 332.43±11.19) and cervical (GI50 282.67±3.97) cell lines and, more important, without hepatotoxicity.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2017-01-01

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

  20. Antitumor Activities of Ethyl Acetate Extracts from Selaginella doederleinii Hieron In Vitro and In Vivo and Its Possible Mechanism

    PubMed Central

    Li, Juan; Zhao, Ping; Ma, Wen-tao; Feng, Xie-he; Chen, Ke-li

    2015-01-01

    The antitumor activities of ethyl acetate extracts from Selaginella doederleinii Hieron (SD extracts) in vitro and in vivo and its possible mechanism were investigated. HPLC method was developed for chemical analysis. SD extracts were submitted to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay on different cells, flow cytometry, and RT-PCR analysis using HepG2 cell and antitumor activity in vivo using H-22 xenograft tumor mice. Six biflavonoids from SD extracts were submitted to molecular docking assay. The results showed that SD extracts had considerable antitumor activity in vitro and in vivo without obvious toxicity on normal cells and could induce cell apoptosis. The mechanisms of tumorigenesis and cell apoptosis induced by SD extracts may be associated with decreasing the ratio of bcl-2 and bax mRNA level, activating caspase-3, suppressing survivin, and decreasing the gene expression of COX-2, 5-LOX, FLAP, and 12-LOX mRNA. The main active component in SD extracts is biflavonoids and some exhibited strong interactions with COX-2, 5-LOX, 12-LOX, and 15-LOX. These results offering evidence of possible mechanisms of SD extracts suppress cell proliferation and promote apoptosis and provide the molecular theoretical basis of clinical application of S. doederleinii for cancer therapy. PMID:25866543

  1. Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin--from bench to bedside.

    PubMed

    Efferth, Thomas

    2007-04-01

    Secondary metabolites from plants serve as defense against herbivores, microbes, viruses, or competing plants. Many medicinal plants have pharmacological activities and may, thus, be a source for novel treatment strategies. During the past 10 years, we have systematically analyzed medicinal plants used in traditional Chinese medicine and focused our interest on Artemisia annua L. (qinhao, sweet wormwood). We found that the active principle of Artemisia annua L., artemisinin, exerts not only antimalarial activity but also profound cytotoxicity against tumor cells. The inhibitory activity of artemisinin and its derivatives towards cancer cells is in the nano- to micromolar range. Candidate genes that may contribute to the sensitivity and resistance of tumor cells to artemisinins were identified by pharmacogenomic and molecular pharmacological approaches. Target validation was performed using cell lines transfected with candidate genes or corresponding knockout cells. The identified genes are from classes with diverse biological functions; for example, regulation of proliferation (BUB3, cyclins, CDC25A), angiogenesis (vascular endothelial growth factor and its receptor, matrix metalloproteinase-9, angiostatin, thrombospondin-1) or apoptosis (BCL-2, BAX, NF-kappaB). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Antioxidant stress genes (thioredoxin, catalase, gamma-glutamylcysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines overexpressing genes that confer resistance to established antitumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that artesunate is not involved in multidrug resistance. The anticancer activity of artesunate has also been shown in human xenograft tumors in mice. First encouraging experience in the clinical treatment of patients suffering from uveal

  2. Cyclopalladated and cycloplatinated benzophenone imines: antitumor, antibacterial and antioxidant activities, DNA interaction and cathepsin B inhibition.

    PubMed

    Albert, Joan; D'Andrea, Lucía; Granell, Jaume; Pla-Vilanova, Pepita; Quirante, Josefina; Khosa, Muhammad Kaleem; Calvis, Carme; Messeguer, Ramon; Badía, Josefa; Baldomà, Laura; Font-Bardia, Mercè; Calvet, Teresa

    2014-11-01

    The antitumor, antibacterial and antioxidant activity, DNA interaction and cathepsin B inhibition of cyclo-ortho-palladated and -platinated compounds [Pd(C,N)]2(μ-X)2 [X=OAc (1), X=Cl (2)] and trans-N,P-[M(C,N)X(PPh3)] [M=Pd, X=OAc (3), M=Pd, X=Cl (4), M=Pt, X=Cl (5)] are discussed [(C,N)=cyclo-ortho-metallated benzophenone imine]. The cytotoxicity of compound 5 has been evaluated towards human breast (MDA-MB-231 and MCF-7) and colon (HCT-116) cancer cell lines and that of compounds 1-4 towards the HCT-116 human colon cancer cell line. These cytotoxicities have been compared with those previously reported for compounds 1-4 towards MDA-MB-231 and MCF-7 cancer cell lines. Compound 3 and 4 were approximately four times more active than cisplatin against the MDA-MB-231 and MCF-7 cancer cell lines, and compound 5, was approximately four times more potent than cisplatin against the HCT-116 cancer cell line. The antibacterial activity of compounds 1-5 was in between the ranges of activity of the commercial antibiotic compounds cefixime and roxithromycin. Complexes 1-2 and 4-5 presented also antioxidant activity. Compounds 1-5 alter the DNA tertiary structure in a similar way to cisplatin, but at higher concentration, and do not present a high efficiency as cathepsin B inhibitors. Compound 5 has not been previously described, and its preparation, characterization, and X-ray crystal structure are reported.

  3. Novel binding interactions of the DNA fragment d(pGpG) cross-linked by the antitumor active compound tetrakis(mu-carboxylato)dirhodium(II,II).

    PubMed

    Chifotides, Helen T; Koshlap, Karl M; Pérez, Lisa M; Dunbar, Kim R

    2003-09-03

    Insight into the N7/O6 equatorial binding interactions of the antitumor active complex Rh(2)(OAc)(4)(H(2)O)(2) (OAc(-) = CH(3)CO(2)(-)) with the nucleotide 5'-GMP and the DNA fragment d(pGpG) has been obtained by one- (1D) and two-dimensional (2D) NMR spectroscopy. The lack of N7 protonation at low pH values and the significant increase in the acidity of N1-H (pK(a) approximately 5.6 as compared to 8.5 for N7 only bound platinum adducts), indicated by the pH dependence study of the H8 (1)H NMR resonance for the HT (head-to-tail) isomer of Rh(2)(OAc)(2)(5'-GMP)(2), are consistent with bidentate N7/O6 binding of the guanine. The H8 (1)H NMR resonance of the HH (head-to-head) Rh(2)(OAc)(2)(5'-GMP)(2) isomer, as well as the 5'-G and 3'-G H8 resonances of the Rh(2)(OAc)(2) [d(pGpG)] adduct exhibit pH-independent titration curves, attributable to the added effect of the 5'-phosphate group deprotonation at a pH value similar to that of the N1 site. The enhancement in the acidity of N1-H, with respect to N7 only bound metal adducts, afforded by the O6 binding of the bases to the rhodium centers, has been corroborated by monitoring the pH dependence of the purine C6 and C2 (13)C NMR resonances for Rh(2)(OAc)(2)(5'-GMP)(2) and Rh(2)(OAc)(2) [d(pGpG)]. The latter studies resulted in pK(a) values in good agreement with those derived from the pH-dependent (1)H NMR titrations of the H8 resonances. Comparison of the (13)C NMR resonances of C6 and C2 for the dirhodium adducts Rh(2)(OAc)(2)(5'-GMP)(2) and Rh(2)(OAc)(2) [d(pGpG)] with the corresponding resonances of the unbound ligands at pH 8.0, showed substantial downfield shifts of Deltadelta approximately 11.0 and 6.0 ppm, respectively. The HH arrangement of the bases in the Rh(2)(OAc)(2) [d(pGpG)] adduct is evidenced by intense H8/H8 ROE cross-peaks in the 2D ROESY NMR spectrum. The presence of the terminal 5'-phosphate group in d(pGpG) results in stabilization of one left-handed Rh(2)(OAc)(2) [d(pGpG)] HH1 L conformer, due to

  4. Oyster (Crassostrea gigas) hydrolysates produced on a plant scale have antitumor activity and immunostimulating effects in BALB/c mice.

    PubMed

    Wang, Yu-Kai; He, Hai-Lun; Wang, Guo-Fan; Wu, Hao; Zhou, Bai-Cheng; Chen, Xiu-Lan; Zhang, Yu-Zhong

    2010-02-02

    Oyster extracts have been reported to have many bioactive peptides. But the function of oyster peptides produced by proteolysis is still unknown. In this study, the oligopeptide-enriched hydrolysates from oyster (Crassostrea gigas) were produced using the protease from Bacillus sp. SM98011 at laboratory level, and scaled up to pilot (100 L) and plant (1,000 L) levels with the same conditions. And the antitumor activity and immunostimulating effects of the oyster hydrolysates in BALB/c mice were investigated. The growth of transplantable sarcoma-S180 was obviously inhibited in a dose-dependent manner in BALB/c mice given the oyster hydrolysates. Mice receiving 0.25, 0.5 and 1 mg/g of body weight by oral gavage had 6.8%, 30.6% and 48% less tumor growth, respectively. Concurrently, the weight coefficients of the thymus and the spleen, the activity of natural killer (NK) cells, the spleen proliferation of lymphocytes and the phagocytic rate of macrophages in S180-bearing mice significantly increased after administration of the oyster hydrolysates. These results demonstrated that oyster hydrolysates produced strong immunostimulating effects in mice, which might result in its antitumor activity. The antitumor and immunostimulating effects of oyster hydrolysates prepared in this study reveal its potential for tumor therapy and as a dietary supplement with immunostimulatory activity.

  5. Dorzolamide synergizes the antitumor activity of mitomycin C against Ehrlich's carcinoma grown in mice: role of thioredoxin-interacting protein.

    PubMed

    Ali, Belal M; Zaitone, Sawsan A; Shouman, Samia A; Moustafa, Yasser M

    2015-12-01

    The antitumor activity of carbonic anhydrase (CA) inhibitors is attributed to their ability to induce a state of intracellular acidification. In fact, acidic intracellular pH was demonstrated to upregulate several tumor suppressor proteins and increase the activity of many chemotherapies. The present study aimed to investigate the antitumor activity of the CA inhibitor, dorzolamide, in combination with mitomycin C and to study the effect of these drugs on tumoral thioredoxin-interacting protein (TXNIP) as well as tumor cell proliferation and apoptosis. Solid tumors were induced by subcutaneous inoculation of Ehrlich's ascites carcinoma (EAC) cells in female mice. Mice were treated with dorzolamide (3, 10, or 30 mg/kg/day, i.p.) and/or mitomycin C (1 mg/kg, i.p.) weekly for 3 weeks. Treatment with mitomycin C increased TXNIP level in EAC solid tumors in mice. Likewise, treatment with dorzolamide upregulated TXNIP and p53 while downregulated bcl-2. Both drug therapies increased tumoral caspase 9, caspase 3, and PARP-1 cleavage in addition to decreasing the proliferative Ki-67-stained nuclear fraction. Indeed, a synergistic effect was detected between mitomycin C and dorzolamide. The current data demonstrated that the antitumor activity of mitomycin C and dorzolamide was, at least in part, mediated through stimulating tumoral expression of TXNIP and enhancing tumor apoptosis.

  6. Drug activity screening based on microsomes-hydrogel system in predicting metabolism induced antitumor effect of oroxylin A

    PubMed Central

    Yang, Huiying; Li, Jianfeng; Zheng, Yuanting; Zhou, Lu; Tong, Shanshan; Zhao, Bei; Cai, Weimin

    2016-01-01

    A novel microsomes-hydrogel added cell culture system (MHCCS) was employed in the antitumor activity screening of natural compounds, aiming to achieve drug screening with better in vivo correlation, higher initiative to explore the potential active metabolites, and investigation of the antitumor mechanism from the perspective of metabolism. MTT assay and cell apoptosis detection showed that test drug oroxylin A (OA) had enhanced cytotoxicity and wogonin (W) with reduced cytotoxicity on MCF-7 cell line upon MHCCS incubation. In vivo antitumor evaluations also demonstrated that OA induced higher tumor inhibition than W at the same dosage. To explore the reasons, nine major metabolites of OA were separated and collected through UPLC-Q-TOF and semi-preparative HPLC. Metabolites M318 exhibited higher cytotoxicity than OA and other metabolites by MTT assay. 1H NMR spectrums, HPLC and TOF MS/MS results revealed that OA was catalyzed into its active metabolite M318 via a ring-opening reaction. M318 induced significant cell apoptosis and S-phase arrest through affecting tumor survival related genes after mechanism study. In conclusion, our MHCCS could be a useful tool for drug activity screening from a perspective of metabolism. PMID:26905263

  7. Antitumor Activity of Kielmeyera Coriacea Leaf Constituents in Experimental Melanoma, Tested in Vitro and in Vivo in Syngeneic Mice

    PubMed Central

    Figueiredo, Carlos Rogério; Matsuo, Alisson Leonardo; Massaoka, Mariana Hiromi; Girola, Natalia; Azevedo, Ricardo Alexandre; Rabaça, Aline Nogueira; Farias, Camyla Fernandes; Pereira, Felipe Valença; Matias, Natalia Silva; Silva, Luciana Pereira; Rodrigues, Elaine Guadelupe; Lago, João Henrique Guilardi; Travassos, Luiz Rodolpho; Silva, Regildo Márcio Gonçalves

    2014-01-01

    Purpose: The antitumor activity of Kielmeyera coriacea (Clusiaceae), a medicinal plant used in the treatment of parasitic, as well as fungal and bacterial infections by the Brazilian Cerrado population, was investigated. Methods: A chloroform extract (CE) of K. coriacea was tested in the murine melanoma cell line (B16F10-Nex2) and a panel of human tumor cell lines. Tumor cell migration was determined by the wound-healing assay and the in vivo antitumor activity of CE was investigated in a melanoma cell metastatic model. 1H NMR and GC/MS were used to determine CE chemical composition. Results: We found that CE exhibited strong cytotoxic activity against murine melanoma cells and a panel of human tumor cell lines in vitro. CE also inhibited growth of B16F10-Nex2 cells at sub lethal concentrations, inducing cell cycle arrest at S phase, and inhibition of tumor cell migration. Most importantly, administration of CE significantly reduced the number of melanoma metastatic nodules in vivo. Chemical analysis of CE indicated the presence of the long chain fatty compounds, 1-eicosanol, 1-docosanol, and 2-nonadecanone as main constituents. Conclusion: These results indicate that K. coriacea is a promising medicinal plant in cancer therapy exhibiting antitumor activity both in vitro and in vivo against different tumor cell lines. PMID:25364658

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

    PubMed

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

    2015-07-01

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

  9. Conversion of abiraterone to D4A drives antitumor activity in prostate cancer

    PubMed Central

    Li, Zhenfei; Bishop, Andrew; Alyamani, Mohammad; Garcia, Jorge A.; Dreicer, Robert; Bunch, Dustin; Liu, Jiayan; Upadhyay, Sunil K.; Auchus, Richard J.; Sharifi, Nima

    2015-01-01

    Summary Prostate cancer resistance to castration occurs because tumors acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signaling by the androgen receptor (AR) and the development of castration-resistant prostate cancer (CRPC)1–3. Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly require enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes4,5. Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival6,7. We hypothesized that abiraterone is converted by an enzyme to the more active Δ4-abiraterone (D4A) that blocks multiple steroidogenic enzymes and antagonizes the androgen receptor (AR), providing an additional explanation for abiraterone’s clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive AR antagonism by D4A is comparable to the potent antagonist, enzalutamide. D4A also has more potent antitumor activity against xenograft tumors than abiraterone. Our findings suggest an additional explanation – conversion to a more active agent – for abiraterone’s survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment. PMID:26030522

  10. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer.

    PubMed

    Gross, Matt I; Demo, Susan D; Dennison, Jennifer B; Chen, Lijing; Chernov-Rogan, Tania; Goyal, Bindu; Janes, Julie R; Laidig, Guy J; Lewis, Evan R; Li, Jim; Mackinnon, Andrew L; Parlati, Francesco; Rodriguez, Mirna L M; Shwonek, Peter J; Sjogren, Eric B; Stanton, Timothy F; Wang, Taotao; Yang, Jinfu; Zhao, Frances; Bennett, Mark K

    2014-04-01

    Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor-positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2(+) cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors.

  11. CYP24A1 Inhibition Enhances the Antitumor Activity of Calcitriol

    PubMed Central

    Muindi, Josephia R.; Yu, Wei-Dong; Ma, Yingyu; Engler, Kristie L.; Kong, Rui-Xian; Trump, Donald L.; Johnson, Candace S.

    2010-01-01

    High systemic exposures to calcitriol are necessary for optimal antitumor effects. Human prostate cancer PC3 cells are insensitive to calcitriol treatment. Therefore, we investigated whether the inhibition of 24-hydroxylase (CYP24A1), the major calcitriol inactivating enzyme, by ketoconazole (KTZ) or RC2204 modulates calcitriol serum pharmacokinetics and biologic effects. Dexamethasone (Dex) was added to minimize calcitriol-induced hypercalcemia and as a steroid replacement for the KTZ inhibition of steroid biosynthesis cytochrome P450 enzymes. KTZ effectively inhibited time-dependent calcitriol-inducible CYP24A1 protein expression and enzyme activity in PC3 cells and C3H/HeJ mouse kidney tissues. Systemic calcitriol exposure area under the curve was higher in mice treated with a combination of calcitriol and KTZ than with calcitriol alone. KTZ and Dex synergistically potentiated calcitriol-mediated antiproliferative effects in PC3 cells in vitro; this effect was associated with enhanced apoptosis. After treatment with calcitriol and KTZ/Dex, although caspase-9 and caspase-3 were not activated and cytochrome c was not released by mitochondria, caspase-8 was activated and the truncated Bid protein level was increased. Translocation of apoptosis-inducing factor to the nucleus was observed, indicating a role of the apoptosis-inducing factor-mediated and caspase-independent apoptotic pathways. Calcitriol and KTZ/Dex combination suppressed the clonogenic survival and enhanced the growth inhibition observed with calcitriol alone in PC3 human prostate cancer xenograft mouse model. Our results show that the administration of calcitriol in combination with CYP24A1 inhibitor enhances antiproliferative effects, increases systemic calcitriol exposure, and promotes the activation of caspase-independent apoptosis pathway. PMID:20591973

  12. Antitumor Effects and Immunomodulating Activities of Phellinus linteus Extract in a CT-26 Cell-Injected Colon Cancer Mouse Model

    PubMed Central

    Hwang, Seung-Lark; Yun, Ik-Jin; Do, Eun-Ju; Lee, Won-Ha; Jung, Young-Mi; Hong, Sung-Chang; Park, Dong-Chan

    2009-01-01

    The antitumor effects of Phellinus linteus extract (Keumsa Linteusan) were investigated in a CT-26 cell-injected colon cancer mouse model. When administered orally (250~1,000 mg/kg body weight), Keumsa Linteusan significantly inhibited the growth of solid colon cancer. The highest dose was highly effective, reducing tumor formation by 26% compared with the control group. The anticomplementary activity of Keumsa Linteusan increased in a dose-dependent manner. Lysosomal enzyme activity of macrophages was increased by 2-fold (100 µg/ml) compared with the control group. Keumsa Linteusan can be regarded as a potent enhancer of the innate immune response, and can be considered as a very promising candidate for antitumor action. PMID:23983521

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

    PubMed

    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.

  14. In vitro antitumor activity of Latcripin-15 regulator of chromosome condensation 1 domain protein

    PubMed Central

    Tian, Li; Wang, Xiaoli; Li, Xingyun; Liu, Ben; Zhang, Wei; Cao, Jing; Ning, Anhong; Huang, Min; Zhong, Mintao

    2016-01-01

    Cancer is one of the most significant health problems worldwide and thus the development of novel therapeutic agents with fewer side effects is required. The present study investigated the in vitro anticancer effects of a newly isolated fungal protein. In this study, Latcripin-15 (LP-15) regulator of chromosome condensation 1 (RCC1) domain protein, which is obtained from the Lentinula edodes C91-3 fungal strain, was identified, cloned, expressed, purified and re-folded to assess the in vitro antitumor activity of the protein. LP-15 RCC1 full-length cDNA was isolated from Lentinula edodes using 3′ and 5′-rapid amplification of cDNA ends and then cloned, expressed, purified and re-folded in vitro. In addition, the effects of the isolated LP-15 RCC1 protein's functional domain on the viability and apoptosis of human lung cancer A549 cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, transmission electron microscopy, flow cytometry and Hoechst 33258 staining. The LP-15 RCC1 functional domain protein was successfully expressed, purified and re-folded in vitro. Treatment with the LP-15 RCC1 functional domain protein significantly reduced tumor cell viability and induced apoptosis in A549 cells. The results of the present study indicate that the LP-15 RCC1 functional domain requires further investigation as a novel therapeutic agent for cancer therapy. PMID:27899975

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

    PubMed Central

    Naguib, Youssef W.; Kumar, Amit; Cui, Zhengrong

    2014-01-01

    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. PMID:25313350

  16. Characterization and antitumor activities of a polysaccharide from the rhizoma of Menispermum dauricum.

    PubMed

    Lin, Mei; Xia, Bairong; Yang, Meng; Gao, Shu; Huo, Yanqiu; Lou, Ge

    2013-02-01

    The rhizome of Menispermum dauricum DC (Menispermaceae) is one of the most commonly used traditional Chinese medicines officially listed in Chinese Pharmacopeia. In present study, we purified a water-soluble polysaccharide (WMDP) from this plant and investigated its physicochemical properties. WMDP was a homogeneous polysaccharide, with an average molecular weight of approximately 3.5×10(4)Da, as determined by high-performance gel-permeation chromatography (HPGPC). Gas chromatography (GC) analysis identified that WMDP was composed of Glc, Gal, Xyl, Rha, Ara and Man in the ratio of 2.45:2.13:1.05:1.29:1.63:1.45. The interreaction between Gongo Red and WMDP in NaOH solutions resulted in the shift of maximum absorption, indicating WMDP had a triple-helix conformation. We also investigated the antitumor activities and mechanisms of WMDP in human ovarian carcinoma SKOV3 cells. The experimental evidence showed that WMDP significantly inhibited cell proliferation and DNA synthesis in SKOV3 cells in a concentration-dependent manner, due to a significant increase in the number of apoptotic cells. Furthermore, treatment with WMDP caused a rapid loss of intracellular glutathione (GSH) content and stimulation of reactive oxygen species (ROS). In addition, nuclear factor-kappa B (NF-κB) in SKOV3 cells received WMDP treatment was inactivated. Taken together, induction of apoptosis on SKOV3 cells by WMDP was mainly associated with ROS production, GSH depletion and NF-κB inactivation.

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

    PubMed

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

    2001-01-01

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

  18. Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity

    PubMed Central

    Ghosh, Arnab; Dogan, Yildirim; Moroz, Maxim; Holland, Amanda M.; Yim, Nury L.; Rao, Uttam K.; Young, Lauren F.; Tannenbaum, Daniel; Masih, Durva; Velardi, Enrico; Tsai, Jennifer J.; Jenq, Robert R.; Penack, Olaf; Hanash, Alan M.; Smith, Odette M.; Piersanti, Kelly; Lezcano, Cecilia; Murphy, George F.; Liu, Chen; Palomba, M. Lia; Sauer, Martin G.; Sadelain, Michel; Ponomarev, Vladimir; van den Brink, Marcel R.M.

    2013-01-01

    Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro–generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD. PMID:23676461

  19. TCRγ4δ1-Engineered αβT Cells Exhibit Effective Antitumor Activity

    PubMed Central

    He, Kangxia; You, Hongqin; Li, Yuxia; Cui, Lianxian; Zhang, Jianmin; He, Wei

    2016-01-01

    T cell engineering with T cell receptors (TCRs) specific for tumors plays an important role in adoptive T cell transfer (ATC) therapy for cancer. Here, we present a novel strategy to redirect peripheral blood-derived αβT cells against tumors via TCRγ4δ1 gene transduction. The broad-spectrum antitumor activity of TCRδ1 cells in innate immunity is dependent on CDR3δ1. TCRγ4δ1-engineered αβT cells were prepared by lentiviral transduction and characterized by analyzing in vitro and in vivo cytotoxicity to tumors, ability of proliferation and cytokine production, and potential role in autoimmunity. Results show that TCRγ4δ1 genes were transduced to approximately 36% of polyclonal αβT cells. TCRγ4δ1-engineered αβT cells exhibited effective in vitro TCRγδ-dependent cytotoxicity against various tumor cells via the perforin-granzyme pathway. They also showed a strong proliferative capacity and robust cytokine production. TCRγ4δ1-engineered αβT cells neither expressed mixed TCR dimers nor bound/killed normal cells in vitro. More important, adoptive transfer of TCRγ4δ1-engineered αβT cells into nude mice bearing a human HepG2 cell line significantly suppressed tumor growth. Our results demonstrate a novel role for TCRγ4δ1 in gene therapy and ATC for cancer. PMID:27463149

  20. Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor.

    PubMed

    Shikata, Yuki; Yoshimaru, Tetsuro; Komatsu, Masato; Katoh, Hiroto; Sato, Reiko; Kanagaki, Shuhei; Okazaki, Yasumasa; Toyokuni, Shinya; Tashiro, Etsu; Ishikawa, Shumpei; Katagiri, Toyomasa; Imoto, Masaya

    2017-01-25

    Xanthohumol (XN), a simple prenylated chalcone, can be isolated from hops and has the potential to be a cancer chemopreventive agent against several human tumor cell lines. We previously identified valosin-containing protein (VCP) as a target of XN; VCP can also play crucial roles in cancer progression and prognosis. Therefore, we investigated the molecular mechanisms governing the contribution of VCP to the antitumor activity of XN. Several human tumor cell lines were treated with XN to investigate which human tumor cell lines are sensitive to XN. Several cell lines exhibited high sensitivity to XN both in vitro and in vivo. shRNA screening and bioinformatics analysis identified that the inhibition of the adenylate cyclase (AC) pathway synergistically facilitated apoptosis induced by VCP inhibition. These results suggest there is crosstalk between the AC pathway and VCP function, and targeting both VCP and the AC pathway is a potential chemotherapeutic strategy for a subset of tumor cells. This article is protected by copyright. All rights reserved.

  1. Antitumor activity of a folate receptor-targeted immunoglobulin G-doxorubicin conjugate

    PubMed Central

    Yang, Tan; Xu, Ling; Li, Bin; Li, Weijie; Ma, Xiang; Fan, Lingling; Lee, Robert J; Xu, Chuanrui; Xiang, Guangya

    2017-01-01

    Development of antibody-drug conjugates (ADCs) is a promising therapeutic strategy for cancer therapy. In this study, folate was conjugated via a polyethyleneglycol (PEG) linker to immunoglobulin G (IgG), which was linked to doxorubicin (DOX), to form a novel ADC folate-PEG-IgG-DOX (FA-PEG-IgG-DOX). The FA-PEG-IgG-DOX showed high targeting efficiency in HeLa and KB cells and significantly improved the uptake and retention of DOX compared with IgG-DOX about 10-fold. Subsequently, FA-PEG-IgG-DOX was shown to have at least 8 times higher antitumor activity than IgG-DOX both in HeLa and KB cells and also induced more apoptosis in those cells than IgG-DOX. Moreover, FA-PEG-IgG-DOX had a 2 times longer circulating time than FA-IgG-DOX, but did not increase the DOX distribution in mouse hearts. Importantly, FA-PEG-IgG-DOX treatment significantly inhibited tumor growth in xenograft mice. Together, our results indicate that FA-PEG-IgG is an effective ADC carrier for delivery of chemotherapeutic agents and that conjugating tumor targeting ligands to antibodies is a promising strategy for producing ADC drugs.

  2. Cationic Polymethacrylate-Modified Liposomes Significantly Enhanced Doxorubicin Delivery and Antitumor Activity

    PubMed Central

    Wang, Wenxi; Shao, Anna; Zhang, Nan; Fang, Jinzhang; Ruan, Jennifer Jin; Ruan, Benfang Helen

    2017-01-01

    Liposome (LP) encapsulation of doxorubicin (DOX) is a clinically validated method for cancer drug delivery, but its cellular uptake is actually lower than the free DOX. Therefore, we modified DOX-LP with a cationic polymer (Eudragit RL100; ER) to improve its cellular uptake and antitumor activity. The resulting DOX-ERLP was a 190 nm nanoparticle that was absorbed efficiently and caused cancer cell death in 5 hrs. Growth as measured by the MTT assay or microscopic imaging demonstrated that DOX-ERLP has at least a two-fold greater potency than the free DOX in inhibiting the growth of a DOX resistant (MCF7/adr) cell and an aggressive liver cancer H22 cell. Further, its in vivo efficacy was tested in H22-bearing mice, where four injections of DOX-ERLP reduced the tumor growth by more than 60% and caused an average of 60% tumor necrosis, which was significantly better than the DOX and DOX-LP treated groups. Our work represents the first use of polymethacrylate derivatives for DOX liposomal delivery, demonstrating the great potential of cationic polymethacrylate modified liposomes for improving cancer drug delivery. PMID:28225062

  3. Anti-tumor Effects of Plasma Activated Media and Correlation with Hydrogen Peroxide Concentration

    NASA Astrophysics Data System (ADS)

    Laroussi, Mounir; Mohades, Soheila; Barekzi, Nazir; Maruthamuthu, Venkat; Razavi, Hamid

    2016-09-01

    Plasma activated media (PAM) can induce death in cancer cells. In our research, PAM is produced by exposing liquid culture medium to a helium plasma pencil. Reactive oxygen and nitrogen species in the aqueous state are known factors in anti-tumor effects of PAM. The duration of plasma exposure determines the concentrations of reactive species produced in PAM. Stability of the plasma generated reactive species and their lifetime depend on parameters such as the chemical composition of the medium. Here, a complete cell culture medium was employed to make PAM. Later, PAM was used to treat SCaBER cancer cells either as an immediate PAM (right after exposure) or as an aged-PAM (after storage). SCaBER (ATCC®HTB-3™) is an epithelial cell line from a human bladder with the squamous carcinoma disease. A normal epithelial cell line from a kidney tissue of a dog - MDCK (ATCC®CCL-34™) - was used to analyze the selective effect of PAM. Correspondingly, we measured the concentration of hydrogen peroxide- as a stable species with biological impact on cell viability- in both immediate PAM and aged-PAM. In addition, we report on the effect of serum supplemented in PAM on the H2O2 concentration measured by Amplex red assay kit. Finally, we evaluate the effects of PAM on growth and morphological changes in MDCK cells using fluorescence microscopy.

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

    SciTech Connect

    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. . E-mail: aw.griffioen@path.unimaas.nl

    2006-10-27

    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.

  5. Generation of antitumor active neutral medium-sized alpha-glycan in apple vinegar fermentation.

    PubMed

    Abe, Kaoru; Kushibiki, Toshisada; Matsue, Hajime; Furukawa, Ken-Ichi; Motomura, Shigeru

    2007-09-01

    The physiologically active substances in apple vinegar have not yet been chemically characterized. We studied the biological functions of apple vinegar produced from crushed apples, and found that the constituent neutral medium-sized alpha-glycan (NMalphaG) acts as an antitumor agent against experimental mouse tumors. NMalphaG is a homoglycan composed of glucose having a molecular weight of about 10,000 and a branched structure bearing alpha (1-4,6) linkages. In this study, we clarified the origin of NMalphaG in apple vinegar by examination of its content in alcohol and acetic acid fermentation products sequentially. We found that NMalphaG appeared in acetic acid fermentation, but not in alcohol fermentation. Furthermore we investigated NMalphaG origin using acetic acid fermentation from alcohol fortifiied apple without alcohol fermentation and from raw material with varying amounts of pomace. The results indicate that NMalphaG originated in the apple fruit body and that its production requires both fermentation processes.

  6. Pharmacological and anti-tumor activities of ganoderma spores processed by top-down approaches.

    PubMed

    Liu, Xin; Wang, Jiang-Hai; Yuan, Jian-Ping

    2005-12-01

    Ganoderma was considered to be the most valuable medicine in ancient China, and it is still widely esteemed as a valuable health supplement and herbal medicine for the prevention and treatment of a variety of chronic diseases. However, the efficiency of Ganoderma in therapy has long been hindered by the uncertainty of its effectual constituents and the pharmaceutical mechanisms. Lately, it has been found that a most effective pharmaceutical component is the Ganoderma spore. Nevertheless, efficiency in using the spores requires further improvement in processing since the spores have rigid and tough walls the size on a micron scale which are difficult to take up and absorb by the human body. This review describes the top-down approaches in Ganoderma spore processing in order to release the effective pharmaceutical constituents such as the triterpenoid. The production of raw Ganoderma spores, the processing techniques to produce the sporoderm-broken germinating Ganoderma spores, the significant pharmacological activities of Ganoderma, the anti-tumor mechanisms elucidated by modern pharmacological studies, the outcome of the clinical trials, and a prospective of future preparations of triterpenoid-enriched Ganoderma spores and Ganoderma triterpenoids for immune regulation and cancer therapy will be discussed.

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

    PubMed

    Liu, Chao; Sun, Yonghai; Mao, Qian; Guo, Xiaolei; Li, Peng; Liu, Yang; Xu, Na

    2016-06-22

    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 (13)C 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.

  8. Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy.

    PubMed

    Paraskar, Abhimanyu S; Soni, Shivani; Chin, Kenneth T; Chaudhuri, Padmaparna; Muto, Katherine W; Berkowitz, Julia; Handlogten, Michael W; Alves, Nathan J; Bilgicer, Basar; Dinulescu, Daniela M; Mashelkar, Raghunath A; Sengupta, Shiladitya

    2010-07-13

    Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O --> Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 +/- 0.16 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras(LSL/+)/Pten(fl/fl) ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.

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

    PubMed

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

    2013-10-01

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

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

    PubMed Central

    Liu, Chao; Sun, Yonghai; Mao, Qian; Guo, Xiaolei; Li, Peng; Liu, Yang; Xu, Na

    2016-01-01

    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. PMID:27338370

  11. Antitumor activity of PEGylated nanoliposomes containing crocin in mice bearing C26 colon carcinoma.

    PubMed

    Rastgoo, Marziyeh; Hosseinzadeh, Hossein; Alavizadeh, Hoda; Abbasi, Azam; Ayati, Zahra; Jaafari, Mahmoud R

    2013-04-01

    Crocin is a pharmacologically active component of Crocus sativus. It is an unusual water-soluble carotenoid responsible for the red color of saffron. In various studies, the anticancer effect of saffron and its constituents has been established. Polyethylene glycolated nanoliposomes with a size range up to 200 nm are suitable for encapsulation of cytotoxic drugs and can target tumors passively through the enhanced permeation and retention effect. The aim of this study was to develop a nanoliposomal formulation containing crocin with a higher therapeutic index for the treatment of cancer. Four formulations of polyethylene glycolated nanoliposomes containing 25 mg/ml crocin were prepared with hydrogenated soy phosphatidylcholine, cholesterol, and methoxy-polyethylene glycol (MW 2000)-distearoylphosphatidylcholine at different molar ratios by a solvent evaporation method plus extrusion. Then the liposomes were characterized for their size, zeta potential, crocin encapsulation, release properties, and in vitro cytotoxicity against C26 colon carcinoma cells. Based on in vitro results, the best formulation was selected for an in vivo study, and its antitumor activity was evaluated in BALB/c mice bearing C26 colon carcinoma. The IC50 of crocin itself against C26 colon carcinoma was 0.73 mM. The characterization of the best formulation was as follow: Z-average size: 127.6 ± 1.5 nm; polydispersity index: 0.087 ± 0.018; zeta potential: - 21.7 mV ± 6.7; % encapsulation: 84.62 ± 0.59; % release after 168 hours in RPMI 1640 containing 30 % FBS: 16.26 ± 0.01 %. Liposomal crocin at doses of 50 and 100 mg/kg significantly decreased tumor size and increased survival rate compared with PBS and crocin in buffer (100 mg/kg) groups. The results of this study indicated that liposomal encapsulation of crocin could increase its antitumorigenic activity. Thus, to obtain an optimal dose for use in humans, the formulation merits further investigation.

  12. Significant antitumor activity in vivo following treatment with the microtubule agent ENMD-1198.

    PubMed

    LaVallee, Theresa M; Burke, Patricia A; Swartz, Glenn M; Hamel, Ernest; Agoston, Gregory E; Shah, Jamshed; Suwandi, Lita; Hanson, Art D; Fogler, William E; Sidor, Carolyn F; Treston, Anthony M

    2008-06-01

    Clinical studies using the microtubule-targeting agent 2-methoxyestradiol (2ME2; Panzem) in cancer patients show that treatment is associated with clinical benefit, including prolonged stable disease, complete and partial responses, and an excellent safety profile. Studies have shown that 2ME2 is metabolized by conjugation at positions 3 and 17 and oxidation at position 17. To define structure-activity relationships for these positions of 2ME2 and to generate metabolically stable analogues with improved anti-tubulin properties, a series of analogues was generated and three lead analogues were selected, ENMD-1198, ENMD-1200, and ENMD-1237. These molecules showed improved metabolic stability with >65% remaining after 2-h incubation with hepatocytes. Pharmacokinetic studies showed that oral administration of the compounds resulted in increased plasma levels compared with 2ME2. All three analogues bind the colchicine binding site of tubulin, induce G(2)-M cell cycle arrest and apoptosis, and reduce hypoxia-inducible factor-1alpha levels. ENMD-1198 and ENMD-1200 showed improved in vitro antiproliferative activities. Significant reductions in tumor volumes compared with vehicle-treated mice were observed in an orthotopic breast carcinoma (MDA-MB-231) xenograft model following daily oral treatment with all compounds (ANOVA, P < 0.05). Significantly improved median survival time was observed with ENMD-1198 and ENMD-1237 (200 mg/kg/d) in a Lewis lung carcinoma metastatic model (P < 0.05). In both tumor models, the high-dose group of ENMD-1198 showed antitumor activity equivalent to that of cyclophosphamide. ENMD-1198 was selected as the lead molecule in this analogue series and is currently in a phase I clinical trial in patients with refractory solid tumors.

  13. In Vivo Anti-Tumor Activity and Toxicological Evaluations of Perillaldehyde 8,9-Epoxide, a Derivative of Perillyl Alcohol

    PubMed Central

    Andrade, Luciana Nalone; Amaral, Ricardo Guimarães; Dória, Grace Anne Azevedo; Fonseca, Cecília Santos; da Silva, Tayane Kayane Mariano; Albuquerque Júnior, Ricardo Luiz Cavalcante; Thomazzi, Sara Maria; do Nascimento, Lázaro Gomes; Carvalho, Adriana Andrade; de Sousa, Damião Pergentino

    2016-01-01

    Recent studies have revealed the high cytotoxicity of p-menthane derivatives against human tumor cells. In this study, the substance perillaldehyde 8,9-epoxide, a p-menthane class derivative obtained from (S)-(−)-perillyl alcohol, was selected in order to assess antitumor activity against experimental sarcoma 180 tumors. Toxicological effects related to the liver, spleen, kidneys and hematology were evaluated in mice submitted to treatment. The tumor growth inhibition rate was 38.4%, 58.7%, 35.3%, 45.4% and 68.1% at doses of 100 and 200 mg/kg/day for perillaldehyde 8,9-epoxide, perillyl alcohol and 25 mg/kg/day for 5-FU intraperitoneal treatments, respectively. No toxicologically significant effect was found in liver and kidney parameters analyzed in Sarcoma 180-inoculated mice treated with perillaldehyde 8,9-epoxide. Histopathological analyses of the liver, spleen, and kidneys were free from any morphological changes in the organs of the animals treated with perillaldehyde 8,9-epoxide. In conclusion, the data suggest that perillaldehyde 8,9-epoxide possesses significant antitumor activity without systemic toxicity for the tested parameters. By comparison, there was no statistical difference for the antitumor activity between perillaldehyde 8,9-epoxide and perillyl alcohol. PMID:26742032

  14. Compositions and Anti-Tumor Activity of Pyropolyporus fomentarius Petroleum Ether Fraction In Vitro and In Vivo

    PubMed Central

    Zhang, Yanhua; Xiao, Yaping; Wang, Pan; Liu, Quanhong

    2014-01-01

    The chemical compositions and anti-tumor activities of the petroleum ether fraction (PE), from mushroom Pyropolyporus fomentarius, were studied. Upon gas chromatography–mass spectrometry (GC–MS) analysis, nine major constituents were identified in the fraction. In vitro, the PE showed cytotoxic activity against murine sarcoma S180 (S180) cells in a dose- and time-dependent manner, and the cytotoxic effects were associated with apoptosis. The mitochondrial membrane potential loss and the intracellular ROS generation were greatly increased in the Pyropolyporus fomentarius PE treated group, suggesting cell apoptosis, induced by the PE in S180 cells, might be mitochondria dependent and ROS mediated. Consistent with in vitro findings, the in vivo study showed that the Pyropolyporus fomentarius PE was also effective in inhibiting the tumor growth induced by S180 cells and had lower immune organ toxicity. We found that the Pyropolyporus fomentarius PE has significant anti-tumor activity and great potential in screening anti-tumor drugs. PMID:25302783

  15. Da0324, an inhibitor of nuclear factor-κB activation, demonstrates selective antitumor activity on human gastric cancer cells

    PubMed Central

    Jin, Rong; Xia, Yiqun; Chen, Qiuxiang; Li, Wulan; Chen, Dahui; Ye, Hui; Zhao, Chengguang; Du, Xiaojing; Shi, Dengjian; Wu, Jianzhang; Liang, Guang

    2016-01-01

    Background The transcription factor nuclear factor-κB (NF-κB) is constitutively activated in a variety of human cancers, including gastric cancer. NF-κB inhibitors that selectively kill cancer cells are urgently needed for cancer treatment. Curcumin is a potent inhibitor of NF-κB activation. Unfortunately, the therapeutic potential of curcumin is limited by its relatively low potency and poor cellular bioavailability. In this study, we presented a novel NF-κB inhibitor named Da0324, a synthetic asymmetric mono-carbonyl analog of curcumin. The purpose of this study is to research the expression of NF-κB in gastric cancer and the antitumor activity and mechanism of Da0324 on human gastric cancer cells. Methods The expressions between gastric cancer tissues/cells and normal gastric tissues/cells of NF-κB were evaluated by Western blot. The inhibition viability of compounds on human gastric cancer cell lines SGC-7901, BGC-823, MGC-803, and normal gastric mucosa epithelial cell line GES-1 was assessed with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Absorption spectrum method and high-performance liquid chromatography method detected the stability of the compound in vitro. The compound-induced changes of inducible NF-κB activation in the SGC-7901 and BGC-823 cells were examined by Western blot analysis and immunofluorescence methods. The antitumor activity of compound was performed by clonogenic assay, matrigel invasion assay, flow cytometric analysis, Western blot analysis, and Hoechst 33258 staining assay. Results High levels of p65 were found in gastric cancer tissues and cells. Da0324 displayed higher growth inhibition against several types of gastric cancer cell lines and showed relatively low toxicity to GES-1. Moreover, Da0324 was more stable than curcumin in vitro. Western blot analysis and immunofluorescence methods showed that Da0324 blocked NF-κB activation. In addition, Da0324 significantly inhibited tumor proliferation

  16. Potentiation of Methoxymorpholinyl Doxorubicin Anti-Tumor Activity by P450 3A4 Gene Transfer#

    PubMed Central

    Lu, Hong; Chen, Chong-Sheng; Waxman, David J.

    2008-01-01

    Summary Preclinical and clinical studies of CYP gene-directed enzyme-prodrug therapy have focused on anticancer prodrugs activated by CYP2B enzymes, which have low endogenous expression in human liver; however, the gene therapeutic potential of CYP3A enzymes, which are highly expressed in human liver, remains unknown. This study investigated methoxymorpholinyl-doxorubicin (MMDX), a novel CYP3A-activated anticancer prodrug. Retroviral transfer of CYP3A4 increased 9L gliosarcoma cell chemosensitivity to MMDX 120-fold (IC50=0.2nM). In CHO cells, overexpression of P450 reductase in combination with CYP3A4 enhanced chemosensitivity to MMDX, and to ifosfamide, another CYP3A4 prodrug, 11–23-fold compared to CYP3A4 expression alone. CYP3A4 expression and MMDX chemosensitivity were increased in human lung (A549) and brain (U251) tumor cells infected with replication-defective adenovirus encoding CYP3A4. Co-infection with Onyx-017, a replication-conditional adenovirus that co-amplifies and co-replicates the Adeno-3A4 virus, led to large increases in CYP3A4 RNA but only modest increases in CYP3A4 protein and activity. MMDX induced remarkable growth delay of 9L/3A4 tumors, but not 9L tumors, in immunodeficient mice administered low-dose MMDX either i.v. or by direct intratumoral injection (60µg/kg, every 7-days ×3), with the intratumoral route being substantially less toxic to the mouse host. No antitumor activity was observed with i.p. MMDX treatment, suggesting a substantial hepatic first pass effect, and with activated MMDX metabolites formed in the liver having poor access to the tumor site. These studies demonstrate that human CYP3A4 has strong potential for MMDX prodrug activation therapy, and suggest that endogenous tumor cell expression of CYP3A4, and not hepatic CYP3A4 activity, is a key determinant of responsiveness to MMDX therapy in cancer patients in vivo. PMID:19011599

  17. CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo

    PubMed Central

    Tian, Gengwen; Courtney, Amy N.; Jena, Bipulendu; Heczey, Andras; Liu, Daofeng; Marinova, Ekaterina; Guo, Linjie; Xu, Xin; Torikai, Hiroki; Mo, Qianxing; Dotti, Gianpietro; Cooper, Laurence J.; Metelitsa, Leonid S.

    2016-01-01

    Vα24-invariant natural killer T cells (NKTs) localize to tumors and have inherent antitumor properties, making them attractive chimeric antigen receptor (CAR) carriers for redirected cancer immunotherapy. However, clinical application of CAR-NKTs has been impeded, as mechanisms responsible for NKT expansion and the in vivo persistence of these cells are unknown. Here, we demonstrated that antigen-induced expansion of primary NKTs in vitro associates with the accumulation of a CD62L+ subset and exhaustion of CD62L– cells. Only CD62L+ NKTs survived and proliferated in response to secondary stimulation. When transferred to immune-deficient NSG mice, CD62L+ NKTs persisted 5 times longer than CD62L– NKTs. Moreover, CD62L+ cells transduced with a CD19-specific CAR achieved sustained tumor regression in a B cell lymphoma model. Proliferating CD62L+ cells downregulated or maintained CD62L expression when activated via T cell receptor alone or in combination with costimulatory receptors. We generated HLAnull K562 cell clones that were engineered to express CD1d and costimulatory ligands. Clone B-8-2 (HLAnullCD1dmedCD86high4-1BBLmedOX40Lhigh) induced the highest rates of NKT expansion and CD62L expression. B-8-2–expanded CAR-NKTs exhibited prolonged in vivo persistence and superior therapeutic activities in models of lymphoma and neuroblastoma. Therefore, we have identified CD62L as a marker of a distinct NKT subset endowed with high proliferative potential and have developed artificial antigen-presenting cells that generate CD62L-enriched NKTs for effective cancer immunotherapy. PMID:27183388

  18. Mesothelin-specific Chimeric Antigen Receptor mRNA-Engineered T cells Induce Anti-Tumor Activity in Solid Malignancies

    PubMed Central

    Beatty, Gregory L.; Haas, Andrew R.; Maus, Marcela V.; Torigian, Drew A.; Soulen, Michael C.; Plesa, Gabriela; Chew, Anne; Zhao, Yangbing; Levine, Bruce L.; Albelda, Steven M.; Kalos, Michael; June, Carl H.

    2014-01-01

    Off-target toxicity due to the expression of target antigens in normal tissue represents a major obstacle to the use of chimeric antigen receptor (CAR)-engineered T cells for treatment of solid malignancies. To circumvent this issue, we established a clinical platform for engineering T cells with transient CAR expression by using in vitro transcribed mRNA encoding a CAR that includes both the CD3-ζ and 4-1BB co-stimulatory domains. We present two case reports from ongoing trials indicating that adoptive transfer of mRNA CAR T cells that target mesothelin (CARTmeso cells) is feasible and safe without overt evidence of off-tumor on-target toxicity against normal tissues. CARTmeso cells persisted transiently within the peripheral blood after intravenous administration and migrated to primary and metastatic tumor sites. Clinical and laboratory evidence of antitumor activity was demonstrated in both patients and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel anti-self antibodies. These data demonstrate the potential of utilizing mRNA engineered T cells to evaluate, in a controlled manner, potential off-tumor on-target toxicities and show that short-lived CAR T cells can induce epitope-spreading and mediate antitumor activity in patients with advanced cancer. Thus, these findings support the development of mRNA CAR-based strategies for carcinoma and other solid tumors. PMID:24579088

  19. Doxorubicin loaded silica nanorattles actively seek tumors with improved anti-tumor effects

    NASA Astrophysics Data System (ADS)

    Gao, Fuping; Li, Linlin; Liu, Tianlong; Hao, Nanjing; Liu, Huiyu; Tan, Longfei; Li, Hongbo; Huang, Xinglu; Peng, Bo; Yan, Chuanmiao; Yang, Liuqing; Wu, Xiaoli; Chen, Dong; Tang, Fangqiong

    2012-05-01

    Silica nanorattles (SNs) have proven to be promising vehicles for drug delivery. In order to further enhance efficacy and minimize adverse effects, active targeted delivery to tumors is necessary. In this work, SNs modified with a tumor specific targeting ligand, folic acid (FA), was used as carrier of doxorubicin (DOX) (DOX-FA-SNs). Drug loading, cytotoxicity and cellular uptake of DOX-FA-SNs in vitro in human cervical carcinoma cells (HeLa cells) were evaluated. DOX-FA-SNs showed a higher cytotoxicity in human cervical carcinoma cells (HeLa cells) than DOX loaded carboxyl (-COOH) and poly(ethylene glycol) (PEG) modified SNs (DOX-COOH-SNs and DOX-PEG-SNs, respectively). However, DOX-FA-SNs showed lower cytotoxicity in folate receptor negative normal mouse fibroblast cells (L929 cells) compared with free DOX. In vivo tumor-targeted fluorescence imaging indicated specific tumor targeting and uptake of FA-SNs in nude mice bearing subcutaneous HeLa cell-derived xenograft tumors. In vivo anti-tumor experiments demonstrated that DOX-FA-SNs (10 mg kg-1 of DOX) significantly regressed the tumor growth and reduced toxicity compared with free DOX. These results have great significance in developing and optimizing SNs as effective intracellular delivery and specific tumor targeting vehicles.Silica nanorattles (SNs) have proven to be promising vehicles for drug delivery. In order to further enhance efficacy and minimize adverse effects, active targeted delivery to tumors is necessary. In this work, SNs modified with a tumor specific targeting ligand, folic acid (FA), was used as carrier of doxorubicin (DOX) (DOX-FA-SNs). Drug loading, cytotoxicity and cellular uptake of DOX-FA-SNs in vitro in human cervical carcinoma cells (HeLa cells) were evaluated. DOX-FA-SNs showed a higher cytotoxicity in human cervical carcinoma cells (HeLa cells) than DOX loaded carboxyl (-COOH) and poly(ethylene glycol) (PEG) modified SNs (DOX-COOH-SNs and DOX-PEG-SNs, respectively). However, DOX

  20. Gene therapy with IL-12 induced enhanced anti-tumor activity in fibrosarcoma mouse model.

    PubMed

    Razi Soofiyani, Saiedeh; Kazemi, Tohid; Lotfipour, Farzaneh; Mohammad Hosseini, Akbar; Shanehbandi, Dariush; Hallaj-Nezhadi, Somayeh; Baradaran, Behzad

    2016-12-01

    Context Immunotherapy is among the most promising modalities for treatment of cancer. Recently, interleukin 12 (IL-12) has been used as an immunotherapeutic agent in cancer gene therapy. IL-12 can activate dendritic cells (DCs) and boost anti-tumor immune responses. Objective In the current study, we have investigated if IL-12 gene therapy can lead to the regression of tumor mass in a mouse model of fibrosarcoma. Material and methods To investigate the therapeutic efficacy of IL-12, WEHI-164 tumor cells were transfected with murine-IL12 plasmids using Lipofectamine. Enzyme linked immunosorbent assay (ELISA) was used to confirm IL-12 expression in transfected cells. The fibrosarcoma mouse model was established by subcutaneous injection of transfected cells to Balb/C mice. Mice were sacrificed and the tumors were extracted. Tumor sizes were measured by caliper. The expression of IL-12 and IFN-γ was studied with real-time PCR and western blotting. The expression of Ki-67(a tumor proliferation marker) in tumor mass was studied by immunohistochemistry staining. Results and discussion The group treated with IL-12 showed a significant decrease in tumor mass volume (P: 0.000). The results of real-time PCR and western blotting showed that IL-12 and IFN-γ expression increased in the group treated with IL-12 (relative expression of IL-12: 1.9 and relative expression of IFN-γ: 1.766). Immunohistochemistry staining showed that Ki-67 expression was reduced in the group treated with IL-12. Conclusion IL-12 gene therapy successfully led to regress of tumor mass in the fibrosarcoma mouse model. This may serve as a candidate therapeutic approach for treatment of cancer.

  1. Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro.

    PubMed

    Zhang, Qi; Pan, Jing; Lubet, Ronald A; Komas, Steven M; Kalyanaraman, Balaraman; Wang, Yian; You, Ming

    2015-04-01

    3-Bromopyruvate (3-BrPA) is an alkylating agent and a well-known inhibitor of energy metabolism. Rapamycin is an inhibitor of the serine/threonine protein kinase mTOR. Both 3-BrPA and rapamycin show chemopreventive efficacy in mouse models of lung cancer. Aerosol delivery of therapeutic drugs for lung cancer has been reported to be an effective route of delivery with little systemic distribution in humans. In this study, 3-BrPA and rapamycin were evaluated in combination for their preventive effects against lung cancer in mice by aerosol treatment, revealing a synergistic ability as measured by tumor multiplicity and tumor load compared treatment with either single-agent alone. No evidence of liver toxicity was detected by monitoring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. To understand the mechanism in vitro experiments were performed using human non-small cell lung cancer (NSCLC) cell lines. 3-BrPA and rapamycin also synergistically inhibited cell proliferation. Rapamycin alone blocked the mTOR signaling pathway, whereas 3-BrPA did not potentiate this effect. Given the known role of 3-BrPA as an inhibitor of glycolysis, we investigated mitochondrial bioenergetics changes in vitro in 3-BrPA-treated NSCLC cells. 3-BrPA significantly decreased glycolytic activity, which may be due to adenosine triphosphate (ATP) depletion and decreased expression of GAPDH. Our results demonstrate that rapamycin enhanced the antitumor efficacy of 3-BrPA, and that dual inhibition of mTOR signaling and glycolysis may be an effective therapeutic strategy for lung cancer chemoprevention.

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

    PubMed

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

    2009-04-01

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

  3. Preexisting antitumor immunity augments the antitumor effects of chemotherapy.

    PubMed

    Zhang, Lingbing; Feng, Dongdong; Yu, Lynda X; Tsung, Kangla; Norton, Jeffrey A

    2013-06-01

    Efficacy of cancer chemotherapy is generally believed to be the result of direct drug killing of tumor cells. However, increased tumor cell killing does not always lead to improved efficacy. Herein, we demonstrate that the status of antitumor immunity at the time of chemotherapy treatment is a critical factor affecting the therapeutic outcome in that tumor-bearing mice that possess preexisting antitumor immunity respond to chemotherapy much better than those that do not. Enhancing antitumor immunity before or at the time of chemotherapy-induced antigen release increases subsequent response to chemotherapy significantly. By in vitro and in vivo measurements of antitumor immunity, we found a close correlation between the intensity of antitumor immunity activated by chemotherapy and the efficacy of treatment. Immune intervention with interleukin-12 during the early phase of chemotherapy-induced immune activation greatly amplifies the antitumor response, often resulting in complete tumor eradication not only at the chemo-treated local site, but also systemically. These findings provide additional evidence for an immune-mediated antitumor response to chemotherapy. Further, our results show that timely immune modification of chemotherapy-activated antitumor immunity can result in enhanced antitumor-immune response and complete tumor eradication.

  4. Antitumor activity and systemic effects of PVM/MA-shelled selol nanocapsules in lung adenocarcinoma-bearing mice

    NASA Astrophysics Data System (ADS)

    de Souza, Ludmilla Regina; Alexandre Muehlmann, Luis; Carneiro Matos, Lívia; Simón-Vázquez, Rosana; Guerreiro Marques Lacava, Zulmira; Maurício Batista De-Paula, Alfredo; Mosiniewicz-Szablewska, Ewa; Suchocki, Piotr; César Morais, Paulo; González-Fernández, África; Nair Báo, Sônia; Bentes Azevedo, Ricardo

    2015-12-01

    Selol is a semi-synthetic compound containing selenite that is effective against cancerous cells and safer for clinical applications in comparison with other inorganic forms of selenite. Recently, we have developed a formulation of poly(methyl vinyl ether-co-maleic anhydride)-shelled selol nanocapsules (SPN), which reduced the proliferative activity of lung adenocarcinoma cells and presented little deleterious effects on normal cells in in vitro studies. In this study, we report on the antitumor activity and systemic effects induced by this formulation in chemically induced lung adenocarcinoma-bearing mice. The in vivo antitumor activity of the SPN was verified by macroscopic quantification, immunohistochemistry and morphological analyses. Toxicity analyses were performed by evaluations of the kidney, liver, and spleen; analyses of hemogram and plasma levels of alanine aminotransferase, aspartate transaminase, urea, and creatinine; and DNA fragmentation and cell cycle activity of the bone marrow cells. Furthermore, we investigated the potential of the SPN formulation to cause hemolysis, activate the complement system, provoke an inflammatory response and change the conformation of the plasma proteins. Our results showed that the SPN reduced the area of the surface tumor nodules but not the total number of tumor nodules. The biochemical and hematological findings were suggestive of the low systemic toxicity of the SPN formulation. The surface properties of the selol nanocapsules point to characteristics that are consistent with the treatment of the tumors in vivo: low hemolytic activity, weak inflammatory reaction with no activation of the complement system, and mild or absent conformational changes of the plasma proteins. In conclusion, this report suggests that the SPN formulation investigated herein exhibits anti-tumoral effects against lung adenocarcinoma in vivo and is associated with low systemic toxicity and high biocompatibility.

  5. Antitumor activity of sorafenib-incorporated nanoparticles of dextran/poly(dl-lactide- co-glycolide) block copolymer

    NASA Astrophysics Data System (ADS)

    Kim, Do Hyung; Kim, Min-Dae; Choi, Cheol-Woong; Chung, Chung-Wook; Ha, Seung Hee; Kim, Cy Hyun; Shim, Yong-Ho; Jeong, Young-Il; Kang, Dae Hwan

    2012-01-01

    Sorafenib-incoporated nanoparticles were prepared using a block copolymer that is composed of dextran and poly( DL-lactide- co-glycolide) [Dex bLG] for antitumor drug delivery. Sorafenib-incorporated nanoparticles were prepared by a nanoprecipitation-dialysis method. Sorafenib-incorporated Dex bLG nanoparticles were uniformly distributed in an aqueous solution regardless of the content of sorafenib. Transmission electron microscopy of the sorafenib-incorporated Dex bLG nanoparticles revealed a spherical shape with a diameter < 300 nm. Sorafenib-incorporated Dex bLG nanoparticles at a polymer/drug weight ratio of 40:5 showed a relatively uniform size and morphology. Higher initial drug feeding was associated with increased drug content in nanoparticles and in nanoparticle size. A drug release study revealed a decreased drug release rate with increasing drug content. In an in vitro anti-proliferation assay using human cholangiocarcinoma cells, sorafenib-incorporated Dex bLG nanoparticles showed a similar antitumor activity as sorafenib. Sorafenib-incorporated Dex bLG nanoparticles are promising candidates as vehicles for antitumor drug targeting.

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

    PubMed Central

    Palma, Enzo; Cho, Moo J.

    2007-01-01

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

  7. Xanthine oxidoreductase is required for genotoxic stress-induced NKG2D ligand expression and gemcitabine-mediated antitumor activity

    PubMed Central

    Xu, Xiulong; Rao, Geetha; Li, Yi

    2016-01-01

    MICA/B (the major histocompatibility antigen-related chain A and B) and Rae I are stress-inducible ligands for the immune-receptor NKG2D. Mechanisms by which genotoxic stress and DNA damage induce the expression of NKG2D ligands remain incompletely understood. Here, we report that inhibition of xanthine oxidoreductase (XOR) activity by allopurinol or inhibition of XOR expression by gene knockdown abrogated genotoxic stress-induced expression of MICA/B and Rae I in three tumor cell lines. XOR knockdown also blocked gemcitabine-mediated antitumor activity in an orthotopic syngeneic mouse model of breast cancer. As a rate-limiting enzyme in the purine catabolic pathway, XOR generates two end-products, uric acid and reactive oxygen species (ROS). ROS scavenging had an insignificant effect on genotoxic drug-induced MICA/B expression but modestly inhibited radiation-induced MICA/B expression. Exogenous uric acid (in the form of monosodium urate) induced MICA/B expression by activating the MAP kinase pathway. Allopurinol blocked genotoxic stress-induced MAP kinase activation. Our study provides mechanistic insights into genotoxic stress-induced activation of the MAP kinase pathway and suggests that XOR is required for genotoxic stress-induced NKG2D ligand expression and gemcitabine-mediated antitumor activity. PMID:27494876

  8. Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.

    PubMed

    Morgado-Palacin, Isabel; Day, Amanda; Murga, Matilde; Lafarga, Vanesa; Anton, Marta Elena; Tubbs, Anthony; Chen, Hua-Tang; Ergan, Aysegul; Anderson, Rhonda; Bhandoola, Avinash; Pike, Kurt G; Barlaam, Bernard; Cadogan, Elaine; Wang, Xi; Pierce, Andrew J; Hubbard, Chad; Armstrong, Scott A; Nussenzweig, André; Fernandez-Capetillo, Oscar

    2016-09-13

    Among the various subtypes of acute myeloid leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies because of an attenuated response by p53, a protein that induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML(MLL) cells (with an MLL-ENL fusion and a constitutively active N-RAS independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AML(MLL) and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AML(MLL) mice. Collectively, these data indicated that ATR or ATM inhibition represent potential therapeutic strategies for the treatment of AML, especially MLL-driven leukemias.

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

    PubMed Central

    2010-01-01

    Background 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. Methods 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. Results 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 <100 KDa in lesser proportion. Regarding the semifermented-dry cacao seed, it was observed that the albumin fraction showed antitumoral activity, since it caused significant decreases (p < 0.05) in the ascetic fluid volume and packed cell volume, inhibiting cell growth in 59.98 ± 13.6% at 60% of the population; while the greatest antioxidant capacity due to free radical scavenging capacity was showed by the albumin and glutelin fraction in both methods assayed. Conclusion This study is the first report on

  10. Antitumor activity of photodynamic therapy performed with nanospheres containing zinc-phthalocyanine

    PubMed Central

    2013-01-01

    Background The increasing incidence of cancer and the search for more effective therapies with minimal collateral effects have prompted studies to find alternative new treatments. Among these, photodynamic therapy (PDT) has been proposed as a very promising new modality in cancer treatment with the lowest rates of side effects, revealing itself to be particularly successful when the photosensitizer is associated with nanoscaled carriers. This study aimed to design and develop a new formulation based on albumin nanospheres containing zinc-phthalocyanine tetrasulfonate (ZnPcS4-AN) for use in the PDT protocol and to investigate its antitumor activity in Swiss albino mice using the Ehrlich solid tumor as an experimental model for breast cancer. Methods Ehrlich tumor’s volume, histopathology and morphometry were used to assess the efficacy of intratumoral injection of ZnPcS4-AN in containing tumor aggressiveness and promoting its regression, while the toxicity of possible treatments was assessed by animal weight, morphological analysis of the liver and kidneys, hemogram, and serum levels of total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase, creatinine and urea. In order to evaluate the efficacy of PDT, groups of animals treated with intratumoral injection of doxorubicin (Dox) were also investigated. Results Intratumoral injection of ZnPcS4-AN was found to be efficient in mediating PDT to refrain tumor aggressiveness and to induce its regression. Although tumor volume reduction was not significant, PDT induced a remarkable increase in the necrosis area seen in the tumor’s central region, as in other experimental groups, including tumor and Dox treated groups, but also in the tumor’s peripheral region. Further, PDT showed minimal adverse effects. Indeed, the use of ZnPcS4-AN in mediating PDT revealed anti-neoplastic activity similar to that

  11. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma.

    PubMed

    Hu-Lieskovan, Siwen; Mok, Stephen; Homet Moreno, Blanca; Tsoi, Jennifer; Robert, Lidia; Goedert, Lucas; Pinheiro, Elaine M; Koya, Richard C; Graeber, Thomas G; Comin-Anduix, Begoña; Ribas, Antoni

    2015-03-18

    Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAF(V600E)-driven melanoma, SM1, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors, and improved in vivo cytotoxicity. Single-agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.

  12. Antitumor Indolequinones Induced Apoptosis in Human Pancreatic Cancer Cells via Inhibition of Thioredoxin Reductase and Activation of Redox Signaling

    PubMed Central

    Yan, Chao; Siegel, David; Newsome, Jeffery; Chilloux, Aurelie; Moody, Christopher J.

    2012-01-01

    Indolequinones (IQs) were developed as potential antitumor agents against human pancreatic cancer. IQs exhibited potent antitumor activity against the human pancreatic cancer cell line MIA PaCa-2 with growth inhibitory IC50 values in the low nanomolar range. IQs were found to induce time- and concentration-dependent apoptosis and to be potent inhibitors of thioredoxin reductase 1 (TR1) in MIA PaCa-2 cells at concentrations equivalent to those inducing growth-inhibitory effects. The mechanism of inhibition of TR1 by the IQs was studied in detail in cell-free systems using purified enzyme. The C-terminal selenocysteine of TR1 was characterized as the primary adduction site of the IQ-derived reactive iminium using liquid chromatography-tandem mass spectrometry analysis. Inhibition of TR1 by IQs in MIA PaCa-2 cells resulted in a shift of thioredoxin-1 redox state to the oxidized form and activation of the p38/c-Jun NH2-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathway. Oxidized thioredoxin is known to activate apoptosis signal-regulating kinase 1, an upstream activator of p38/JNK in the MAPK signaling cascade and this was confirmed in our study providing a potential mechanism for IQ-induced apoptosis. These data describe the redox and signaling events involved in the mechanism of growth inhibition induced by novel inhibitors of TR1 in human pancreatic cancer cells. PMID:22147753

  13. Non-thermal atmospheric pressure plasma activates lactate in Ringer’s solution for anti-tumor effects

    PubMed Central

    Tanaka, Hiromasa; Nakamura, Kae; Mizuno, Masaaki; Ishikawa, Kenji; Takeda, Keigo; Kajiyama, Hiroaki; Utsumi, Fumi; Kikkawa, Fumitaka; Hori, Masaru

    2016-01-01

    Non-thermal atmospheric pressure plasma is a novel approach for wound healing, blood coagulation, and cancer therapy. A recent discovery in the field of plasma medicine is that non-thermal atmospheric pressure plasma not only directly but also indirectly affects cells via plasma-treated liquids. This discovery has led to the use of non-thermal atmospheric pressure plasma as a novel chemotherapy. We refer to these plasma-treated liquids as plasma-activated liquids. We chose Ringer’s solutions to produce plasma-activated liquids for clinical applications. In vitro and in vivo experiments demonstrated that plasma-activated Ringer’s lactate solution has anti-tumor effects, but of the four components in Ringer’s lactate solution, only lactate exhibited anti-tumor effects through activation by non-thermal plasma. Nuclear magnetic resonance analyses indicate that plasma irradiation generates acetyl and pyruvic acid-like groups in Ringer’s lactate solution. Overall, these results suggest that plasma-activated Ringer’s lactate solution is promising for chemotherapy. PMID:27824103

  14. Non-thermal atmospheric pressure plasma activates lactate in Ringer’s solution for anti-tumor effects

    NASA Astrophysics Data System (ADS)

    Tanaka, Hiromasa; Nakamura, Kae; Mizuno, Masaaki; Ishikawa, Kenji; Takeda, Keigo; Kajiyama, Hiroaki; Utsumi, Fumi; Kikkawa, Fumitaka; Hori, Masaru

    2016-11-01

    Non-thermal atmospheric pressure plasma is a novel approach for wound healing, blood coagulation, and cancer therapy. A recent discovery in the field of plasma medicine is that non-thermal atmospheric pressure plasma not only directly but also indirectly affects cells via plasma-treated liquids. This discovery has led to the use of non-thermal atmospheric pressure plasma as a novel chemotherapy. We refer to these plasma-treated liquids as plasma-activated liquids. We chose Ringer’s solutions to produce plasma-activated liquids for clinical applications. In vitro and in vivo experiments demonstrated that plasma-activated Ringer’s lactate solution has anti-tumor effects, but of the four components in Ringer’s lactate solution, only lactate exhibited anti-tumor effects through activation by non-thermal plasma. Nuclear magnetic resonance analyses indicate that plasma irradiation generates acetyl and pyruvic acid-like groups in Ringer’s lactate solution. Overall, these results suggest that plasma-activated Ringer’s lactate solution is promising for chemotherapy.

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

    PubMed

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

    2017-01-10

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

  16. Antioxidant, anti-adipocyte differentiation, antitumor activity and anthelmintic activities against Anisakis simplex and Hymenolepis nana of yakuchinone A from Alpinia oxyphylla

    PubMed Central

    2013-01-01

    Background Alpinia oxyphylla is a common remedy in traditional Chinese medicine. Yakuchinone A is a major constituent of A. oxyphylla and exhibits anti-inflammatory, antitumor, antibacterial, and gastric protective activities. Methods Antioxidant and antitumor characteristics of yakuchinone A in skin cancer cells as well as novel mechanisms for the inhibition of adipocyte differentiation, cestocidal activities against Hymenolepis nana adults, and nematocidal activities against Anisakis simplex larvae are investigated. Results Yakuchinone A presents the ability of the removal of DPPH·and ABTS+ free radicals and inhibition of lipid peroxidation. Yakuchinone A suppresses intracellular lipid accumulation during adipocyte differentiation in 3 T3-L1 cells and the expressions of leptin and peroxisome proliferator-activated receptor γ (PPARγ). Yakuchinone A induces apoptosis and inhibits cell proliferation in skin cancer cells. The inhibition of cell growth by yakuchinone A is more significant for non-melanoma skin cancer (NMSC) cells than for melanoma (A375 and B16) and noncancerous (HaCaT and BNLCL2) cells. Treatment BCC cells with yakuchinone A shows down-regulation of Bcl-2, up-regulation of Bax, and an increase in cleavage poly (ADP-ribose) polymerase (PARP). This suggests that yakuchinone A induces BCC cells apoptosis through the Bcl-2-mediated signaling pathway. The anthelmintic activities of yakuchinone A for A. simplex are better than for H. nana. Conclusions In this work, yakuchinone A exhibits antioxidative properties, anti-adipocyte differentiation, antitumor activity, and anthelmintic activities against A. simplex and H. nana. PMID:24070160

  17. In vitro and ex vivo vanadium antitumor activity in (TGF-β)-induced EMT. Synergistic activity with carboplatin and correlation with tumor metastasis in cancer patients.

    PubMed

    Petanidis, Savvas; Kioseoglou, Efrosini; Domvri, Kalliopi; Zarogoulidis, Paul; Carthy, Jon M; Anestakis, Doxakis; Moustakas, Aristidis; Salifoglou, Athanasios

    2016-05-01

    Epithelial to mesenchymal transition (EMT) plays a key role in tumor progression and metastasis as a crucial event for cancer cells to trigger the metastatic niche. Transforming growth factor-β (TGF-β) has been shown to play an important role as an EMT inducer in various stages of carcinogenesis. Previous reports had shown that antitumor vanadium inhibits the metastatic potential of tumor cells by reducing MMP-2 expression and inducing ROS-dependent apoptosis. However, the role of vanadium in (TGF-β)-induced EMT remains unclear. In the present study, we report for the first time on the inhibitory effects of vanadium on (TGF-β)-mediated EMT followed by down-regulation of ex vivo cancer stem cell markers. The results demonstrate blockage of (TGF-β)-mediated EMT by vanadium and reduction in the mitochondrial potential of tumor cells linked to EMT and cancer metabolism. Furthermore, combination of vanadium and carboplatin (a) resulted in synergistic antitumor activity in ex vivo cell cultures, and (b) prompted G0/G1 cell cycle arrest and sensitization of tumor cells to carboplatin-induced apoptosis. Overall, the findings highlight the multifaceted antitumor action of vanadium and its synergistic antitumor efficacy with current chemotherapy drugs, knowledge that could be valuable for targeting cancer cell metabolism and cancer stem cell-mediated metastasis in aggressive chemoresistant tumors.

  18. Antitumor activity of mutant bacterial cytosine deaminase gene for colon cancer

    PubMed Central

    Deng, Long-Ying; Wang, Jian-Ping; Gui, Zhi-Fu; Shen, Li-Zong

    2011-01-01

    AIM: To evaluate bacterial cytosine deaminase (bCD) mutant D314A and 5-fluorocytosine (5-FC) for treatment of colon cancer in a mouse model. METHODS: Recombinant lentivirus vectors that contained wild-type bCD gene (bCDwt), and bCD mutant D314A gene (bCD-D314A) with green fluorescence protein gene were constructed and used to infect human colon carcinoma LoVo cells, to generate stable transfected cells, LoVo/null, LoVo/bCDwt or LoVo/bCD-D314A. These were injected subcutaneously into Balb/c nude mice to establish xenograft models. Two weeks post-LoVo cell inoculation, PBS or 5-FC (500 mg/kg) was administered by intraperitoneal (i.p.) injection once daily for 14 d. On the day after LoVo cell injection, mice were monitored daily for tumor volume and survival. RESULTS: Sequence analyses confirmed the construction of recombinant lentiviral plasmids that contained bCDwt or bCD-D314A. The lentiviral vector had high efficacy for gene delivery, and RT-PCR showed that bCDwt or bCD-D314A gene was transferred to LoVo cells. Among these treatment groups, gene delivery or 5-FC administration alone had no effect on tumor growth. However, bCDwt/5-FC or bCD-D314A/5-FC treatment inhibited tumor growth and prolonged survival of mice significantly (P < 0.05). Importantly, the tumor volume in the bCD-D314A/5-FC-treated group was lower than that in the bCDwt/5-FC group (P < 0.05), and bCD-D314A plus 5-FC significantly prolonged survival of mice in comparison with bCDwt plus 5-FC (P < 0.05). CONCLUSION: The bCD mutant D314A enhanced significantly antitumor activity in human colon cancer xenograft models, which provides a promising approach for human colon carcinoma therapy. PMID:21734808

  19. Antitumor activity of celastrol nanoparticles in a xenograft retinoblastoma tumor model

    PubMed Central

    Li, Zhanrong; Wu, Xianghua; Li, Jingguo; Yao, Lin; Sun, Limei; Shi, Yingying; Zhang, Wenxin; Lin, Jianxian; Liang, Dan; Li, Yongping

    2012-01-01

    Background Celastrol, a Chinese herbal medicine, has shown antitumor activity against various tumor cell lines. However, the effect of celastrol on retinoblastoma has not yet been analyzed. Additionally, the poor water solubility of celastrol restricts further therapeutic applications. The goal of this study was to evaluate the effect of celastrol nanoparticles (CNPs) on retinoblastoma and to investigate the potential mechanisms involved. Methods Celastrol-loaded poly(ethylene glycol)-block-poly(ɛ-caprolactone) nanopolymeric micelles were developed to improve the hydrophilicity of celastrol. The 2-(2-methoxy-4- nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulf-ophenyl)-2H tetrazolium monosodium salt (WST-8) assay was used to determine the inhibitory effect of CNPs on SO-Rb 50 cell proliferation in vitro. Immunofluorescence was used to evaluate the apoptotic effect of CNPs on nuclear morphology, and flow cytometry was used to quantify cellular apoptosis. The expression of Bcl-2, Bax, NF-κB p65, and phospo-NF-κB p65 proteins was assessed by Western blotting. A human retinoblastoma xenograft model was used to evaluate the inhibitory effects of CNPs on retinoblastoma in NOD-SCID mice. Hematoxylin and eosin staining was used to assess the apoptotic effects of CNPs on retinoblastoma. Results CNPs inhibit the proliferation of SO-Rb 50 cells in a dose- and time-dependent manner with an IC50 of 17.733 μg/mL (celastrol-loading content: 7.36%) after exposure to CNPs for 48 hours. CNPs induce apoptosis in SO-Rb 50 cells in a dose-dependent manner. The expression of Bcl-2, NF-κB p65, and phospo-NF-κB p65 proteins decreased after exposure to CNPs 54.4 μg/mL for 48 hours. Additionally, the Bax/Bcl-2 ratio increased, whereas the expression of Bax itself was not significantly altered. CNPs inhibit the growth of retinoblastoma and induce apoptosis in retinoblastoma cells in mice. Conclusion CNPs inhibit the growth of retinoblastoma in mouse xenograft model by inducing apoptosis in

  20. Synthesis and anti-tumor activity evaluation of gallic acid-mangiferin hybrid molecule.

    PubMed

    Hu, Xiang-yu; Deng, Jia-gang; Wang, Lin; Yuan, Ye-fei

    2013-12-01

    To improve the anti-tumor effects of gallic acid and mangiferin, a gallic acid-mangiferin hybrid molecule (GAMA) was synthesized from gallic acid with mangiferin in the presence of ionic liquid ChC1(choline chloride)·2SnC12. Chemical and spectroscopic methods, such as (1)H and (13)C NMR spectroscopy, and HR-ESIMS were used for the structure identification of GA-MA. Using the cell counting kit-8 (CCK-8) assay, the in vitro anti-tumor effects were compared between GA-MA, gallic acid and mangiferin on human hepatoma HepG2, human nasopharyngeal carcinoma CNE, human lung cancer NCI-H460, human ovarian cancer SK-OV-3, and human cervical cancer Hela cells. The results showed that the half inhibitory concentration (IC50) of GA-MA on HepG2, CNE, NCI-H460, SK-OV-3, and Hela cells was significantly lower than that of gallic acid or mangiferin. This showed that GA-MA has a better in vitro anti-tumor effect than gallic acid and mangi-ferin.

  1. Molecular and Cellular Mechanisms of Antitumor Immune Response Activation by Dendritic Cells

    PubMed Central

    Markov, O. V.; Mironova, N. L.; Vlasov, V. V.; Zenkova, M. A.

    2016-01-01

    Dendritic cells (DCs) play a crucial role in the initiation and regulation of the antitumor immune response. Already , DC-based antitumor vaccines have been thoroughly explored both in animal tumor models and in clinical trials. DC-based vaccines are commonly produced from DC progenitors isolated from peripheral blood or bone marrow by culturing in the presence of cytokines, followed by loading the DCs with tumor-specific antigens, such as DNA, RNA, viral vectors, or a tumor cell lysate. However, the efficacy of DC-based vaccines remains low. Undoubtedly, a deeper understanding of the molecular mechanisms by which DCs function would allow us to enhance the antitumor efficacy of DC-based vaccines in clinical applications. This review describes the origin and major subsets of mouse and human DCs, as well as the differences between them. The cellular mechanisms of presentation and cross-presentation of exogenous antigens by DCs to T cells are described. We discuss intracellular antigen processing in DCs, cross-dressing, and the acquisition of the antigen cross-presentation function. A particular section in the review describes the mechanisms of tumor escape from immune surveillance through the suppression of DCs functions. PMID:27795841

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

    PubMed Central

    Russo, Sofía; Berois, Nora; Fernández, Gabriel; Freire, Teresa; Osinaga, Eduardo

    2013-01-01

    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. PMID:24023528

  3. Synthesis and anti-tumor activity evaluation of rhein-aloe emodin hybrid molecule.

    PubMed

    Yuan, Ye-Fei; Hu, Xiang-Yu; He, Ying; Deng, Jia-Gang

    2012-02-01

    To improve the anti-tumor effects of rhein and aloe-emodin, a rhein-aloe-emodin hybrid molecule (RH-AE) was synthesized from rhein and aloe-emodin in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). Chemical and spectroscopic methods, such as 1H and 13C NMR spectroscopy, and HR-ESIMS were used for the structure identification of RH-AE. Using the cell counting kit-8 (CCK-8) assay, the in vitro anti-tumor effects were compared between RH-AE, rhein and aloe-emodin on human hepatoma HepG2, human nasopharyngeal carcinoma CNE, human lung cancer NCI-H460, human ovarian cancer SK-OV-3, and human cervical cancer Hela cells. The results showed that the half inhibitory concentration (IC50) of RH-AE on HepG2, CNE, NCI-H460, SK-OV-3, and Hela cells were significantly lower than those of rhein and aloe-emodin. This showed that RH-AE has a better in vitro anti-tumor effect than rhein and aloe-emodin.

  4. A novel approach to the discovery of anti-tumor pharmaceuticals: searching for activators of liponecrosis

    PubMed Central

    Arlia-Ciommo, Anthony; Svistkova, Veronika; Mohtashami, Sadaf; Titorenko, Vladimir I.

    2016-01-01

    A recently conducted chemical genetic screen for pharmaceuticals that can extend longevity of the yeast Saccharomyces cerevisiae has identified lithocholic acid as a potent anti-aging molecule. It was found that this hydrophobic bile acid is also a selective anti-tumor chemical compound; it kills different types of cultured cancer cells if used at concentrations that do not compromise the viability of non-cancerous cells. These studies have revealed that yeast can be successfully used as a model organism for high-throughput screens aimed at the discovery of selectively acting anti-tumor small molecules. Two metabolic traits of rapidly proliferating fermenting yeast, namely aerobic glycolysis and lipogenesis, are known to be similar to those of cancer cells. The mechanisms underlying these key metabolic features of cancer cells and fermenting yeast have been established; such mechanisms are discussed in this review. We also suggest how a yeast-based chemical genetic screen can be used for the high-throughput development of selective anti-tumor pharmaceuticals that kill only cancer cells. This screen consists of searching for chemical compounds capable of increasing the abundance of membrane lipids enriched in unsaturated fatty acids that would therefore be toxic only to rapidly proliferating cells, such as cancer cells and fermenting yeast. PMID:26636650

  5. Boswellic acids synergize antitumor activity and protect against the cardiotoxicity of doxorubicin in mice bearing Ehrlich's carcinoma.

    PubMed

    Ali, Shimaa A; Zaitone, Sawsan A; Moustafa, Yasser M

    2015-08-01

    This study aimed to test whether boswellic acids add to the antitumor effects of doxorubicin against solid tumors of Ehrlich's ascites carcinoma (EAC) grown in mice, and to investigate the protective effects of boswellic acids against doxorubicin-induced cardiotoxicity. Sixty-four female Swiss albino mice bearing EAC solid tumors were distributed among 8 groups as follows: group 1, EAC control group; group 2, doxorubicin treatment group [mice were injected with doxorubicin (6 mg·(kg body mass)(-1)·week(-1)) for 3 weeks]; groups 3-5, these mice were treated with boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively; groups 6-8, these mice were treated with a combination of doxorubicin and boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively, for 3 weeks. The results indicated that boswellic acids synergized the antitumor activity of doxorubicin. Doxorubicin-treated mice showed elevated serum activities of lactate dehydrogenase and creatine kinase isoenzyme MB as well as cardiac malondialdehyde. Further, decreases in cardiac levels of reduced glutathione, superoxide dismutase, and catalase activities were observed. These effects were accompanied by an increase in cardiac expression of caspase 3. Thus, treatment with boswellic acids attenuated doxorubicin-evoked disturbances in the above-mentioned parameters, highlighting antioxidant and antiapoptotic activities. Therefore, boswellic acids could be potential candidates for ameliorating the cardiotoxicity of doxorubicin.

  6. GS-9219/VDC-1101 - a prodrug of the acyclic nucleotide PMEG has antitumor activity inspontaneous canine multiple myeloma

    PubMed Central

    2014-01-01

    Background Multiple myeloma (MM) is an important human and canine cancer for which novel therapies remain necessary. VDC-1101 (formerly GS-9219), a novel double prodrug of the anti-proliferative nucleotide analog 9-(2-phosphonylmethoxyethyl) guanine (PMEG), possesses potent cytotoxic activity in vitro in human lymphoblasts and leukemia cell lines and in vivo in spontaneous canine lymphoma. Given the similarity in lineage between lymphoma and MM, we hypothesized that VDC-1101 would be active against MM. Results We evaluated the in vitro antiproliferative effects of VDC-1101 against 3 human MM cell lines, and we performed a phase-II clinical trial in 14 dogs with spontaneous MM. Each dog was treated with a maximum of 6 doses of VDC-1101 monotherapy over 10–15 weeks. Dose-dependent antiproliferative activity was observed in all evaluated cell lines. Major antitumor responses (reduction of serum paraprotein and resolution of hypercalcemia, peripheral cytopenias and bone marrow plasmacytosis) were observed in 9 of 11 evaluable dogs for a median of 172 days, including a durable stringent complete response (>1047 days) in a dog with melphalan-refractory disease. 2 dogs were euthanized due to presumed pulmonary fibrosis; there were no other dose-limiting toxicities encountered. Conclusions In conclusion, VDC-1101 has significant anti-tumor activity at well-tolerated doses in spontaneous canine MM. PMID:24460928

  7. Effects of activation of maternal immune system at early stages of pregnancy on antitumor immunity of the progeny.

    PubMed

    Obernikhin, S S

    2013-11-01

    The effects of maternal immune system on the formation and functioning of the fetus is an important problem. Single stimulation of immune system of female C57Bl/6 mice with concanavalin A at the early stages of pregnancy before the formation of fetal immune organs was followed by impairment of antitumor immunity in the progeny by the time of puberty. These changes manifested in the increased survival rate of B16 melanoma, high rate of death of tumor-bearing animals, and low cytotoxic activity of spleen cells on L-929 fibrosarcoma cells.

  8. Improved in vitro anti-tumoral activity, intracellular uptake and apoptotic induction of gemcitabine-loaded pegylated unilamellar liposomes.

    PubMed

    Celia, Christian; Calvagno, Maria Grazia; Paolino, Donatella; Bulotta, Stefania; Ventura, Cinzia Anna; Russo, Diego; Fresta, Massimo

    2008-04-01

    Anaplastic thyroid carcinoma is one of the most aggressive and lethal solid carcinomas affecting humans. A major limit of the chemotherapeutic agents is represented by their low therapeutic index. In this work, we investigated the possibility of improving the anti-tumoral activity of gemcitabine by using pegylated unilamellar liposomes. Liposomes were made up of 1,2-dipalmitoyl-sn-glycero-3-phospocholine monohydrate/cholesterol/N-(carbonyl-methoxypolyethylene glycol-2000)-1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (6:3:1 molar ratio) and they were prepared with a pH gradient to improve the gemcitabine loading capacity. The anti-tumoral efficacy of the liposomal formulation was tested in vitro on human anaplastic thyroid carcinoma cells (ARO) in culture, comparing the effects with those of the free drug. Gemcitabine-loaded unilamellar liposomes had a mean size approximately 200 nm with a zeta potential approximately -2 mV. The liposomal carrier noticeably improved the anti-tumoral activity of gemcitabine against ARO cells in terms of both dose-dependent cytotoxic effect and of drug exposition effect. Namely, gemcitabine-loaded liposomes showed a cytotoxic effect (58.2% increase of cell mortality at 1 microM with respect to free drug) after 12 h incubation, while the free drug showed a significant activity only after 72 h incubation. Moreover, a significant effect on the cell mortality appeared at 0.1 microM and 100% mortality was detected at a concentration of 1 microM of gemcitabine-loaded liposomes, while the free drug elicited the same effect at a concentration of 100 microM. The improved anti-tumoral activity of gemcitabine determined by the liposomal carrier was due to a greater intracellular uptake. The intracellular gemcitabine levels as a function of time showed a sinusoidal profile with peaks after 2 h, 6 h and 11 h, related to the cellular cycle of ARO. PARP cleavage and DNA fragmentation analysis provided clear evidence of the apoptosis induction in

  9. Solution-phase parallel synthesis and screening of anti-tumor activities from fenbufen and ethacrynic acid libraries.

    PubMed

    Su, Yuan-Hsiao; Chiang, Li-Wu; Jeng, Kee-Ching; Huang, Ho-Lien; Chen, Jenn-Tzong; Lin, Wuu-Jyh; Huang, Chia-Wen; Yu, Chung-Shan

    2011-03-01

    The derivatives with fenbufen and ethacrynic acid core compounds was synthesized through a facial preparation of 1-amino-4-azidobutane. The subsequent coupling with 102 members of carboxylic acids afforded amide products. The in situ screening using colorimetric assay with 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide showed that fenbufen but not ethacrynic acid butyl amide members displayed the cytotoxicities to tumor cells substantially, including two human cell lines (MCF7 and A549) and two murine cell lines (C26 and TRAMP-C1). Three fenbufen analogs were found to have a good anti-tumor activity comparable to cisplatin.

  10. A New Ex Vivo Method for Effective Expansion and Activation of Human Natural Killer Cells for Anti-Tumor Immunotherapy.

    PubMed

    Yang, Hui; Tang, Ruihua; Li, Jing; Liu, Yaxiong; Ye, Linjie; Shao, Dongyan; Jin, Mingliang; Huang, Qingsheng; Shi, Junling

    2015-12-01

    Preserving the activities of natural killer (NK) cells in human peripheral blood mononuclear cells (PBMCs) after ex vivo expansion and activation is critical for NK cell-based therapy. Collected from human PBMCs, the NK cells were expanded and activated. The expressions of surface receptors, cytotoxicity against tumor cells, and antibody-dependent cell-mediated cytotoxicity (ADCC) of the NK cells before and after expansion and activation were, respectively, compared. After expansion, the ADCC activity of healthy human NK cells was improved by 32 %, and the cytotoxicity against four types of tumor cells was increased by 19, 29, 26, and 28 %, respectively. The positive expression rates for the activating receptors NKG2D, CD94, NKp46, NKp30, and NKp44 of healthy human NK cells expanded ex vivo were increased by 60, 40, 20, 40, and 63 %, respectively, whereas those for the inhibitory receptors CD158b, NKB1, and NKAT showed no significant changes. The addition of an immunologically active peptide, "TKD," during cell expansion further increased NK cytotoxicity by approximately 10 %. The expanded and activated NK cells from cancer patients achieved average purity which was greater than 90 %, and the cytotoxicity against K562 cells was increased by more than 17 %. Compared with resting NK cells, NK cells both from healthy volunteers and cancer patients expanded and activated ex vivo using our method were significantly more active and demonstrated significantly increased anti-tumor activity. This method could be therefore used as a new and effective approach to meet requirements for anti-tumor immunotherapy.

  11. Ergosterol-loaded poly(lactide-co-glycolide) nanoparticles with enhanced in vitro antitumor activity and oral bioavailability

    PubMed Central

    Zhang, Hui-yun; Firempong, Caleb Kesse; Wang, Yuan-wen; Xu, Wen-qian; Wang, Miao-miao; Cao, Xia; Zhu, Yuan; Tong, Shan-shan; Yu, Jiang-nan; Xu, Xi-ming

    2016-01-01

    Aim: Ergosterol is a plant sterol with anti-tumor and anti-angiogenic activities, but is poorly soluble. In this study, we attempted to enhance its anti-tumor action and oral bioavailability via poly(lactide-co-glycolide) (PLGA) nanoparticle encapsulation. Methods: Ergosterol-loaded PLGA nanoparticles (NPs/Erg) were prepared using the emulsion/solvent evaporation technique. Their physicochemical properties were characterized, and their cytotoxicity against human cancer cell lines was evaluated with MTT assay. The pharmacokinetics and tissue distribution of NPs/Erg were investigated in rats and mice, respectively. Results: NPs/Erg were spherical in shape with a particle size of 156.9±4.8 nm and a Zeta potential of -19.27±1.13 mV, and had acceptable encapsulation efficiency and loading capacity. NPs/Erg exerted much stronger cytotoxicity against human cancer cells than the free ergosterol, and showed significantly reduced IC50 values (14.69±0.48 μg/mL in glioma U251 cells; 9.43±0.52 μg/mL in breast cancer MCF-7 cells; 4.70±0.41 μg/mL in hepatoma HepG2 cells). After oral administration of a single dose in rats, NPs/Erg displayed a prolonged plasma circulation with a 4.9-fold increase of oral bioavailability compared with the free ergosterol. After mice received NPs/Erg, the ergosterol in NPs/Erg was rapidly distributed in stomach, kidneys, liver, brain, spleen, and virtually non-existent in heart and lungs. The presence of NPs/Erg in brain was particularly improved compared with the free ergosterol. Conclusion: The PLGA nanoparticles serve as a promising carrier for the poorly soluble ergosterol and significantly improve its bioavailability, biodistribution and in vitro anti-tumor activities. PMID:27133301

  12. Schedule dependency of the antitumor activity and toxicity of polyethylene glycol-modified interleukin 2 in murine tumor models.

    PubMed

    Zimmerman, R J; Aukerman, S L; Katre, N V; Winkelhake, J L; Young, J D

    1989-12-01

    Modification of recombinant human interleukin 2 (rhIL-2) with monomethoxy polyethylene glycol has been shown to alter its pharmacokinetic properties. Therefore, we investigated the pharmacological parameters of schedule and dose in order to assess the impact on the in vivo antitumor activity of this modification. The antitumor efficacy, as well as the toxicity, of polyethylene glycol-interleukin 2 (PEG-IL-2) was compared to that of rhIL-2 in three transplantable syngeneic murine tumor models, Meth A fibrosarcoma, B16 melanoma, and Pan-02 pancreatic carcinoma. At equitoxic dose levels, the antitumor activity of PEG-IL-2 was far superior to that of rhIL-2 in all three tumor models. This efficacy of PEG-IL-2 was dose dependent and was greatest on a Q7D x 2 schedule in Meth A and B16. When the same total doses were further divided and delivered on any of several alternative schedules, either the efficacy was reduced or the toxicity of the treatments was increased. In Pan-02, a rhIL-2-resistant tumor, PEG-IL-2 treatment on either the Q7D x 2, Q4D x 3, or Q3D x 4 schedule resulted in approximately a 200% increase in lifespan; however, the toxicity of the treatment increased as the interval between doses was shortened. Simulations of the pharmacokinetic profiles of these various regimens suggested that the toxicity of PEG-IL-2 and rhIL-2 was related to the minimum plasma concentration that was obtained and the time interval between peak levels. The efficacy of the treatment was associated with the interleukin 2 plasma peak height, since a dose response was observed; however, peak plasma concentration did not appear to be the only parameter which determined efficacy. We hypothesize that this observed schedule dependence is also affected by the kinetics of the host's biological response to rhIL-2.

  13. Immune-associated proteins with potential in vivo anti-tumor activities are upregulated in lung cancer cells treated with umbelliprenin: A proteomic approach

    PubMed Central

    Khaghanzadeh, Narges; Nakamura, Kazuyuki; Kuramitsu, Yasuhiro; Ghaderi, Abbas; Mojtahedi, Zahra

    2016-01-01

    Umbelliprenin (Umb), a natural coumarin, has demonstrated anti-tumor activities, both in vitro and particularly in vivo, in several types of cancer, including lung cancer. The present study aimed to identify molecular targets of Umb using a high-throughput approach. Lung cancer cell lines, QU-DB (large-cell lung carcinoma) and A549 (adenocarcinoma), were treated with Umb. Differentially-expressed proteins were identified using two-dimensional electrophoresis coupled to mass spectrometry. In the QU-DB cells, differential expression of proteins, including downregulation of the tumorigenic protein heat shock protein 90 kDa and upregulation of the potential anti-tumor proteins Nipsnap1 and glycine-tRNA ligase (GRS), suggested that Umb is a strong anti-tumor compound. In the A549 cells, differential expression of proteins indicated possible contradictory effects of Umbregarding tumorigenesis, which included downregulation of the tumorigenic protein cyclophilin and the tumor suppressor MST, and upregulation of stathmin (tumorigenic) and calreticulin. Calreticulun, in addition to GRS in QU-DB cells, stimulates anti-tumor immune responses in vivo. To the best of our knowledge, the present study is the first to use a high-throughput approach to identify targets of Umb in cancer. These molecular targets suggested that Umb may exhibit stronger in vitro anti-tumor activity against the large-cell carcinoma model than the adenocarcinoma model. Furthermore, it has been reported that Umb exhibits higher cytotoxicity against QU-DB cells than A549 cells in vitro, and significant Umb anti-tumor activity against lung cancer in vivo, which is consistent with previously published literature. In each cell type, immune-associated molecules were upregulated, indicating that this naturally occurring compound exhibits marked anti-tumor activity in vivo. However, further studies that investigate the effect of Umb in different in vitro models of cancer are required. PMID:28105238

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

    SciTech Connect

    Xavier, Sandhya; MacDonald, Shannon; Roth, Jennifer; Caunt, Maresa; Akalu, Abebe; Morais, Danielle; Buckley, Michael T.; Liebes, Leonard; Formenti, Silvia C.; Brooks, Peter C. . E-mail: peter.brooks@med.nyu.edu

    2006-06-01

    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{sup 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{sup 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.

  15. Antitumor activity of curcumin is involved in down-regulation of YAP/TAZ expression in pancreatic cancer cells

    PubMed Central

    Wang, Lixia; Yin, Xuyuan; Yan, Jingzhe; Wang, Zhiwei

    2016-01-01

    Pancreatic cancer (PC) is one of the most aggressive human malignancies worldwide and is the fourth leading cause of cancer-related deaths. Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant. Certain studies have demonstrated that curcumin exerts its anti-tumor function in a variety of human cancers including PC, via targeting multiple therapeutically important cancer signaling pathways. However, the detailed molecular mechanisms are not fully understood. Two transcriptional co-activators, YAP (Yes-associated protein) and its close paralog TAZ (transcriptional coactivator with PDZ-binding motif) exert oncogenic activities in various cancers. Therefore, in this study we aimed to determine the molecular basis of curcumin-induced cell proliferation inhibition in PC cells. First, we detected the anti-tumor effects of curcumin on PC cell lines using CTG assay, Flow cytometry, clonogenic assay, wound healing assay and Transwell invasion assay. We found that curcumin significantly suppressed cell growth, weakened clonogenic potential, inhibited migration and invasion, and induced apoptosis and cell cycle arrest in PC cells. We further measured that overexpression of YAP enhanced cell proliferation and abrogated the cytotoxic effects of curcumin on PC cells. Moreover, we found that curcumin markedly down-regulated YAP and TAZ expression and subsequently suppressed Notch-1 expression. Collectively, these findings suggest that pharmacological inhibition of YAP and TAZ activity may be a promising anticancer strategy for the treatment of PC patients. PMID:27738325

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

    SciTech Connect

    Xi, Wei-Hong; Yang, Li-Yun; Cao, Zhong-Yi; Qian, Yong

    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.

  17. Salvianolic acid B, a novel autophagy inducer, exerts antitumor activity as a single agent in colorectal cancer cells

    PubMed Central

    Zhang, Lumin; Chen, Liuxi; Zhang, Xiaomin; Liang, Xiao; Xie, Jiansheng; Fang, Yong; Sui, Xinbing; Han, Weidong; Pan, Hongming

    2016-01-01

    Salvianolic Acid B (Sal B), an active compound extracted from the Chinese herb Salvia miltiorrhiza, is attracting more and more attention due to its biological activities, including antioxidant, anticoagulant and antitumor effects. However, autophagy induction in cancer cells by Sal B has never been recognized. In this study, we demonstrated that Sal B induced cell death and triggered autophagy in HCT116 and HT29 cells in a dose-dependent manner. Specific inhibition of autophagy by 3-MA or shRNA targeting Atg5 rescued Sal B-induced cell death in vitro and in vivo, suggesting that Sal B-induced autophagy may play a pro-death role and contribute to the cell death of colorectal cancer cell lines. Furthermore, AKT/mTOR signaling pathway was demonstrated to be a critical mediator in regulating Sal B-induced cell death. Overexpression of AKT by the transfection with AKT plasmid or pretreatment with insulin decreased Sal B-induced autophagy and cell death. Inversely, inhibition of AKT by LY294002 treatment markedly enhanced Sal B-induced autophagy and cell death. Taken together, our results demonstrate, for the first time, that Sal B is a novel autophagy inducer and exerts its antitumor activity as a single agent in colorectal cancer cells through the suppression of AKT/mTOR pathway. PMID:27557491

  18. Salvianolic acid B, a novel autophagy inducer, exerts antitumor activity as a single agent in colorectal cancer cells.

    PubMed

    Jing, Zhao; Fei, Weiqiang; Zhou, Jichun; Zhang, Lumin; Chen, Liuxi; Zhang, Xiaomin; Liang, Xiao; Xie, Jiansheng; Fang, Yong; Sui, Xinbing; Han, Weidong; Pan, Hongming

    2016-09-20

    Salvianolic Acid B (Sal B), an active compound extracted from the Chinese herb Salvia miltiorrhiza, is attracting more and more attention due to its biological activities, including antioxidant, anticoagulant and antitumor effects. However, autophagy induction in cancer cells by Sal B has never been recognized. In this study, we demonstrated that Sal B induced cell death and triggered autophagy in HCT116 and HT29 cells in a dose-dependent manner. Specific inhibition of autophagy by 3-MA or shRNA targeting Atg5 rescued Sal B-induced cell death in vitro and in vivo, suggesting that Sal B-induced autophagy may play a pro-death role and contribute to the cell death of colorectal cancer cell lines. Furthermore, AKT/mTOR signaling pathway was demonstrated to be a critical mediator in regulating Sal B-induced cell death. Overexpression of AKT by the transfection with AKT plasmid or pretreatment with insulin decreased Sal B-induced autophagy and cell death. Inversely, inhibition of AKT by LY294002 treatment markedly enhanced Sal B-induced autophagy and cell death. Taken together, our results demonstrate, for the first time, that Sal B is a novel autophagy inducer and exerts its antitumor activity as a single agent in colorectal cancer cells through the suppression of AKT/mTOR pathway.

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

    NASA Astrophysics Data System (ADS)

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

    2017-01-01

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

  20. Bisphosphonates Inhibit Stellate Cell Activity and Enhance Antitumor Effects of Nanoparticle Albumin Bound-Paclitaxel in Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Gonzalez-Villasana, Vianey; Rodriguez-Aguayo, Cristian; Arumugam, Thiruvengadam; Cruz-Monserrate, Zobeida; Fuentes-Mattei, Enrique; Deng, Defeng; Hwang, Rosa F.; Wang, Huamin; Ivan, Cristina; Garza, Raul Joshua; Cohen, Evan; Gao, Hui; Armaiz-Pena, Guillermo N.; Monroig-Bosque, Paloma del C.; Philip, Bincy; Rashed, Mohammed H.; Aslan, Burcu; Erdogan, Mumin Alper; Gutierrez-Puente, Yolanda; Ozpolat, Bulent; Reuben, James M.; Sood, Anil K.; Logsdon, Craig; Lopez-Berestein, Gabriel

    2014-01-01

    Pancreatic stellate cells (PSCs) have been recognized as the principal cells responsible for the production of fibrosis in PDAC. Recently PSCs have been noted to share characteristics with cells of monocyte-macrophage lineage (MML cells). Thus, we tested whether PSCs could be targeted with the nitrogen-containing bisphosphonates (NBPs) [pamidronate (Pam) or zoledronic acid (ZA)], which are potent MML cell inhibitors. In addition, we tested NBPs treatment combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to enhance antitumor activity. In vitro we observed that PSCs possess α-naphthyl butyrate esterase (ANBE) enzyme activity, a specific marker of MML cells. Moreover NBPs inhibited PSCs proliferation, activation, release of macrophage chemoattractant protein-1 (MCP-1) and type I collagen expression. NBPs also induced PSC apoptosis and cell cycle arrest in the G1 phase. In vivo, NBPs inactivated PSCs; reduced fibrosis; inhibited tumor volume, tumor weight, peritoneal dissemination, angiogenesis, and cell proliferation; and increased apoptosis in an orthotopic murine model of PDAC. These in vivo antitumor effects were enhanced when NBPs were combined with nab-paclitaxel but not gemcitabine (Gem). Our study suggests that targeting PSCs and tumor cells with NBPs in combination with nab-paclitaxel may be a novel therapeutic approach to PDAC. PMID:25193509

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

    PubMed

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

    2013-08-01

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

  2. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background.

    PubMed

    Davies, Barry R; Greenwood, Hannah; Dudley, Phillippa; Crafter, Claire; Yu, De-Hua; Zhang, Jingchuan; Li, Jing; Gao, Beirong; Ji, Qunsheng; Maynard, Juliana; Ricketts, Sally-Ann; Cross, Darren; Cosulich, Sabina; Chresta, Christine C; Page, Ken; Yates, James; Lane, Clare; Watson, Rebecca; Luke, Richard; Ogilvie, Donald; Pass, Martin

    2012-04-01

    AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 μmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 μmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused dose- and time-dependent reduction of PRAS40, GSK3β, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC(50) ~ 0.1 μmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2(+) breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials.

  3. The effect of pH dependence of antibody-antigen interactions on subcellular trafficking dynamics

    PubMed Central

    Devanaboyina, Siva Charan; Lynch, Sandra M; Ober, Raimund J; Ram, Sripad; Kim, Dongyoung; Puig-Canto, Alberto; Breen, Shannon; Kasturirangan, Srinath; Fowler, Susan; Peng, Li; Zhong, Haihong; Jermutus, Lutz; Wu, Herren; Webster, Carl; Ward, E Sally; Gao, Changshou

    2013-01-01

    A drawback of targeting soluble antigens such as cytokines or toxins with long-lived antibodies is that such antibodies can prolong the half-life of the target antigen by a “buffering” effect. This has motivated the design of antibodies that bind to target with higher affinity at near neutral pH relative to acidic endosomal pH (~pH 6.0). Such antibodies are expected to release antigen within endosomes following uptake into cells, whereas antibody will be recycled and exocytosed in FcRn-expressing cells. To understand how the pH dependence of antibody-antigen interactions affects intracellular trafficking, we generated three antibodies that bind IL-6 with different pH dependencies in the range pH 6.0–7.4. The behavior of antigen in the presence of these antibodies has been characterized using a combination of fixed and live cell fluorescence microscopy. As the affinity of the antibody:IL-6 interaction at pH 6.0 decreases, an increasing amount of antigen dissociates from FcRn-bound antibody in early and late endosomes, and then enters lysosomes. Segregation of antibody and FcRn from endosomes in tubulovesicular transport carriers (TCs) into the recycling pathway can also be observed in live cells, and the extent of IL-6 association with TCs correlates with increasing affinity of the antibody:IL-6 interaction at acidic pH. These analyses result in an understanding, in spatiotemporal terms, of the effect of pH dependence of antibody-antigen interactions on subcellular trafficking and inform the design of antibodies with optimized binding properties for antigen elimination. PMID:24492341

  4. Enhanced antitumor activities of (-)-epigallocatechin-3-O-gallate fatty acid monoester derivatives in vitro and in vivo

    SciTech Connect

    Matsumura, Kazuaki; Kaihatsu, Kunihiro; Mori, Shuichi; Cho, Han Hee; Kato, Nobuo; Hyon, Suong Hyu

    2008-12-26

    (-)-Epigallocatechin-3-O-gallate (EGCG) monoesters modified with butanoyl (EGCG-C4), octanoyl (EGCG-C8), palmitoyl groups (EGCG-C16) were synthesized by a lipase-catalyzed transesterification method and their antitumor activities were investigated in vitro and in vivo. The in vitro antitumor activities of EGCG-monoester derivatives increased in an alkyl chain length-dependent manner. The cytotoxicity of EGCG, EGCG-C4, EGCG-C8 was mainly caused by H{sub 2}O{sub 2} which was generated with their oxidation. On the other hand, EGCG-C16 was more stable than EGCG and it did not generate H{sub 2}O{sub 2} in the cell culture medium. Furthermore, EGCG-C16 inhibited cell proliferation and induced apoptosis in the presence of catalase. EGCG-C16 was found to inhibit the phosphorylation of the epidermal growth factor receptor (EGFR), which is related to various types of tumor growth. EGCG-C16 suppressed tumor growth in vivo in colorectal tumor bearing mice in comparison to an untreated control, vector control (DMSO) and EGCG.

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

    PubMed Central

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

    2016-01-01

    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. PMID:27241877

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

    PubMed

    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 <0.2, zeta potential negative values and I3C encapsulation efficiency around 42%, without any influence of the 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.

  7. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice.

    PubMed

    Wang, Zili; Celis, Esteban

    2015-08-01

    Therapeutic vaccines to induce anti-tumor CD8 T cells have been used in clinical trials for advanced melanoma patients, but the clinical response rate and overall survival time have not improved much. We believe that these dismal outcomes are caused by inadequate number of antigen-specific CD8 T cells generated by most vaccines. In contrast, huge CD8 T cell responses readily occur during acute viral infections. High levels of type-I interferon (IFN-I) are produced during these infections, and this cytokine not only exhibits anti-viral activity but also promotes CD8 T cell responses. The studies described here were performed to determine whether promoting the production of IFN-I could enhance the potency of a peptide vaccine. We report that cyclic diguanylate monophosphate (c-di-GMP), which activates the stimulator of interferon genes, potentiated the immunogenicity and anti-tumor effects of a peptide vaccine against mouse B16 melanoma. The synergistic effects of c-di-GMP required co-administration of costimulatory anti-CD40 antibody, the adjuvant poly-IC, and were mediated in part by IFN-I. These findings demonstrate that peptides representing CD8 T cell epitopes can be effective inducers of large CD8 T cell responses in vaccination strategies that mimic acute viral infections.

  8. Antitumor and Antimetastasis Activities of Heparin-based Micelle Served As Both Carrier and Drug.

    PubMed

    Mei, Ling; Liu, Yayuan; Zhang, HuaJin; Zhang, Zhirong; Gao, Huile; He, Qin

    2016-04-20

    Effective treatments for tumors are not easy to achieve due to the existence of metastases, which are responsible for most tumor death. Hence, a new drug delivery system is a pressing need, which should be biocompatible, stimuli-responsive, and multifunctional, including antitumor, antimetastasis, and antiangiogenesis effects. However, it is challenging to achieve all of these properties in one drug delivery system. Here, we developed a system of drug DOX and heparin into one self-assemble nanoparticle via pH-sensitive hydrazone bond and hydrophobic groups, deoxycholate. In the process, heparin itself was not only as the hydrophilic segments of the carrier, but also processed multiple biological functions such as antiangiogenesis and antimetastasis effect. The micelle nanoparticle HD-DOX processed good stability and acidic pH-triggered drug release property. After systemic administration, heparin-based micelle nanoparticle showed longer half-time and enhanced accumulation of DOX in tumors through the enhanced permeability and retention effect, leading to more efficient antitumor effects. In addition, heparin could hinder platelet-induced tumor cells epithelial-mesenchymal transition (EMT) and partially affect cell actin cytoskeletal arrangement, resulting in the disorganization of the actin cytoskeleton. Therefore, HD-DOX exhibited significant inhibitory effect on the metastasis in melanoma animal model in C57BL/6 mouse. Meanwhile, benefited from the antiangiogenesis effect of heparin, tube formations in endothelial cells were effectively inhibited and tumor vascular density was decreased by HD-DOX. Taken together, our study developed a self-assembly nanoplatform that both the drug and carrier had therapeutic effects with ideal antitumor efficacy.

  9. Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases.

    PubMed

    Wan, Xinhai; Corn, Paul G; Yang, Jun; Palanisamy, Nallasivam; Starbuck, Michael W; Efstathiou, Eleni; Li Ning Tapia, Elsa M; Tapia, Elsa M Li-Ning; Zurita, Amado J; Aparicio, Ana; Ravoori, Murali K; Vazquez, Elba S; Robinson, Dan R; Wu, Yi-Mi; Cao, Xuhong; Iyer, Matthew K; McKeehan, Wallace; Kundra, Vikas; Wang, Fen; Troncoso, Patricia; Chinnaiyan, Arul M; Logothetis, Christopher J; Navone, Nora M

    2014-09-03

    Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell-bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in serum prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors.

  10. pH-Triggered Surface Charge Reversed Nanoparticle with Active Targeting To Enhance the Antitumor Activity of Doxorubicin.

    PubMed

    Du, Jiang-Bo; Cheng, Ying; Teng, Zeng-Hui; Huan, Meng-Lei; Liu, Miao; Cui, Han; Zhang, Bang-le; Zhou, Si-Yuan

    2016-05-02

    PLGA nanoparticles are widely used in tumor targeting drug delivery systems. However, the naked PLGA nanoparticles (NNPs) not only have low drug loading but also can be rapidly removed from blood circulation by the immune system. The aim of this study was to prepare pH-triggered surface charge reversed lipid hybrid PLGA nanoparticles (LNPs) to enhance drug loading and drug delivery efficiency. CHO-Arg-His-OMe and FA-PEG-DSPE were synthesized to modify PLGA nanoparticles to prepare LNPs. The drug loading and encapsulation rate of LNPs were greatly improved as compared with NNPs. In pH 7.4 medium, doxorubicin (DOX)-loaded LNPs showed negative charge and released DOX slowly. In pH 5.0 medium, DOX-loaded LNPs exhibited positive charge and released DOX quickly. DOX-loaded LNPs delivered more DOX to the nucleus of KB cells and MBA-MD-231/ADR cells than did free DOX. In addition, DOX-loaded LNPs significantly inhibited the proliferation of KB cells and MBA-MD-231/ADR cells. Compared with free DOX, the same dose of the DOX-loaded LNPs delivered more DOX to tumor tissue. Thus, DOX-loaded LNPs significantly inhibited the growth of tumor in tumor-bearing nude mice and obviously reduced the systemic toxicity of DOX. In conclusion, pH-triggered surface charge reversed DOX-loaded LNPs significantly enhanced the antitumor activity of DOX in vitro and in vivo. DOX-loaded LNPs had great potential in tumor targeted chemotherapy.

  11. In vivo modulation of alternative pathways of P-450-catalyzed cyclophosphamide metabolism: impact on pharmacokinetics and antitumor activity.

    PubMed

    Yu, L J; Drewes, P; Gustafsson, K; Brain, E G; Hecht, J E; Waxman, D J

    1999-03-01

    The widely used anticancer prodrug cyclophosphamide (CPA) is activated in liver by a 4-hydroxylation reaction primarily catalyzed by cytochrome P-4502B and P-4502C enzymes. An alternative metabolic pathway involves CPA N-dechloroethylation to yield chloroacetaldehyde (CA), a P-4503A-catalyzed deactivation/neurotoxication reaction. The in vivo modulation of these alternative, competing pathways of P-450 metabolism was investigated in pharmacokinetic studies carried out in the rat model. Peak plasma concentrations (Cmax) for 4-OH-CPA and CA were increased by 3- to 4-fold, and apparent plasma half-lives of both metabolites were correspondingly shortened in rats pretreated with phenobarbital (PB), an inducer of P-4502B and P-4503A enzymes. However, PB had no net impact on the extent of drug activation or its partitioning between these alternative metabolic pathways, as judged from AUC values (area-under-the-plasma concentration x time curve) for 4-OH-CPA and CA. The P-4503A inhibitor troleandomycin (TAO) decreased plasma Cmax and AUC of CA (80-85% decrease) without changing the Cmax or AUC of 4-OH-CPA in uninduced rats. In PB-induced rats, TAO decreased AUCCA by 73%, whereas it increased AUC4-OH-CPA by 93%. TAO thus selectively suppresses CPA N-dechloroethylation, thereby increasing the availability of drug for P-450 activation via 4-hydroxylation. By contrast, dexamethasone, a P-4503A inducer and antiemetic widely used in patients with cancer, stimulated large, undesirable increases in the Cmax and AUC of CA (8- and 4-fold, respectively) while reducing the AUC of the 4-hydroxylation pathway by approximately 60%. Tumor excision/in vitro colony formation and tumor growth delay assays using an in vivo 9L gliosarcoma solid tumor model revealed that TAO suppression of CPA N-dechloroethylation could be achieved without compromising the antitumor effect of CPA. The combination of PB with TAO did not, however, enhance the antitumor activity of CPA, despite the approximately 2

  12. Anti-tumor activity of phenoxybenzamine hydrochloride on malignant glioma cells.

    PubMed

    Lin, Xian-Bin; Jiang, Lei; Ding, Mao-Hua; Chen, Zhen-Hua; Bao, Yi; Chen, Yi; Sun, Wei; Zhang, Chen-Ran; Hu, Hong-Kang; Cai, Zhen; Lu, Cheng-Yin; Zhou, Jue-Yu; Qian, Jun; Wu, Xiao-Jun; Jin, Wei-Lin; Hu, Guo-Han

    2016-03-01

    Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to explore the anti-tumor function of PHEN in glioma. Cell proliferation assay was used to assess glioma cell growth. Migration and invasion capacity of glioma cells was monitored by wound-healing and transwell assay, respectively. Neurosphere formation test was adopted for the tumorigenesis of glioma cells, which was also confirmed by soft agar cloning formation test in vitro and a nude mouse model in vivo. Finally, we explored the potential pathway utilized by PHEN using Western blot and immunofluoresce staining. PHEN exhibited a significant inhibitory effect on the proliferation of both U251 and U87MG glioma cell lines in a positive dose-dependent manner. PHEN apparently attenuated the malignancy of glioma in terms of migration and invasion and also suppressed the tumorigenic capacity both in vitro and in vivo. Mechanism study showed that PHEN promoted tumor suppression by inhibiting the TrkB-Akt pathway. The results of the present study demonstrated that PHEN suppressed the proliferation, migration, invasion, and tumorigenesis of glioma cells, induced LINGO-1 expression, and inhibited the TrkB-Akt pathway, which may prove to be the mechanisms underlying the anti-tumor effect of PHEN on glioma cells.

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

    PubMed

    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).

  14. Antitumor Activity of 2,9-Di-Sec-Butyl-1,10-Phenanthroline

    PubMed Central

    Amin, A. R. M. Ruhul; Rahman, Mohammad Aminur; Nannapaneni, Sreenivas; Liu, Yuan; Shin, Dong M.; Saba, Nabil F.; Eichler, Jack F.; Chen, Zhuo G.

    2016-01-01

    The anti-tumor effect of a chelating phen-based ligand 2,9-di-sec-butyl-1,10-phenanthroline (dsBPT) and its combination with cisplatin were examined in both lung and head and neck cancer cell lines and xenograft animal models in this study. The effects of this agent on cell cycle and apoptosis were investigated. Protein markers relevant to these mechanisms were also assessed. We found that the inhibitory effect of dsBPT on lung and head and neck cancer cell growth (IC50 ranged between 0.1–0.2 μM) was 10 times greater than that on normal epithelial cells. dsBPT alone induced autophagy, G1 cell cycle arrest, and apoptosis. Our in vivo studies indicated that dsBPT inhibited tumor growth in a dose-dependent manner in a head and neck cancer xenograft mouse model. The combination of dsBPT with cisplatin synergistically inhibited cancer cell growth with a combination index of 0.3. Moreover, the combination significantly reduced tumor volume as compared with the untreated control (p = 0.0017) in a head and neck cancer xenograft model. No organ related toxicities were observed in treated animals. Our data suggest that dsBPT is a novel and potent antitumor drug that warrants further preclinical and clinical development either as a single agent or in combination with known chemotherapy drugs such as cisplatin. PMID:28033401

  15. Antimicrobial, antioxidant, and antitumor activity of epsilon-poly-L-lysine and citral, alone or in combination

    PubMed Central

    Shi, Ce; Zhao, Xingchen; Liu, Zonghui; Meng, Rizeng; Chen, Xiangrong; Guo, Na

    2016-01-01

    Background Food safety is an important worldwide public health concern, and microbial contamination in foods not only leads to food deterioration and shelf life reduction but also results in economic losses and disease. Objective The main aim of the present study was to evaluate the effect of epsilon-poly-L-lysine (ε-PL) and citral combination against Escherichia coli O157:H7 (E. coli O157:H7) strains. The preliminary antioxidant and antitumor activities were also studied. Design Synergism is a positive interaction created when two compounds combine and exert an inhibitory effect that is greater than the sum of their individual effects. The synergistic antimicrobial effect of ε-PL and citral was studied using the checkerboard method against E. coli O157:H7. The minimal inhibitory concentration, time-kill, and scanning electron microscope assays were used to determine the antimicrobial activity of ε-PL and citral alone or in combination; 2,2-diphenyl-1-picrylhydrazyl-scavenging assay and western blotting were used in antioxidant activity assays; cell viability assay was carried out to finish preliminary antitumor test. Results Minimal inhibitory concentrations of ε-PL and citral resisted to the five E. coli O157:H7 strains were 2–4 µg/mL and 0.5–1 µg/mL, and the fractional inhibitory concentration indices were 0.25–0.375. The results of time-kill assay revealed that a stronger bactericidal effect in a laboratory medium might be exerted in the combination against E. coli O157:H7 than that in a food model. The compounds alone or in combination exhibited a potential 2,2-diphenyl-1-picrylhydrazyl radical–scavenging activity, and the expression of superoxide dismutase 1 and glutathione peroxidase 1 protein increased. The preliminary antitumor activity effect of the combination was better than ε-PL or citral alone. Conclusions These findings indicated that the combination of ε-PL and citral could not only be used as a promising naturally sourced food

  16. A novel polysaccharide from Lentinus edodes Mycelia exhibits potential antitumor activity on laryngeal squamous cancer cell line Hep-2.

    PubMed

    Cao, Xiangyu; Liu, Ruihua; Liu, Jianli; Huo, Yapeng; Yang, Wei; Zeng, Meng; Yang, Chao

    2013-11-01

    A novel polysaccharide [Lentinus edodes mycelia polysaccharide 2 (LMP2)] with a molecular weight of 2.27 × 10(4) Da was isolated from the Lentinus edodes mycelia and purified by Sephadex G-200 and diethylaminoethyl-32 column chromatography. HPLC results indicated that LMP2 contained mannose, arabinose, galactose, xylose, and rhamnose with a relative molar ratio of 1:0.74:3.23:1.18:10.98. Its antitumor activity was evaluated in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, and transwell assay. LMP2 showed a remarkable inhibitory effect on the proliferation of Hep-2 cells, and at the concentration of 200 mg/ml, the inhibition ratio was 37.2 % after 72 h. Furthermore, colony formation of Hep-2 cells was reduced significantly after treatment with LMP2. Invasion of Hep-2 cells was inhibited significantly by LMP2. These results suggested that LMP2 could be explored as a potential antitumor material for laryngeal carcinoma.

  17. Esterification of Ginsenoside Rh2 Enhanced Its Cellular Uptake and Antitumor Activity in Human HepG2 Cells.

    PubMed

    Chen, Fang; Deng, Ze-Yuan; Zhang, Bing; Xiong, Zeng-Xing; Zheng, Shi-Lian; Tan, Chao-Li; Hu, Jiang-Ning

    2016-01-13

    Our previous research had indicated that the octyl ester derivative of ginsenoside Rh2 (Rh2-O) might have a higher bioavailability than Rh2 in the Caco-2 cell line. The aim of this study was to investigate the cellular uptake and antitumor effects of Rh2-O in human HepG2 cells as well as its underlying mechanism compared with Rh2. Results showed that Rh2-O exhibited a higher cellular uptake (63.24%) than Rh2 (36.76%) when incubated with HepG2 cells for 24 h. Rh2-O possessed a dose- and time-dependent inhibitory effect against the proliferation of HepG2 cells. The IC50 value of Rh2-O for inhibition of HepG2 cell proliferation was 20.15 μM, which was roughly half the value of Rh2. Rh2-O induced apoptosis of HepG2 cells through a mitochondrial-mediated intrinsic pathway. In addition, the accumulation of ROS was detected in Rh2-O-treated HepG2 cells, which participated in the apoptosis of HepG2 cells. Conclusively, the findings above all suggested that Rh2-O as well as Rh2 inducing HepG2 cells apoptosis might involve similar mechanisms; however, Rh2-O had better antitumor activities than Rh2, probably due to its higher cellular uptake.

  18. l-Tyrosine-loaded nanoparticles increase the antitumoral activity of direct electric current in a metastatic melanoma cell model

    PubMed Central

    de Campos, Vânia Emerich Bucco; Teixeira, Cesar Augusto Antunes; da Veiga, Venicio Feo; Júnior, Eduardo Ricci; Holandino, Carla

    2010-01-01

    Inhibition of tumor growth induced by treatment with direct electric current (DC) has been reported in several models. One of the mechanisms responsible for the antitumoral activity of DC is the generation of oxidative species, known as chloramines. With the aim of increasing chloramine production in the electrolytic medium and optimizing the antitumoral effects of DC, poly(ɛ-caprolactone) (PCL) nanoparticles (NPs) loaded with the amino acid tyrosine were obtained. The physical–chemical characterization showed that the NPs presented size in nanometric range and monomodal distribution. A slightly negative electrokinetic potential was also found in both blank NPs and l-tyrosine-loaded PCL NPs. The yield of the loading process was approximately 50%. Within 3 h of dissolution assay, a burst release of about 80% l-tyrosine was obtained. The in vitro cytotoxicity of DC was significantly increased when associated with l-tyrosine-loaded NPs, using a murine multidrug-resistant melanoma cell line model. This study showed that the use of the combination of nanotechnology and DC has a promising antineoplastic potential and opens a new perspective in cancer therapy. PMID:21187948

  19. PRIMA-1Met/APR-246 displays high antitumor activity in multiple myeloma by induction of p73 and Noxa.

    PubMed

    Saha, Manujendra N; Jiang, Hua; Yang, Yijun; Reece, Donna; Chang, Hong

    2013-11-01

    Targeting p53 by the small-molecule PRIMA-1(Met)/APR-246 has shown promising preclinical activity in various cancer types. However, the mechanism of PRIMA-1(Met)-induced apoptosis is not completely understood and its effect on multiple myeloma cells is unknown. In this study, we evaluated antitumor effect of PRIMA-1(Met) alone or its combination with current antimyeloma agents in multiple myeloma cell lines, patient samples, and a mouse xenograft model. Results of our study showed that PRIMA-1(Met) decreased the viability of multiple myeloma cells irrespective of p53 status, with limited cytotoxicity toward normal hematopoietic cells. Treatment of multiple myeloma cells with PRIMA-1(Met) resulted in induction of apoptosis, inhibition of colony formation, and migration. PRIMA-1(Met) restored wild-type conformation of mutant p53 and induced activation of p73 upregulating Noxa and downregulating Mcl-1 without significant modulation of p53 level. siRNA-mediated silencing of p53 showed a little effect on apoptotic response of PRIMA-1(Met), whereas knockdown of p73 led to substantial attenuation of apoptotic activity in multiple myeloma cells, indicating that PRIMA-1(Met)-induced apoptosis is, at least in part, p73-dependent. Importantly, PRIMA-1(Met) delayed tumor growth and prolonged survival of mice bearing multiple myeloma tumor. Furthermore, combined treatment of PRIMA-1(Met) with dexamethasone or doxorubicin displayed synergistic effects in both multiple myeloma cell lines and primary multiple myeloma samples. Consistent with our in vitro observations, cotreatment with PRIMA-1(Met) and dexamethasone resulted in enhanced antitumor activity in vivo. Our study for the first time shows antimyeloma activity of PRIMA-1(Met) and provides the rationale for its clinical evaluation in patients with multiple myeloma, including the high-risk group with p53 mutation/deletion.

  20. 1,25D3 enhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models

    PubMed Central

    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

  1. T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy.

    PubMed

    Raber, Patrick L; Sierra, Rosa A; Thevenot, Paul T; Shuzhong, Zhang; Wyczechowska, Dorota D; Kumai, Takumi; Celis, Esteban; Rodriguez, Paulo C

    2016-04-05

    The success of adoptive T cell-based immunotherapy (ACT) in cancer is limited in part by the accumulation of myeloid-derived suppressor cells (MDSC), which block several T cell functions, including T cell proliferation and the expression of various cytotoxic mediators. Paradoxically, the inhibition of CD8+ T cell differentiation into cytotoxic populations increased their efficacy after ACT into tumor-bearing hosts. Therefore, we aimed to test the impact of conditioning CD8+ T cells with MDSC on their differentiation potential and ACT efficacy. Our results indicate that MDSC impaired the progression of CD8+ T cells into effector populations, without altering their activation status, production of IL-2, or signaling through the T cell receptor. In addition, culture of CD8+ T cells with MDSC resulted in an increased ACT anti-tumor efficacy, which correlated with a higher frequency of the transferred T cells and elevated IFNγ production. Interestingly, activated CD62L+ CD8+ T cells were responsible for the enhanced anti-tumor activity showed by MDSC-exposed T cells. Additional results showed a decreased protein synthesis rate and lower activity of the mammalian/mechanistic target of rapamycin (mTOR) in T cells conditioned with MDSC. Silencing of the negative mTOR regulator tuberous sclerosis complex-2 in T cells co-cultured with MDSC restored mTOR activity, but resulted in T cell apoptosis. These results indicate that conditioning of T cells with MDSC induces stress survival pathways mediated by a blunted mTOR signaling, which regulated T cell differentiation and ACT efficacy. Continuation of this research will enable the development of better strategies to increase ACT responses in cancer.

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

    PubMed Central

    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. PMID:27806086

  3. Novel Natural Product-like Caged Xanthones Bearing a Carbamate Moiety Exhibit Antitumor Potency and Anti-Angiogenesis Activity In vivo

    PubMed Central

    Xu, Xiaoli; Wu, Yue; Hu, Mingyang; Li, Xiang; Bao, Qichao; Bian, Jinlei; You, Qidong; Zhang, Xiaojin

    2016-01-01

    DDO-6101, a simplified structure obtained from the Garcinia natural product (NP) gambogic acid (GA), has been previously shown to possess high cytotoxicity to a variety of human tumour cell lines. To improve its physicochemical properties and in vivo cytotoxic potency, a series of novel carbamate-bearing derivatives based on DDO-6101 was synthesized and characterized. The structural modifications revealed that the presence of a carbamate moiety was useful for obtaining comparable cytotoxicity and improved aqueous solubility and permeability. 8n, which contains a bipiperidine carbamate moiety, displayed better drug properties and potential in in vivo antitumor activity. In addition, an antitumor mechanistic study suggested that 8n (DDO-6337) inhibited the ATPase activity of Hsp90 (Heat shock protein 90), leading to the inhibition of HIF-1a and ultimately contributing to its anti-angiogenesis and antitumor properties. PMID:27767192

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

    PubMed

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

    2014-11-11

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

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

    NASA Astrophysics Data System (ADS)

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

    2014-11-01

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

  6. 2-Chloroethyl-3-sarcosinamide-1-nitrosourea, a novel chloroethylnitrosourea analogue with enhanced antitumor activity against human glioma xenografts.

    PubMed

    Marcantonio, D; Panasci, L C; Hollingshead, M G; Alley, M C; Camalier, R F; Sausville, E A; Dykes, D J; Carter, C A; Malspeis, L

    1997-09-15

    Nitrosoureas are among the most widely used agents used in the treatment of malignant gliomas. Here, the activity of 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) was compared with that of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), in vivo against s.c. implanted SF-295 and U-251 central nervous system (CNS) tumor xenografts. When given i.v., q4d for 3 doses, to athymic mice bearing s.c. SF-295 tumors, SarCNU, at an optimum of 167 mg/kg/dose, produced 9 tumor-free animals of 10 total animals, 1 regression, and no evidence of overt toxicity (> or =20% body weight loss). With a similar dosing schedule, BCNU produced no tumor-free animals, six regressions, and one drug-related death at its optimum of 30 mg/kg/dose. Furthermore, SarCNU retained high antitumor activity at two lower dose levels, 66 and 45% of the optimal dose, whereas BCNU demonstrated a progressive loss of antitumor activity at lower doses. Following p.o. administration, SarCNU similarly demonstrated antitumor activity that was superior to that of BCNU. In the U-251 CNS tumor model, SarCNU yielded six of six tumor-free animals at 80 mg/kg/dose with i.p. administration q.d. for 5 days, starting on day 14, whereas BCNU, at 9 mg/kg/dose, yielded three of six tumor-free mice and one drug-related death. Again, SarCNU resulted in tumor-free animals at 66 and 45% of its optimal dose and was relatively nontoxic, in contrast to BCNU. Results of testing to date indicate that SarCNU is clearly more effective than BCNU against the human CNS tumors SF-295 and U-251 in vivo. These results encourage the initiation of clinical trials for SarCNU, in an effort to improve therapeutic approaches to glioma, but clinical trials must determine whether superiority of SarCNU in preclinical models can be extrapolated to patients.

  7. Production of interferon-gamma by in vivo tumor-sensitized T cells: Association with active antitumor immunity

    SciTech Connect

    Bursuker, I.; Pearce, M.T. )

    1990-02-01

    The state of active immunity to Meth A fibrosarcoma in mice immunized with an admixture of Meth A cells and Propionibacterium acnes is associated with possession by the host of spleen cells capable of producing interferon-gamma (IFN-gamma) upon in vitro restimulation with irradiated tumor cells. The ability of spleen cells from immunized mice to produce IFN-gamma in response to irradiated Meth A cells decays as active antitumor immunity is replaced by a state of immunological memory. The IFN-producing cells are L3T4+Ly2+, cyclophosphamide-sensitive and radiosensitive T cells, as determined by their sensitivity to corresponding monoclonal antibodies and complement. The induction of IFN-gamma production by in vivo tumor-sensitized T cells is tumor specific, in that spleen cells from mice immunized against Meth A fibrosarcoma can produce IFN in response to irradiated Meth A cells but not in response to another syngeneic tumor M109 lung carcinoma.

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

    PubMed

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

    2004-06-01

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

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

    PubMed Central

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

    2014-01-01

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

  10. Antitumor activity of tripterine via cell-penetrating peptide-coated nanostructured lipid carriers in a prostate cancer model

    PubMed Central

    Yuan, Ling; Liu, Congyan; Chen, Yan; Zhang, Zhenhai; Zhou, Lei; Qu, Ding

    2013-01-01

    Background The purpose of this study was to evaluate the antitumor effect of cell-penetrating peptide-coated tripterine-loaded nanostructured lipid carriers (CT-NLC) on prostate tumor cells in vitro and in vivo. Methods CT-NLC were developed to improve the hydrophilicity of tripterine. The antiproliferative effects of CT-NLC, tripterine-loaded nanostructured lipid carriers (T-NLC), and free tripterine in a human prostatic carcinoma cell line (PC-3) and a mouse prostate carcinoma cell line (RM-1) were evaluated using an MTT assay. The advantage of CT-NLC over T-NLC and free tripterine with regard to antitumor activity in vivo was evaluated in a prostate tumor-bearing mouse model. The induced tumor necrosis factor-alpha and interleukin-6 cytokine content was investigated by enzyme-linked immunosorbent assay to determine the effect of CT-NLC, T-NLC, and free tripterine on immune responses. Histologic and TUNEL assays were carried out to investigate the mechanisms of tumor necrosis and apoptosis. Results CT-NLC, T-NLC, and free tripterine showed high antiproliferative activity in a dose-dependent manner, with an IC50 of 0.60, 0.81, and 1.02 μg/mL in the PC-3 cell line and 0.41, 0.54, and 0.89 μg/mL in the RM-1 cell line after 36 hours. In vivo, the tumor inhibition rates for cyclophosphamide, high-dose (4 mg/kg) and low-dose (2 mg/kg) tripterine, high-dose (4 mg/kg) and low-dose (2 mg/kg) T-NLC, high-dose (4 mg/kg) and low-dose (2 mg/kg) CT-NLC were 76.51%, 37.07%, 29.53%, 63.56%, 48.25%, 72.68%, and 54.50%, respectively, showing a dose-dependent pattern. The induced tumor necrosis factor-alpha and interleukin-6 cytokine content after treatment with CT-NLC and T-NLC was significantly higher than that of high-dose tripterine. Moreover, CT-NLC showed the expected advantage of inducing necrosis and apoptosis in prostate tumor cells. Conclusion CT-NLC noticeably enhanced antitumor activity in vitro and in vivo and showed dramatically improved cytotoxicity in normal cells

  11. P450 inhibitor ketoconazole increased the intratumor drug levels and antitumor activity of fenretinide in human neuroblastoma xenograft models.

    PubMed

    Lopez-Barcons, Lluis; Maurer, Barry J; Kang, Min H; Reynolds, C Patrick

    2017-03-24

    We previously reported that concurrent ketoconazole, an oral anti-fungal agent and P450 enzyme inhibitor, increased plasma levels of the cytotoxic retinoid, fenretinide (4-HPR) in mice. We have now determined the effects of concurrent ketoconazole on 4-HPR cytotoxic dose-response in four neuroblastoma (NB) cell lines in vitro and on 4-HPR activity against two cell line-derived, subcutaneous NB xenografts (CDX) and three patient-derived NB xenografts (PDX). Cytotoxicity in vitro was assessed by DIMSCAN assay. Xenografted animals were treated with 4-HPR/LXS (240 mg/kg/day) + ketoconazole (38 mg/kg/day) in divided oral doses in cycles of five continuous days a week. In one model, intratumoral levels of 4-HPR and metabolites were assessed by HPLC assay, and in two models intratumoral apoptosis was assessed by TUNEL assay, on Day 5 of the first cycle. Antitumor activity was assessed by Kaplan-Meier event-free survival (EFS). The in vitro cytotoxicity of 4-HPR was not affected by ketoconazole (P ≥ 0.06). Ketoconazole increased intratumoral levels of 4-HPR (P = 0.02), of the active 4-oxo-4-HPR metabolite (P = 0.04), and intratumoral apoptosis (P ≤ 0.002), compared to 4-HPR/LXS-alone. Concurrent ketoconazole increased EFS in both CDX models compared to 4-HPR/LXS-alone (P ≤ 0.01). 4-HPR + ketoconazole also increased EFS in PDX models compared to controls (P ≤ 0.03). Thus, concurrent ketoconazole decreased 4-HPR metabolism with resultant increases of plasma and intratumoral drug levels and antitumor effects in neuroblastoma murine xenografts. These results support the clinical testing of concurrent ketoconazole and oral fenretinide in neuroblastoma. This article is protected by copyright. All rights reserved.

  12. Targeting gemcitabine containing liposomes to CD44 expressing pancreatic adenocarcinoma cells causes an increase in the antitumoral activity.

    PubMed

    Dalla Pozza, Elisa; Lerda, Carlotta; Costanzo, Chiara; Donadelli, Massimo; Dando, Ilaria; Zoratti, Elisa; Scupoli, Maria Teresa; Beghelli, Stefania; Scarpa, Aldo; Fattal, Elias; Arpicco, Silvia; Palmieri, Marta

    2013-05-01

    Pancreatic adenocarcinoma is often diagnosed when metastatic events have occurred. The early spread of circulating cancer cells expressing the CD44 receptor may play a crucial role in this process. In this study, we have investigated the cellular delivery ability and both in vitro and in vivo anti-tumoral activity of liposomes conjugated with two different low molecular weight hyaluronic acids (HA 4.8kDa and HA 12kDa), the primary ligand of CD44, and containing a lipophilic gemcitabine (GEM) pro-drug. By confocal microscopy and flow cytometry analyses, we demonstrate that the cellular uptake into a highly CD44-expressing pancreatic adenocarcinoma cell line is higher with HA-conjugated (12kDa>4.8kDa) than non-conjugated liposomes. Consistently, in vitro cytotoxic assays display an increased sensitivity towards GEM containing HA-liposomes, compared to non-conjugated liposomes. Conversely, CD44 non-expressing normal cells show a similar uptake and in vitro cytotoxicity with both HA-conjugated and non-conjugated liposomes. Furthermore, we demonstrate that the HA-liposomes are taken up into the cells via lipid raft-mediated endocytosis. All the liposome formulations containing GEM show a higher antitumoral activity than free GEM in a mouse xenograft tumor model of human pancreatic adenocarcinoma. The 12kDa HA-liposomes have the strongest efficiency, while non-conjugated liposomes and the 4.8kDa HA-liposomes are similarly active. Taken together, our results provide a strong rationale for further development of HA-conjugated liposomes to treat pancreatic adenocarcinoma.

  13. Synthesis, spectroscopic characterization and pH dependent photometric and electrochemical fate of Schiff bases.

    PubMed

    Rauf, Abdur; Shah, Afzal; Abbas, Saghir; Rana, Usman Ali; Khan, Salah Ud-Din; Ali, Saqib; Zia-Ur-Rehman; Qureshi, Rumana; Kraatz, Heinz-Bernhard; Belanger-Gariepy, Francine

    2015-03-05

    A new Schiff base, 1-((4-bromophenylimino) methyl) naphthalen-2-ol (BPIMN) was successfully synthesized and characterized by (1)H NMR, (13)C NMR, FTIR and UV-Vis spectroscopy. The results were compared with a structurally related Schiff base, 1-((4-chlorophenylimino) methyl) naphthalen-2-ol (CPIMN). The photometric and electrochemical fate of BPIMN and CPIMN was investigated in a wide pH range. The experimental findings were supported by quantum mechanical approach. The redox mechanistic pathways were proposed on the basis of results obtained electrochemical techniques. Moreover, pH dependent UV-Vis spectroscopy of BPIMN and CPIMN was carried out and the appearance of isosbestic points indicated the existence of these compounds in different tautomeric forms.

  14. pH dependence of uranyl retention in a quartz/solution system: an XPS study.

    PubMed

    Froideval, A; Del Nero, M; Barillon, R; Hommet, J; Mignot, G

    2003-10-15

    We have investigated the pH dependence of U(VI) retention in quartz/10(-4) M uranyl solution systems, under conditions favoring formation of polynuclear aqueous species and of colloids of amorphous schoepite as U(VI) solubility-limiting phases. X-ray photoelectron spectroscopy was used to gain insights into the coordination environments of sorbed/precipitated uranyl ions in the centrifuged quartz samples. The U4f XPS spectra made it possible to identify unambiguously the presence of two uranyl components. A high binding energy component, whose relative proportion increases with pH, exhibits the U4f lines characteristic of a reference synthetic metaschoepite. Such a high binding energy component is interpreted as a component having a U(VI) oxide hydrate character, either as polynuclear surface oligomers and/or as amorphous schoepite-like (surface) precipitates. Its pH dependence suggests that a binding of polynuclear species at quartz surfaces and/or a formation of amorphous schoepite-like (surface) precipitates is favored when the proportion of aqueous polynuclear species increases. A second surface component exhibits binding energies for the U4f core levels at values significantly lower (DeltaE(b)=1.2 eV) than for metaschoepite, evidencing uranyl ions in a distinct coordination environment. Such a low binding energy component may be attributed to monomeric uranyl surface complexes on the basis of published EXAFS data. Such a hypothesis is supported by a major contribution of the low binding energy component to the U4f XPS spectra of reference samples for uranyl sorbed on quartz from very acidic 10(-3) M uranyl solutions where UO(2)(2+) ions predominate.

  15. Gemcitabine-treated pancreatic cancer cell medium induces the specific CTL antitumor activity by stimulating the maturation of dendritic cells.

    PubMed

    Pei, Qingshan; Pan, Jianmei; Zhu, Hao; Ding, Xiwei; Liu, Wenjia; Lv, Ying; Zou, Xiaoping; Luo, Hesheng

    2014-03-01

    Gemcitabine (GEM) is a first line chemotherapeutic drug for advanced pancreatic cancer. Dendritic cell (DC) vaccine is a promising method of immunotherapy for malignant tumor. Recent research has indicated that gemcitabine can enhance the efficacy of DC vaccine, but precise mechanism is still unknown. Here, we aimed to investigate the effect of GEM on DCs. The results showed that GEM-treated pancreatic cancer cell medium stimulated maturation of DCs. When co-cultured with autologous T lymphocytes, the pulsed DCs promoted the proliferation of T cells, and exhibited specific cytotoxic T lymphocytes (CTLs) antitumor activity. Further research showed that stimulation of DC maturation may be related to the elevated level of Hsp70 induced by GEM. Our study indicates that GEM changes the immunogenicity of tumor cells, and enhances the efficacy of DC based immunotherapy for pancreatic cancer.

  16. Extraction, preliminary characterization and evaluation of in vitro antitumor and antioxidant activities of polysaccharides from Mentha piperita.

    PubMed

    Liu, Xin; Sun, Zhen-Liang; Jia, Ai-Rong; Shi, Ya-Ping; Li, Rui-Hong; Yang, Pei-Ming

    2014-09-15

    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.

  17. Organotin(IV) carboxylates of (E)-3-(2-nitrophenyl) propenoic acid: Synthesis, spectroscopic characterization, crystal structure and antitumor activity

    NASA Astrophysics Data System (ADS)

    Liu, Chunling; Liu, Shuangshuang; Du, Dafeng; Zhu, Dongsheng; Xu, Lin

    2011-09-01

    Two organotin(IV) carboxylates of (E)-3-(2-nitrophenyl) propenoic acid (HL), [Ph 3SnL] n ( 1) and {[Bu 2SnL] 2O} 2 ( 2), have been synthesized. All the complexes were characterized by elemental analysis, FT-IR and NMR ( 1H, 13C) spectroscopy. In addition, the molecular structures of 1 and 2 have been determined by single crystal X-ray diffraction analysis. Complex 1 consisted of a 1D chain polymer and was interconnected by C sbnd H⋯π stacking to aggregate in 2D framework. Complex 2 contained a dimeric tetraorganodistannoxane of ladder arrangement and was linked by C sbnd H⋯O hydrogen bonds to form a 1D chain. Their antitumor activities were also investigated.

  18. Human Uterine Cervical Stromal Stem Cells (hUCESCs): Why and How they Exert their Antitumor Activity

    PubMed Central

    SCHNEIDER, JOSÉ; EIRÓ, NOEMÍ; PÉREZ-FERNÁNDEZ, ROMÁN; MARTÍNEZ-ORDÓÑEZ, ANXO; VIZOSO, FRANCISCO

    2016-01-01

    Our research team has recently isolated and characterized a new stromal stem cell line (hUCESCs) obtained from cytological smears, as routinely performed for cervical cancer screening. We have, furthermore, described that both hUCESCs directly, as well as the secretome contained in the conditioned medium used for growing them (hUCESCs-CM) have potent antitumoral, anti-inflammatory, antibiotic, antimycotic and re-epitheliasation-enhancing properties. The scientific explanation our team proposes for these pleiotropic effects are directly related to the site of origin of hUCESCs, the human cervical transition zone, which has unique features that biologically justify the different actions of hUCESCs and hUCESCs-CM. We, herein, expose our working theory for the biological activity of hUCESCs and hUCESCs-CM. PMID:27566652

  19. Extraction, Preliminary Characterization and Evaluation of in Vitro Antitumor and Antioxidant Activities of Polysaccharides from Mentha piperita

    PubMed Central

    Liu, Xin; Sun, Zhen-Liang; Jia, Ai-Rong; Shi, Ya-Ping; Li, Rui-Hong; Yang, Pei-Ming

    2014-01-01

    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. PMID:25226538

  20. Synthesis and Evaluation of Antitumor Activity of Novel N-Acyllavendamycin Analogues and Quinoline -5,8- diones

    PubMed Central

    Behforouz, Mohammad; Cai, Wen; Mohammadi, Farahnaz; Stocksdale, Mark G.; Gu, Zhengxiang; Ahmadian, Mohammad; Baty, Darric E.; Etling, Michele R.; Al-Anzi, Charmaine H.; Swiftney, Tyson M.; Tanzer, Lee R.; Merriman, Ronald R.; Behforouz, Nancy C.

    2007-01-01

    A series of 7-N-acyllavendamycins with zero, one or two substitutents at the C-2′, C-3′ and C-11′ were synthesized through short and efficient methods. Pictet-Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptamine or tryptophans produced the desired lavendamycins. Screening data on a panel of three ras oncogene transformed cell lines and the non-transformed parent cell line showed that a significant number of these analogues are potent antitumor agents and appear to be particularly active against K-ras transformed cells. Compared with the corresponding quinolinediones, these novel lavendamycins are much more inhibitory toward the transformed cells indicating that the β-carboline moiety of the lavendamycin analogues plays an important role in its potency and selective toxicity. PMID:17035024

  1. [The genetic activity of superlow doses of antitumor antibiotics and 2-nitrofluorene: the ecological aspects of the problem].

    PubMed

    Vasil'eva, S V; Makhova, E V

    1996-01-01

    The genetic (mutagenic) activity of ultralow doses (below 1 x 10(-12)M of the antitumor antibiotics, anthracyclines and bleomycin, as well as the typical pollutant and component of the urban atmosphere 2-nitrofluorene, was studied on the model of Salmonella typhimurium LT2 TA98 his D3052. It was shown for the first time that carminomycin and 2-nitrofluorene at 1 x 10(-17) and 1 x 10(-22) M induced a two- to threefold increase in the number of revertants-prototrophs over the spontaneous background. The areas of increase (1 x 10(-15) M) and decrease (1 x 10(-19) and 1 x 10(-21) M) in the number of mutants, as compared with the spontaneous background, were found in the curve of dose dependence of the number of mutants in the presence of bleomycin. The results obtained were discussed in terms of their ecological importance.

  2. Human Uterine Cervical Stromal Stem Cells (hUCESCs): Why and How they Exert their Antitumor Activity.

    PubMed

    Schneider, José; Eiró, Noemí; Pérez-Fernández, Román; Martínez-Ordóñez, Anxo; Vizoso, Francisco

    Our research team has recently isolated and characterized a new stromal stem cell line (hUCESCs) obtained from cytological smears, as routinely performed for cervical cancer screening. We have, furthermore, described that both hUCESCs directly, as well as the secretome contained in the conditioned medium used for growing them (hUCESCs-CM) have potent antitumoral, anti-inflammatory, antibiotic, antimycotic and re-epitheliasation-enhancing properties. The scientific explanation our team proposes for these pleiotropic effects are directly related to the site of origin of hUCESCs, the human cervical transition zone, which has unique features that biologically justify the different actions of hUCESCs and hUCESCs-CM. We, herein, expose our working theory for the biological activity of hUCESCs and hUCESCs-CM.

  3. Host-guest inclusion system of artesunate with β-cyclodextrin and its derivatives: Characterization and antitumor activity

    NASA Astrophysics Data System (ADS)

    Xie, Hudie; Yang, Bo; Wang, Fen; Zhao, Yulin

    2015-04-01

    Inclusion complexes between artesunate (ATS) and three cyclodextrins, namely β-cyclodextrin (β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD), were prepared by a suspension method. The complexes in both liquid and solid were characterized by phase-solubility diagram, nuclear magnetic resonance (NMR), powder X-ray diffraction (XRD) and thermoanalysis. The results suggested that artesunate was partly encapsulated within the cyclodextrin cavity to form a 1:1 stoichiometry host-guest compound. Especially in the SBE-β-CD complex, displayed the greatest stability constant. Significant enhancement of water solubility and thermal stability of ATS in present of β-CDs was shown. The calculated IC50 values indicated that the antitumor activities of inclusion complexes were better than that of ATS. Satisfactory aqueous solubility, along with high thermal stability of inclusion complexes will be potentially useful for their application on the formulation design of natural medicine.

  4. Green synthesis of silver nanoparticles using cell extracts of Anabaena doliolum and screening of its antibacterial and antitumor activity.

    PubMed

    Singh, Garvita; Babele, Piyoosh K; Shahi, Shailesh K; Sinha, Rajeshwar P; Tyagi, Madhu B; Kumar, Ashok

    2014-10-01

    In the present work, we describe a simple, cheap, and unexplored method for "green" synthesis of silver nanoparticles using cell extracts of the cyanobacterium Anabaena doliolum. An attempt was also made to test the antimicrobial and antitumor activities of the synthesized nanoparticles. Analytical techniques, namely UV-vis spectroscopy, X-ray diffraction, Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), and TEMselected area electron diffraction, were used to elucidate the formation and characterization of silver-cyanobacterial nanoparticles (Ag-CNPs). Results showed that the original color of the cell extract changed from reddish blue to dark brown after addition of silver nitrate solution (1 mM) within 1 h, suggesting the synthesis of Ag-CNPs. That the formation Ag-CNPs indeed occurred was also evident from the spectroscopic analysis of the reaction mixture, wherein a prominent peak at 420 nm was noted. TEM images revealed well-dispersed, spherical Ag- CNPs with a particle size in the range of 10-50 nm. The X-ray diffraction spectrum suggested a crystalline nature of the Ag-CNPs. FTIR analysis indicated the utilization of a hydroxyl (-OH) group in the formation of Ag-CNPs. Ag-CNPs exhibited strong antibacterial activity against three multidrug-resistant bacteria. Additionally, Ag-CNPs strongly affected the survival of Dalton's lymphoma and human carcinoma colo205 cells at a very low concentration. The Ag-CNPs-induced loss of survival of both cell types may be due to the induction of reactive oxygen species generation and DNA fragmentation, resulting in apoptosis. Properties exhibited by the Ag-CNP suggest that it may be used as a potential antibacterial and antitumor agent.

  5. Improving the antitumor activity of squalenoyl-paclitaxel conjugate nanoassemblies by manipulating the linker between paclitaxel and squalene.

    PubMed

    Caron, Joachim; Maksimenko, Andrei; Wack, Séverine; Lepeltier, Elise; Bourgaux, Claudie; Morvan, Estelle; Leblanc, Karine; Couvreur, Patrick; Desmaële, Didier

    2013-01-01

    A series of new lipid prodrugs of paclitaxel, which can be formulated as nanoassemblies, are described. These prodrugs which are designed to overcome the limitations due to the systemic toxicity and low water solubility of paclitaxel consist of a squalene chain bound to the 2'-OH of paclitaxel through a 1,4-cis,cis-dienic linker. This design allows the squalene-conjugates to self-assemble as nanoparticular systems while preserving an efficient release of the free drug, thanks to the dienic spacer. The size, steric hindrance, and functional groups of the spacer have been modulated. All these prodrugs self-assemble into nanosized aggregates in aqueous solution as characterized by dynamic light scattering and transmission electron microscopy and appear stable in water for several days as determined by particle size measurement. In vitro biological assessment shows that these squalenoyl-paclitaxel nanoparticles display notable cytotoxicity on several tumor cell lines including A549 lung cell line, colon cell line HT-29, or KB 3.1 nasopharyngeal epidermoid cell line. The cis,cis-squalenyl-deca-5,8-dienoate prodrug show improved activity over simple 2'-squalenoyl-paclitaxel prodrug highlighting the favourable effect of the dienic linker. The antitumor efficacy of the nanoassemblies constructed with the more active prodrugs has been investigated on human lung (A549) carcinoma xenograft model in mice. The prodrug bearing the cis,cis-deca-5,8-dienoyl linker shows comparable antitumor efficacy to the parent drug, but reveals a much lower subacute toxicity as seen in body weight loss. Thus, nanoparticles with the incorporated squalenoyl paclitaxel prodrug may prove useful for replacement of the toxic Cremophor EL.

  6. New application of an old drug: Antitumor activity and mechanisms of doxycycline in small cell lung cancer.

    PubMed

    Wang, Sheng-Qi; Zhao, Bo-Xin; Liu, Yuan; Wang, Ya-Tian; Liang, Qian-Ying; Cai, Yun; Zhang, Yun-Qi; Yang, Jiang-Hong; Song, Zhi-Hua; Li, Guo-Feng

    2016-04-01

    Small cell lung cancer (SCLC) remains one of the most aggressive tumors with a poor prognosis. The clinical outcome of SCLC patients has reached its plateau with the existing standard treatment and thus new therapies are urgently required. Accumulating evidences have indicated that doxycycline, a commonly used antibiotic, has antitumor activity against several malignancies. However, whether doxycycline has antitumor activity in SCLC and its underlying mechanisms remain unclear. Our investigation demonstrated that doxycycline could significantly inhibit the proliferation and colony formulation of SCLC cells (p<0.05). Furthermore, both Hoechst 33258 dye staining and TUNEL assays indicated that doxycycline could induce remarkable apoptosis of H446 cells in a concentration-dependent manner. RT-PCR and western blot assays proved that apoptosis induction effect of doxycycline was achieved via inducing the expression of caspase-3 and bax, as well as attenuating the expression of survivin and bcl-2. Moreover, the wound healing assay and Transwell assay indicated that doxycycline could significantly suppress the migration and invasion of H446 cells in a concentration-dependent manner (p<0.05). ELISA assay proved that the inhibitory effect of doxycycline on the migration and invasion of H446 cells was achieved via decreasing the secretion of MMP-2, MMP-9 and VEGF, as well as increasing the secretion of TIMP-2. Taken together, doxycycline dose-dependently suppressed the proliferation, colony formulation, migration and invasion of SCLC cells, as well as induced apoptosis. These findings encourage further investigations on the potential of doxycycline as a candidate drug for the treatment of SCLC.

  7. Antitumor activity of enkephalin analogues in inhibiting PYB6 tumor growth in mice and immunological effects of methionine enkephalinamide.

    PubMed

    Srisuchart, B; Fuchs, B A; Sikorski, E E; Munson, A E; Loveless, S E

    1989-01-01

    Recent evidence has implicated enkephalins as immunomodulators. Several studies have reported the regulation of tumor growth by methionine enkephalin (ME). However, there has been little effort to relate the immunological significance of enkephalins to the development of anticancer drugs. The present study had three aims: first, to compare the antitumor activity of the synthetic peptide, D-[Ala2]methionine enkephalinamide (MEA), with endogenous enkephalins on PYB6 fibrosarcoma tumor growth; second, to determine whether tumor growth inhibition was mediated by an opiate receptor; and third, to investigate the effects of MEA on selected immune responses. Female B6C3F1 mice were injected i.p. daily for 7 days with 50-4000 micrograms/kg of ME, MEA, leucine enkephalin (LE) or D-[Ala2]leucine enkephalinamide (LEA), beginning 1 day after PYB6 inoculation. ME and MEA, but not LE or LEA, decreased the PYB6 growth rate. The dose of 50 micrograms/kg MEA exerted the maximum inhibition of tumor growth (nearly 72% on day 15 post tumor transplantation). MEA was not directly toxic to PYB6 tumor cells, as evaluated by the measurement of DNA synthesis and cellular ATP levels of PYB6 cells exposed to MEA in vitro. No [3H]-etorphine specific bindings were detected on the cell membrane or sonicates of splenic lymphocytes or PYB6 cells. Therefore, the antitumor activity by MEA is likely mediated by an indirect mechanism. Immunological studies indicated that MEA selectively enhanced the lymphoproliferative response to the T-cell mitogen, concanavalin A, but not to the B-cell mitogen, lipopolysaccharide.(ABSTRACT TRUNCATED AT 250 WORDS)

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

    SciTech Connect

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

    2014-12-12

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

  9. Amphiregulin activates regulatory T lymphocytes and suppresses CD8+ T cell-mediated anti-tumor response in hepatocellular carcinoma cells

    PubMed Central

    Yuan, Chun-Hui; Sun, Xiao-Ming; Zhu, Cheng-Liang; Liu, Shao-Ping; Wu, Long; Chen, Hao; Feng, Mao-Hui; Wu, Ke; Wang, Fu-Bing

    2015-01-01

    CD8+ T cell-mediated immune response plays an important role in inhibiting progression of hepatocellular carcinoma (HCC). For strategic immunotherapy, it is critical to understand why some of the tumor cells escape from this immune attack. In this study, we investigated how HCC cells alter endogenous anti-tumor immunity and their related signaling pathways. We found that HCC cells, both in vitro and in vivo, substantially secret and express amphiregulin (AR). AR in turn activates immunosuppressive function of intratumoral CD4+Foxp3+ regulatory T cells (Tregs), a major inhibitor of CD8+ T cells. Using either lentiviral siRNA, or AR neutralizing antibody, we blocked the expression and function of AR to test the specificity of AR mediated activation of Tregs, Biochemical and cell biology studies were followed and confirmed that blocking of AR inhibited Tregs activation. In addition, we found that AR can trigger the activation of rapamycin complex 1(mTORC1) signaling in Tregs. The mTORC1 inhibitor rapamycin treatment led to compromise Treg function and resulted in enhancing anti-tumor function of CD8+ T cells. Blocking AR/EGFR signaling in Tregs with Gefitinib also enhanced anti-tumor immunity and decreased tumor size in a mouse xenograft tumor model. Taken together, our study suggested a novel mechanism of functional interaction between HCC and Tregs for regulating anti-tumor function of CD8+ T cells. PMID:26451607

  10. A vaccine that co-targets tumor cells and cancer associated fibroblasts results in enhanced antitumor activity by inducing antigen spreading.

    PubMed

    Gottschalk, Stephen; Yu, Feng; Ji, Minjun; Kakarla, Sunitha; Song, Xiao-Tong

    2013-01-01

    Dendritic cell (DC) vaccines targeting only cancer cells have produced limited antitumor activity in most clinical studies. Targeting cancer-associated fibroblasts (CAFs) in addition to cancer cells may enhance antitumor effects, since CAFs, the central component of the tumor stroma, directly support tumor growth and contribute to the immunosuppressive tumor microenvironment. To co-target CAFs and tumor cells we developed a new compound DC vaccine that encodes an A20-specific shRNA to enhance DC function, and targets fibroblast activation protein (FAP) expressed in CAFs and the tumor antigen tyrosine-related protein (TRP)2 (DC-shA20-FAP-TRP2). DC-shA20-FAP-TRP2 vaccination induced robust FAP- and TRP2-specific T-cell responses, resulting in greater antitumor activity in the B16 melanoma model in comparison to monovalent vaccines or a vaccine encoding antigens and a control shRNA. DC-shA20-FAP-TRP2 vaccination enhanced tumor infiltration of CD8-positive T cells, and induced antigen-spreading resulting in potent antitumor activity. Thus, co-targeting of tumor cells and CAFs results in the induction of broad-based tumor-specific T-cell responses and has the potential to improve current vaccine approaches for cancer.

  11. A Vaccine That Co-Targets Tumor Cells and Cancer Associated Fibroblasts Results in Enhanced Antitumor Activity by Inducing Antigen Spreading

    PubMed Central

    Gottschalk, Stephen; Yu, Feng; Ji, Minjun; Kakarla, Sunitha; Song, Xiao-Tong

    2013-01-01

    Dendritic cell (DC) vaccines targeting only cancer cells have produced limited antitumor activity in most clinical studies. Targeting cancer-associated fibroblasts (CAFs) in addition to cancer cells may enhance antitumor effects, since CAFs, the central component of the tumor stroma, directly support tumor growth and contribute to the immunosuppressive tumor microenvironment. To co-target CAFs and tumor cells we developed a new compound DC vaccine that encodes an A20-specific shRNA to enhance DC function, and targets fibroblast activation protein (FAP) expressed in CAFs and the tumor antigen tyrosine-related protein (TRP)2 (DC-shA20-FAP-TRP2). DC-shA20-FAP-TRP2 vaccination induced robust FAP- and TRP2-specific T-cell responses, resulting in greater antitumor activity in the B16 melanoma model in comparison to monovalent vaccines or a vaccine encoding antigens and a control shRNA. DC-shA20-FAP-TRP2 vaccination enhanced tumor infiltration of CD8-positive T cells, and induced antigen-spreading resulting in potent antitumor activity. Thus, co-targeting of tumor cells and CAFs results in the induction of broad-based tumor-specific T-cell responses and has the potential to improve current vaccine approaches for cancer. PMID:24349329

  12. Calcitriol enhances gemcitabine antitumor activity in vitro and in vivo by promoting apoptosis in a human pancreatic carcinoma model system

    PubMed Central

    Yu, Wei-Dong; Ma, Yingyu; Flynn, Geraldine; Muindi, Josephia R; Kong, Rui-Xian; Trump, Donald L

    2010-01-01

    Gemcitabine is the standard care chemotherapeutic agent to treat pancreatic cancer. Previously we demonstrated that calcitriol (1, 25-dihydroxycholecalciferol) has significant anti-proliferative effects in vitro and in vivo in multiple tumor models and enhances the activity of a variety of chemotherapeutic agents. We therefore investigated whether calcitriol could potentiate the cytotoxic activity of gemcitabine in the human pancreatic cancer Capan-1 model system. Isobologram analysis revealed that calcitriol and gemcitabine had synergistic antiproliferative effect over a wide range of drug concentrations. Calcitriol did not reduce the cytidine deaminase activity in Capan-1 tumors nor in the livers of Capan-1 tumor bearing mice. Calcitriol and gemcitabine combination promoted apoptosis in Capan-1 cells compared with either agent alone. The combination treatment also increased the activation of caspases-8, -9, -6 and -3 in Capan-1 cells. This result was confirmed by substrate-based caspase activity assay. Akt phosphorylation was reduced by calcitriol and gemcitabine combination treatment compared to single agent treatment. However, ERK1/2 phosphorylation was not modulated by either agent alone or by the combination. Tumor regrowth delay studies showed that calcitriol in combination with gemcitabine resulted in a significant reduction of Capan-1 tumor volume compared to single agent treatment. Our study suggests that calcitriol and gemcitabine in combination promotes caspase-dependent apoptosis, which may contribute to increased anti-tumor activity compared to either agent alone. PMID:20699664

  13. Immune-system-dependent anti-tumor activity of a plant-derived polyphenol rich fraction in a melanoma mouse model

    PubMed Central

    Gomez-Cadena, A; Urueña, C; Prieto, K; Martinez-Usatorre, A; Donda, A; Barreto, A; Romero, P; Fiorentino, S

    2016-01-01

    Recent findings suggest that part of the anti-tumor effects of several chemotherapeutic agents require an intact immune system. This is in part due to the induction of immunogenic cell death. We have identified a gallotannin-rich fraction, obtained from Caesalpinia spinosa (P2Et) as an anti-tumor agent in both breast carcinoma and melanoma. Here, we report that P2Et treatment results in activation of caspase 3 and 9, mobilization of cytochrome c and externalization of annexin V in tumor cells, thus suggesting the induction of apoptosis. This was preceded by the onset of autophagy and the expression of immunogenic cell death markers. We further demonstrate that P2Et-treated tumor cells are highly immunogenic in vaccinated mice and induce immune system activation, clearly shown by the generation of interferon gamma (IFN-γ) producing tyrosine-related protein 2 antigen-specific CD8+ T cells. Moreover, the tumor protective effects of P2Et treatment were abolished in immunodeficient mice, and partially lost after CD4 and CD8 depletion, indicating that P2Et's anti-tumor activity is highly dependent on immune system and at least in part of T cells. Altogether, these results support the hypothesis that the gallotannin-rich fraction P2Et's anti-tumor effects are mediated to a great extent by the endogenous immune response following to the exposure to immunogenic dying tumor cells. PMID:27253407

  14. The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models.

    PubMed

    Pajtler, Kristian W; Sadowski, Natalie; Ackermann, Sandra; Althoff, Kristina; Schönbeck, Kerstin; Batzke, Katharina; Schäfers, Simon; Odersky, Andrea; Heukamp, Lukas; Astrahantseff, Kathy; Künkele, Annette; Deubzer, Hedwig E; Schramm, Alexander; Sprüssel, Annika; Thor, Theresa; Lindner, Sven; Eggert, Angelika; Fischer, Matthias; Schulte, Johannes H

    2017-01-24

    Polo-like kinase 1 (PLK1) is a serine/threonine kinase that promotes G2/M-phase transition, is expressed in elevated levels in high-risk neuroblastomas and correlates with unfavorable patient outcome. Recently, we and others have presented PLK1 as a potential drug target for neuroblastoma, and reported that the BI2536 PLK1 inhibitor showed antitumoral actvity in preclinical neuroblastoma models. Here we analyzed the effects of GSK461364, a competitive inhibitor for ATP binding to PLK1, on typical tumorigenic properties of preclinical in vitro and in vivo neuroblastoma models. GSK461364 treatment of neuroblastoma cell lines reduced cell viability and proliferative capacity, caused cell cycle arrest and massively induced apoptosis. These phenotypic consequences were induced by treatment in the low-dose nanomolar range, and were independent of MYCN copy number status. GSK461364 treatment strongly delayed established xenograft tumor growth in nude mice, and significantly increased survival time in the treatment group. These preclinical findings indicate PLK1 inhibitors may be effective for patients with high-risk or relapsed neuroblastomas with upregulated PLK1 and might be considered for entry into early phase clinical trials in pediatric patients.

  15. 2-Deoxyglucose conjugated platinum (II) complexes for targeted therapy: design, synthesis, and antitumor activity.

    PubMed

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

    2016-11-01

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

  16. Synthesis of 6-aziridinylbenzimidazole derivatives and their in vitro antitumor activities.

    PubMed

    Ahn, C M; Kim, S K; Han, J L

    1998-10-01

    In search for new antitumor agents, twelve 6-aziridinylbenzimidazole derivatives were synthesized and their cytotoxicities were tested against three cancer cell lines (mouse lymphocytic leukemia P388 and B16, and human gastric carcinoma SNU-16). From 4-amino-3-nitrotoluene as the starting material, 2-(acetoxymethyl)benzimidazoles (5a-d) were obtained by Phillips reaction. These benzimidazoles were then reacted with Fremy's salt to give a mixture of three 2-(acetoxymethyl) (8a-c) and four 2-(hydroxymethyl)benzimidazole-4,7-diones (9a-d). Addition of these quinones with aziridine afforded 6-aziridinyl-2-(acetoxymethyl) (10a-c) and 6-aziridinyl-2-(hydroxymethyl)benzimidazole-4,7-diones (11a-d). Utilizing 2-(hydroxymethyl)benzimidazole-4,7-diones (9b,d), esters 10d and 13e-h were prepared by the sequential reactions of esterification and addition. The synthesized compounds show potent cytotoxicity against all of three cell lines tested. The cytotoxicities of 10a-d or 11a-d against SNU-16 were superior to those of 13e-h, and were equal to or slightly higher than that of mitomycin C. Compounds 11a-d were slightly more cytotoxic than 10a-d in all cell lines tested.

  17. Synthesis and antitumor activity of 10-alkyl-10-deazaminopterins. A convenient synthesis of 10-deazaminopterin.

    PubMed

    DeGraw, J I; Brown, V H; Tagawa, H; Kisliuk, R L; Gaumont, Y; Sirotnak, F M

    1982-10-01

    Requirements for large-scale synthesis of the potent antitumor drug 10-deazaminopterin have led to development of a facile synthesis of this compound and its 10-alkyl analogues. The lithium diisopropyl amide generated dianions of appropriate p-alkylbenzoic acids were alkylated with 3-methoxyallyl chloride. The resulting 4-(p-carboxyphenyl)-1-methoxy-1-butenes were brominated at pH 7-8 to afford the 2-bromo-4-(p-carboxyphenyl)butyraldehydes. Condensation with 2,4,5,6-tetraminopyrimidine and subsequent in situ oxidation of the resulting dihydropteridines yielded crystalline 10-alkyl-10-deaza-4-amino-4-deoxypteroic acids. The pteroic acids were coupled with diethyl glutamate via the mixed anhydride method, followed by saponification at room temperature, to give the target 10-deazaminopterins. The 10-alkyl compounds were approximately equipotent to 10-deazaminopterin as growth inhibitors of folate-dependent bacteria. Their abilities to inhibit Lactobacillus casei and L1210 derived dihydrofolate reductases were also similar. Transport properties in vitro were suggestive of an improved therapeutic index for the 10-alkyl analogues. Against L1210 in mice, the percent increase in life span at the LD10 dosage was +151% (methotrexate), +178% (10-deazaminopterin), +235% (10-methyl analogue), and +211% (10-ethyl analogue). 10,10-Dimethyl-10-deazaminopterin was less effective at an equimolar dosage, but the ILS at the maximum dose tested (72 mg/kg) was +135%. It was far less toxic than the other analogues possibly because of enhanced clearance.

  18. Herbal Medicine Goshajinkigan Prevents Paclitaxel-Induced Mechanical Allodynia without Impairing Antitumor Activity of Paclitaxel.

    PubMed

    Bahar, Muh Akbar; Andoh, Tsugunobu; Ogura, Keisuke; Hayakawa, Yoshihiro; Saiki, Ikuo; Kuraishi, Yasushi

    2013-01-01

    Chemotherapy-induced peripheral neuropathy is a major dose-limiting side effect of commonly used chemotherapeutic agents. However, there are no effective strategies to treat the neuropathy. We examined whether Goshajinkigan, a herbal medicine, would prevent paclitaxel-induced allodynia without affecting the anticancer action in mice. Murine breast cancer 4T1 cells were inoculated into the mammary fat pad. Paclitaxel (10 and 20 mg/kg, intraperitoneal, alternate day from day 7 postinoculation) inhibited the tumor growth, and Goshajinkigan (1 g/kg, oral, daily from day 2 postinoculation) did not affect the antitumor action of paclitaxel. Mechanical allodynia developed in the inoculated region due to tumor growth and in the hind paw due to paclitaxel-induced neuropathy. Paclitaxel-induced allodynia was markedly prevented by Goshajinkigan, although tumor-associated allodynia was not inhibited by Goshajinkigan. These results suggest that Goshajinkigan prevents paclitaxel-induced peripheral neuropathy without interfering with the anti-cancer action of paclitaxel.

  19. The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models

    PubMed Central

    Pajtler, Kristian W; Sadowski, Natalie; Ackermann, Sandra; Althoff, Kristina; Schönbeck, Kerstin; Batzke, Katharina; Sch, Simonäfers; Odersky, Andrea; Heukamp, Lukas; Astrahantseff, Kathy; Künkele, Annette; Deubzer, Hedwig E; Schramm, Alexander; Spr, Annikaüssel; Thor, Theresa; Lindner, Sven; Eggert, Angelika; Fischer, Matthias; Schulte, Johannes H

    2017-01-01

    Polo-like kinase 1 (PLK1) is a serine/threonine kinase that promotes G2/M-phase transition, is expressed in elevated levels in high-risk neuroblastomas and correlates with unfavorable patient outcome. Recently, we and others have presented PLK1 as a potential drug target for neuroblastoma, and reported that the BI2536 PLK1 inhibitor showed antitumoral actvity in preclinical neuroblastoma models. Here we analyzed the effects of GSK461364, a competitive inhibitor for ATP binding to PLK1, on typical tumorigenic properties of preclinical in vitro and in vivo neuroblastoma models. GSK461364 treatment of neuroblastoma cell lines reduced cell viability and proliferative capacity, caused cell cycle arrest and massively induced apoptosis. These phenotypic consequences were induced by treatment in the low-dose nanomolar range, and were independent of MYCN copy number status. GSK461364 treatment strongly delayed established xenograft tumor growth in nude mice, and significantly increased survival time in the treatment group. These preclinical findings indicate PLK1 inhibitors may be effective for patients with high-risk or relapsed neuroblastomas with upregulated PLK1 and might be considered for entry into early phase clinical trials in pediatric patients. PMID:28036269

  20. Enhancement of anti-tumor activity of Newcastle disease virus by the synergistic effect of cytosine deaminase.

    PubMed

    Lv, Zheng; Zhang, Tian-Yuan; Yin, Jie-Chao; Wang, Hui; Sun, Tian; Chen, Li-Qun; Bai, Fu-Liang; Wu, Wei; Ren, Gui-Ping; Li, De-Shan

    2013-01-01

    This study was conducted to investigate enhancement of anti-tumor effects of the lentogenic Newcastle disease virus Clone30 strain (NDV rClone30) expressing cytosine deaminase (CD) gene against tumor cells and in murine groin tumor-bearing models. Cytotoxic effects of the rClone30-CD/5-FC on the HepG2 cell line were examined by an MTT method. Anti-tumor activity of rClone30-CD/5-FC was examined in H22 tumor-bearing mice. Compared to the rClone30-CD virus treatment alone, NDV rClone30-CD/5-FC at 0.1 and 1 MOIs exerted significant cytotoxic effects (P<0.05) on HepG2 cells. For treatment of H22 tumor-bearing mice, recombinant NDV was injected together with 5-FC given by either intra-tumor injection or tail vein injection. When 5-FC was administered by intra-tumor injection, survival for the rClone30-CD/5-FC-treated mice was 4/6 for 80 days period vs 1/6 , 0/6 and 0/6 for the mice treated with rClone30-CD, 5-FC and saline alone, respectively. When 5-FC was given by tail vein injection, survival for the rClone30-CD/5-FC-treated mice was 3/6 vs 2/6 , 0/6 and 0/6 for the mice treated with rClone30-CD, 5-FC or saline alone, respectively. In this study, NDV was used for the first time to deliver the suicide gene for cancer therapy. Incorporation of the CD gene in the lentogenic NDV genome together with 5-FC significantly enhances cell death of HepG2 tumor cells in vitro, decreases tumor volume and increases survival of H22 tumor-bearing mice in vivo.

  1. Influence of autologous dendritic cells on cytokine-induced killer cell proliferation, cell phenotype and antitumor activity in vitro.

    PubMed

    Cao, Jingsong; Chen, Cong; Wang, Yuhuan; Chen, Xuecheng; Chen, Zeying; Luo, Xiaoling

    2016-09-01

    Dendritic cell (DCs) are essential antigen processing and presentation cells that play a key role in the immune response. In this study, DCs were co-cultured with cytokine-induced killer cells (DC-CIKs) in vitro to detect changes in cell proliferation, cell phenotype and cell cytotoxicity. The results revealed that the DCs were suitable for co-culture with CIKs at day 7, and that cell quantity of DC-CIKs was lower than that of CIKs until day 11, but it was significantly improved to 1.17-fold that of CIKs at day 13. Flow cytometry was used to detect the cell phenotype of CIKs and DC-CIKs. Compared with CIKs at day 13, the percentage of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+) and CD3(+)CD56(+) T cells in DC-CIKs was significantly improved 1.02, 1.79, 1.26 and 2.44-fold, respectively. In addition, trypan blue staining analysis demonstrated that the cell viability of CIKs and DC-CIKs was 96% and 98%, respectively. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis verified that CIK and DC-CIK cytotoxicity in Hela cells was 58% and 80%, respectively, with a significant difference. Taken together, our results indicate that the cell proliferation, cell phenotype and antitumor activity of CIKs were all enhanced following co-culture with DCs in vitro. These results are likely to be useful for DC-CIK application in antitumor therapies.

  2. Antitumor Compounds from Marine Actinomycetes

    PubMed Central

    Olano, Carlos; Méndez, Carmen; Salas, José A.

    2009-01-01

    Chemotherapy is one of the main treatments used to combat cancer. A great number of antitumor compounds are natural products or their derivatives, mainly produced by microorganisms. In particular, actinomycetes are the producers of a large number of natural products with different biological activities, including antitumor properties. These antitumor compounds belong to several structural classes such as anthracyclines, enediynes, indolocarbazoles, isoprenoides, macrolides, non-ribosomal peptides and others, and they exert antitumor activity by inducing apoptosis through DNA cleavage mediated by topoisomerase I or II inhibition, mitochondria permeabilization, inhibition of key enzymes involved in signal transduction like proteases, or cellular metabolism and in some cases by inhibiting tumor-induced angiogenesis. Marine organisms have attracted special attention in the last years for their ability to produce interesting pharmacological lead compounds. PMID:19597582

  3. Antioxidant, Antityrosinase and Antitumor Activity Comparison: The Potential Utilization of Fibrous Root Part of Bletilla striata (Thunb.) Reichb.f.

    PubMed Central

    Huang, Yanfen; Chen, Yitao; Jin, Bo; Chen, Nipi; Ding, Zhishan; Ding, Xinghong

    2013-01-01

    This study was carried out to evaluate the utilization probability of the fibrous root part (FRP) of Bletilla striata, which was usually discarded and harvesting pseudobulb part (PSP). The chemical composition, total phenolic content, DPPH radical scavenging activity, Ferric-reducing antioxidant power and tyrosinase inhibition activity were compared between FRP and PSP. Antioxidant and pro-oxidant effect as well as antitumor effect of the extract of FRP and PSP were analyzed by in vitro cell system as well. Thin layer chromatography and high performance liquid chromatography analysis indicated that the chemical compositions in the two parts were similar, but the content in FRP was much higher than PSP. Meanwhile, the FRP extracts showed higher phenolic content, stronger DPPH scavenging activity, Ferric-reducing antioxidant capacity and tyrosinase inhibition activity. Sub-fraction analysis revealed that the distribution characteristic of phenolic components and other active constituents in FRP and PSP were consistent, and mainly deposited in chloroform and acetoacetate fractions. Especially, the chloroform sub-fraction (sch) of FRP showed extraordinary DPPH scavenging activity and tyrosinase inhibition activity, with IC50 0.848 mg/L and 4.3 mg/L, respectively. Besides, tyrosinase inhibition activity was even stronger than the positive compound arbutin (31.8 mg/L). Moreover, In vitro cell system analysis confirmed that FRP extract exerts comparable activity with PSP, especially, the sub-fraction sch of FRP showed better antioxidant activity at low dosage and stronger per-oxidant activity at high dosage, and both sch of FRP and PSP can dose-dependent induce HepG2 cells apoptosis, which implied tumor therapeutic effect. Considering that an additional 0.3 kg FRP would be obtained when producing 1.0 kg PSP, our work demonstrated that FRP is very potential to be used together with PSP. PMID:23469127

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

    PubMed

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

    2014-10-30

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

  5. pH dependence of melanoma cell migration: protons extruded by NHE1 dominate protons of the bulk solution.

    PubMed

    Stüwe, Laura; Müller, Markus; Fabian, Anke; Waning, Judith; Mally, Sabine; Noël, Josette; Schwab, Albrecht; Stock, Christian

    2007-12-01

    Migration and morphology of human melanoma cells (MV3) depend on extracellular pH (pHe) and the activity of the Na+/H+ exchanger NHE1. To distinguish effects of NHE1 activity per se from effects of pHe we compared an NHE1-deficient mutant with rescued and wild-type cells. Time lapse video microscopy was used to investigate migratory and morphological effects caused by pHe and NHE1 activity, and a membrane-bound fluorescein conjugate was employed for ratiometric pH measurements at the outer leaflet of the cell membrane. As long as NHE1 remained inactive due to deficiency or inhibition by cariporide (HOE642) neither migration nor morphology was affected by changes in pHe. Under these conditions pH at the outer leaflet of the plasma membrane was uniform all over the cell surface. The typical pH dependence of MV3 cell migration and morphology could be reconstituted by restoring NHE1 activity. At the same time the proton gradient at the outer leaflet of the plasma membrane with the higher proton concentration at the leading edge and the lower one at the cell rear was re-established as well. Hence, NHE1 activity generates a proton gradient at the cell surface accompanied by the cells' ability to respond to changes in pHe (bulk pH). We conclude that NHE1 activity contributes to the generation of a well-defined cell surface pH by creating a proton gradient at the outer leaflet of the plasma membrane that is needed for (i) the development of a variety of morphologies including a distinct polarity and (ii) migration. A missing proton gradient at the cell surface cannot be compensated for by varying pHe.

  6. Leishmanicidal and antitumoral activities of endophytic fungi associated with the Antarctic angiosperms Deschampsia antarctica Desv. and Colobanthus quitensis (Kunth) Bartl.

    PubMed

    Santiago, Iara F; Alves, Tânia M A; Rabello, Ana; Sales Junior, Policarpo A; Romanha, Alvaro J; Zani, Carlos L; Rosa, Carlos A; Rosa, Luiz H

    2012-01-01

    A total of 564 isolates of endophytic fungi were recovered from the plants Deschampsia antarctica and Colobanthus quitensis collected from Antarctica. The isolates were screened against parasites Leishmania amazonensis and Trypanosoma cruzi and against the human tumour cell lines. Of the 313 fungal isolates obtained from D. antarctica and 251 from C. quitensis, 25 displayed biological activity. Nineteen extracts displayed leishmanicidal activity, and six inhibited the growth of at least one tumour cell line. These fungi belong to 19 taxa of the genera Alternaria, Antarctomyces, Cadophora, Davidiella, Helgardia, Herpotrichia, Microdochium, Oculimacula, Phaeosphaeria and one unidentified fungus. Extracts of 12 fungal isolates inhibited the proliferation of L. amazonesis at a low IC(50) of between 0.2 and 12.5 μg ml(-1). The fungus Phaeosphaeria herpotrichoides displayed only leishmanicidal activity with an IC(50) of 0.2 μg ml(-1), which is equivalent to the inhibitory value of amphotericin B. The extract of Microdochium phragmitis displayed specific cytotoxic activity against the UACC-62 cell line with an IC(50) value of 12.5 μg ml(-1). Our results indicate that the unique angiosperms living in Antarctica shelter an interesting bioactive fungal community that is able to produce antiprotozoal and antitumoral molecules. These molecules may be used to develop new leishmanicidal and anticancer drugs.

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

    PubMed

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

    2017-01-01

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

  8. Potential antitumor agents. 29. Quantitative structure-activity relationships for the antileukemic bisquaternary ammonium heterocycles.

    PubMed

    Denny, W A; Atwell, G J; Baguley, B C; Cain, B F

    1979-02-01

    Quantitative relationships between physicochemical drug properties and antileukemic (L1210) efficacy have been examined for a series of bisquaternary ammonium heterocycles employing multiple variable regression analysis. Three measures of biologic response were examined: ILSmax, the percentage increase in mean life span of leukemic animals at the LD10 dose; D40, the drug dose necessary to provide 40% increase in life span; and CI (=LD 10/D40), the chemotherapeutic index. A cross correlation matrix between these three measures and the LD10 values demonstrates ILSmax and CI to be independent of toxicity. D40 is highly inversely correlated with LD10 and positively correlated with ILSmax, suggesting that this parameter measures a composite of both drug selectivity and toxicity. Superior regression equations resulted at all stages employing ILSmax as a measure of antitumor selectivity. Acceptable equations modeling LD10 could not be obtained. There was a parabolic relationship between agent lipophilic-hydrophilic balance, measured as chromatographic Rm values, and ILSmax. To reduce residual variance in the L1210 screening data, not accepted by this parabolic equation, measures of agent-DNA interaction were investigated as possible indices of site fit. Relative levels of drug-DNA interaction were obtained by spectrofluorimetric quantitation of drug displacement of DNA-bound ethidium. Addition to regression equations of agent C50 values for calf thymus DNA, those micromolar drug concentrations necessary to displace 50% of the ethidium bound to that DNA, provided a significant reduction in the screening data variance. C50 values for drug interactions with poly[d(A-T)] and poly[d(G-C)] were also investigated as possible indicators of drug selectivity towards different DNA sites. Marked differences were observed in the C50 values for the two synthetic nucleic acids, with those for calf thymus DNA and poly[d(G-C)] proving highly covariant. A regression equation containing a

  9. Correlation of ph dependant equilibrium isotherms of heavy metal biosorption with a modified Freundlich model.

    PubMed

    Liu, X; Goodfellow, M R; Yu, Q; Zheng, C

    2004-12-01

    Equilibrium isotherms of heavy metal biosorption are commonly correlated with adsorption models such as the Freundlich model. On the other hand, the adsorption properties of heavy metal biosorption are strongly influenced by the solution pH of the biosorption system. Therefore, standard adsorption models are limited to the correlation of equilibrium isotherms under constant pH values. In this paper, a modified Freundlich model was developed for the correlation of pH dependent equilibrium isotherms of heavy metal biosorption. The model was based on the mechanism that the functional groups for heavy metal interactions are weakly acidic groups and the uptake capacities of the biomass are affected through the association and dissociation equilibrium between two apparent ionic forms. Both the standard and the modified Freundlich models were tested with isotherm data for Cd2+, Cu2+ and Ni2+ biosorption onto pre-treated biomass of marine alga Durvillaea potatorum under various solution pH values. Regression analyses indicated that the developed model correlated the experimental data well.

  10. Synthesis of a pH dependent covalent imprinted polymer able to recognize organotin species.

    PubMed

    Gallego-Gallegos, Mercedes; Muñoz-Olivas, Riansares; Cámara, C; Mancheño, María J; Sierra, Miguel A

    2006-01-01

    The covalent imprinting approach has for the first time been successfully applied for the synthesis of an imprinted polymer able to recognize organotin species. The synthesis has been accomplished by co-polymerization of the complex Bu(2)SnO-m-vinylbenzoin as the imprinting template plus co-monomer sodium methacrylate, and ethylene glycol dimethacrylate as cross-linker. The imprinting effect has been evidenced within the narrow pH range 2.5< pH< 3.5. At lower pH values, the imprinting effect is prevented by the exclusive existence of non-specific interactions, whereas pH>3.5 provokes a strong rebind of the template in both imprinted and non-imprinted polymers. This pH dependency can be explained as a selective chemical modification which reduces bind diversity following a model based on enolization by protonation of the specific cavities. Characterization of the adsorption isotherms showed good agreement with the Langmuir-Freundlich (LF) model, presenting quite homogeneous binding sites for a bulk material and high capacity in the imprinting pH range. In addition, the affinity spectrum (AS) method has been represented showing the typical profiles of LF isotherm for both sub-saturation and saturation levels, being in general agreement with the encountered values for fitting coefficients. The covalent molecular imprinted polymer has been successfully evaluated in a SPE process for further OTC determination in the certified mussel tissue (CRM 477).

  11. pH dependence of friction forces between silica surfaces in solutions.

    PubMed

    Taran, Elena; Donose, Bogdan C; Vakarelski, Ivan U; Higashitani, Ko

    2006-05-01

    The pH dependence of the friction between a silica particle and a silica wafer was investigated using lateral force microscopy. Measurements were done in the range of 3.6 < or = pH < or = 10.6 and the effect of high loading force was also examined. It is found that the friction is independent of the pH of solutions and increases linearly with the applied load, when the pH is between 3.6 and 8.6. On the other hand, once the pH is above 9.0, the friction becomes extremely small and the dependence on the applied load becomes nonlinear. It is postulated that this transition is due to the development of a gel layer composed of polymer-like segments of silicilic acid anchored on the surface; at the lower applied load, this layer acts as a boundary lubricant between the surfaces, but, at the higher applied load, the entanglements of these segments and more direct contact between two solid surfaces leads to the increase of the friction. The effects found here are expected to play an important role in elucidating the basic mechanism of the planarization process of silica wafers.

  12. Control and pH dependence of ligand binding to heme proteins.

    PubMed

    Doster, W; Beece, D; Bowne, S F; DiIorio, E E; Eisenstein, L; Frauenfelder, H; Reinisch, L; Shyamsunder, E; Winterhalter, K H; Yue, K T

    1982-09-28

    The recombination after flash photolysis of dioxygen and carbon monoxide with sperm whale myoglobin (Mb), and separated beta chains of human hemoglobin (beta A) and hemoglobin Zürich (beta ZH), has been studied as a function of pH and temperature from 300 to 60 K. At physiological temperatures, a preequilibrium is established between the ligand molecules in the solvent and in the heme pocket. The ligand in the pocket binds to the heme iron by overcoming a barrier at the heme. The association rate is controlled by this final binding step. The association rate of CO to Mb and beta A is modulated by a single titratable group with a pK at 300 K of 5.7. The binding of CO to beta ZH, in which the distal histidine is replaced by arginine, does not depend on pH. Oxygen recombination is independent of pH in all three proteins. Comparison of the binding of CO at 300 K and at low temperatures shows that pH does not affect the preequilibrium but changes the barrier height at the heme. The pH dependence and the difference between O2 and CO binding can be explained by a charge-dipole interaction between the distal histidine and CO.

  13. pH dependence of the dissociation of multimeric hemoglobin probed by high hydrostatic pressure.

    PubMed

    Bispo, Jose A C; Santos, Jose L R; Landini, Gustavo F; Goncalves, Juliana M; Bonafe, Carlos F S

    2007-02-01

    We investigated the thermodynamic features of the classic alkaline dissociation of multimeric hemoglobin (3.1 MDa) from Glossoscolex paulistus (Annelidea) using high hydrostatic pressure. Light scattering measurements up to microscopic thermodynamic equilibrium indicated a high pH dependency of dissociation and association. Electron microscopy and gel filtration corroborated these findings. The volume change of dissociation decreased in absolute values from -48.0 mL/mol of subunit at pH 6.0 to -19.2 mL/mol at pH 9.0, suggesting a lack of protein interactions under alkaline conditions. Concomitantly, an increase in pH reduced the Gibbs free energy of dissociation from 37.7 to 27.5 kJ/mol of subunit. The stoichiometry of proton release calculated from the pressure-induced dissociation curves was +0.602 mol of H(+)/mol of subunit. These results provide a direct quantification of proton participation in stabilizing the aggregated state of the hemoglobin, and contribute to our understanding of protein-protein interactions and of the surrounding conditions that modulate the process of aggregation.

  14. The pH dependence of photosensory responses in Stentor coeruleus and model system.

    PubMed

    Walker, E B; Yoon, M; Song, P S

    1981-02-12

    1. Live Stentor coeruleus exhibits a substantially red-shifted fluorescence maximum, corresponding to the anionic species of the photoreceptor chromophore. No change was observed in either the absorption or fluorescence excitation spectrum, indicating an efficient deprotonation of the photoreceptor pigment upon excitation by light. 2 Changes in external pH exhibit a dramatic effect on the pulmonary response of Stentor. Phototaxis is specifically inhibited at pH less than 6, with loss of photosensory perception which is restored when the pH is returned to pH greater than 6. 3. Fluorescence changes of 9-aminoacridine in suspensions of live Stentor indicate the generation of a pH gradient upon irradiation with light. Both pH gradient and phototaxis were inhibited by the addition of nigericin and p-tri-fluoromethoxy carbonyl cyanide phenylhydrazone (FCCP). 4. Incorporation of the Stentor photoreceptor protein in to artificial liposomes demonstrates the ability of the system to generate pH gradients across model membranes as monitored by the quenching of 9-aminoacridine fluorescence. The effect of external pH on net proton movement in the model system is strikingly similar to the pH dependent of the liver Stentor, thus lending support for transient proton flux being an important mode of light signal processing for photosensory transduction.

  15. Thylakoid targeting of Tat passenger proteins shows no delta pH dependence in vivo.

    PubMed

    Finazzi, Giovanni; Chasen, Claudia; Wollman, Francis-André; de Vitry, Catherine

    2003-02-17

    The Tat pathway is a major route for protein export in prokaryotes and for protein targeting to thylakoids in chloroplasts. Based on in vitro studies, protein translocation through this pathway is thought to be strictly dependent on a transmembrane delta pH. In this paper, we assess the delta pH sensitivity of the Tat pathway in vivo. Using Chlamydomonas reinhardtii, we observed changes in the efficiency of thylakoid targeting in vivo by mutating the Tat signal of the Rieske protein. We then employed two endogenous pH probes located on the lumen side of the thylakoid membranes to estimate spectroscopically the delta pH in vivo. Using experimental conditions in which the trans-thylakoid delta pH was almost zero, we found no evidence for a delta pH dependence of the Tat pathway in vivo. We confirmed this observation in higher plants using attached barley leaves. We conclude that the Tat pathway does not require a delta pH under physiological conditions, but becomes delta pH sensitive when probed in vitro/in organello because of the loss of some critical intracellular factors.

  16. Fabrication and characterization of a fritless microfabricated electroosmotic pump with reduced pH dependence.

    PubMed

    Razunguzwa, Trust T; Timperman, Aaron T

    2004-03-01

    A fritless electroosmotic pump with reduced pH dependence has been fabricated on a glass microchip and its performance characterized. The chip design consists of two 500-microm channels, one packed with anion exchange beads and the other packed with cation exchange beads, which produce convergent electroosmotic flow streams. The electroosmotically pumped solution flows away from the intersection of the two pumping channels through a field-free channel. This simple design allows for the production of a fritless electroosmotic pump and easy replacement of the ion exchange beads whose charged surfaces generate the flow. The pump was found to produce volumetric flow rates of up to 2 microL/min for an applied voltage of 3 kV at a pH of 6.8. Moreover, the electroosmotic pump can generate high flow rates over an extended pH range of at least 2-12, a significant advantage over previously fabricated electroosmotic pumps, which typically have a more limited range in which they can achieve high flow rates.

  17. In vitro anti-tumor promoting and anti-parasitic activities of the quassinoids from Eurycoma longifolia, a medicinal plant in Southeast Asia.

    PubMed

    Jiwajinda, Suratwadee; Santisopasri, Vilai; Murakami, Akira; Sugiyama, Hiromu; Gasquet, Monique; Riad, Elias; Balansard, Guy; Ohigashi, Hajime

    2002-09-01

    Some quassinoids (1-6) isolated previously as plant growth inhibitors from the leaves of Eurycoma longifolia Jack. (Simaroubaceae) were subjected to in vitro tests on anti-tumor promoting, antischistosomal and plasmodicidal activities. The most active compound for inhibition of tumor promoter-induced Epstein-Barr virus activation (anti-tumor promotion) was 14,15beta-dihydroxyklaineanone (5, IC(50) = 5 microM). Longilactone (1) gave significant antischistosomal effect at a concentration of 200 microg/ml. 11-Dehydroklaineanone (3) and 15beta-O-acetyl-14-hydroxyklaineanone (6) showed potent plasmodicidal activity (IC(50) = 2 microg/ml). Thus it was suggested that E. longifolia possesses high medicinal values due to the occurrence of a variety of quassinoids.

  18. Synthesis and in vitro antitumor activity of new series of benzothiazole and pyrimido[2,1-b]benzothiazole derivatives.

    PubMed

    Gabr, Moustafa T; El-Gohary, Nadia S; El-Bendary, Eman R; El-Kerdawy, Mohamed M

    2014-10-06

    New series of benzothiazole and pyrimido[2,1-b]benzothiazole derivatives were synthesized and characterized by analytical and spectrometrical methods (IR, HRMS, (1)H and (13)C NMR). Nineteen of the synthesized compounds were selected by the National Cancer Institute (NCI), USA, to be screened for their antitumor activity at a single dose (10 μM) against a panel of 60 cancer cell lines. The most active compounds, 4, 6, 10, 14, 17 and 20 were selected for further evaluation at five dose level screening. Compounds 17 (GI50 = 0.44 μM, TGI = 1.2 μM and LC50 MG-MID = 6.6 μM) and 4 (GI50 = 0.77 μM, TGI = 2.08 μM and LC50 MG-MID = 11.74 μM) were proved to be the most active members in this study. 3D and 2D pharmacophoric maps for the structural features of both compounds were studied.

  19. Screening a Small Library of Xanthones for Antitumor Activity and Identification of a Hit Compound which Induces Apoptosis.

    PubMed

    Barbosa, João; Lima, Raquel T; Sousa, Diana; Gomes, Ana Sara; Palmeira, Andreia; Seca, Hugo; Choosang, Kantima; Pakkong, Pannee; Bousbaa, Hassan; Pinto, Madalena M; Sousa, Emília; Vasconcelos, M Helena; Pedro, Madalena

    2016-01-13

    Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1·HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1·HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1·HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis.

  20. Antitumor Activity of Lenvatinib (E7080): An Angiogenesis Inhibitor That Targets Multiple Receptor Tyrosine Kinases in Preclinical Human Thyroid Cancer Models

    PubMed Central

    Tohyama, Osamu; Matsui, Junji; Kodama, Kotaro; Hata-Sugi, Naoko; Kimura, Takayuki; Iwata, Masao; Funahashi, Yasuhiro

    2014-01-01

    Inhibition of tumor angiogenesis by blockading the vascular endothelial growth factor (VEGF) signaling pathway is a promising therapeutic strategy for thyroid cancer. Lenvatinib mesilate (lenvatinib) is a potent inhibitor of VEGF receptors (VEGFR1–3) and other prooncogenic and prooncogenic receptor tyrosine kinases, including fibroblast growth factor receptors (FGFR1–4), platelet derived growth factor receptor α (PDGFRα), KIT, and RET. We examined the antitumor activity of lenvatinib against human thyroid cancer xenograft models in nude mice. Orally administered lenvatinib showed significant antitumor activity in 5 differentiated thyroid cancer (DTC), 5 anaplastic thyroid cancer (ATC), and 1 medullary thyroid cancer (MTC) xenograft models. Lenvatinib also showed antiangiogenesis activity against 5 DTC and 5 ATC xenografts, while lenvatinib showed in vitro antiproliferative activity against only 2 of 11 thyroid cancer cell lines: that is, RO82-W-1 and TT cells. Western blot analysis showed that cultured RO82-W-1 cells overexpressed FGFR1 and that lenvatinib inhibited the phosphorylation of FGFR1 and its downstream effector FRS2. Lenvatinib also inhibited the phosphorylation of RET with the activated mutation C634W in TT cells. These data demonstrate that lenvatinib provides antitumor activity mainly via angiogenesis inhibition but also inhibits FGFR and RET signaling pathway in preclinical human thyroid cancer models. PMID:25295214

  1. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models.

    PubMed

    Tohyama, Osamu; Matsui, Junji; Kodama, Kotaro; Hata-Sugi, Naoko; Kimura, Takayuki; Okamoto, Kiyoshi; Minoshima, Yukinori; Iwata, Masao; Funahashi, Yasuhiro

    2014-01-01

    Inhibition of tumor angiogenesis by blockading the vascular endothelial growth factor (VEGF) signaling pathway is a promising therapeutic strategy for thyroid cancer. Lenvatinib mesilate (lenvatinib) is a potent inhibitor of VEGF receptors (VEGFR1-3) and other prooncogenic and prooncogenic receptor tyrosine kinases, including fibroblast growth factor receptors (FGFR1-4), platelet derived growth factor receptor α (PDGFRα), KIT, and RET. We examined the antitumor activity of lenvatinib against human thyroid cancer xenograft models in nude mice. Orally administered lenvatinib showed significant antitumor activity in 5 differentiated thyroid cancer (DTC), 5 anaplastic thyroid cancer (ATC), and 1 medullary thyroid cancer (MTC) xenograft models. Lenvatinib also showed antiangiogenesis activity against 5 DTC and 5 ATC xenografts, while lenvatinib showed in vitro antiproliferative activity against only 2 of 11 thyroid cancer cell lines: that is, RO82-W-1 and TT cells. Western blot analysis showed that cultured RO82-W-1 cells overexpressed FGFR1 and that lenvatinib inhibited the phosphorylation of FGFR1 and its downstream effector FRS2. Lenvatinib also inhibited the phosphorylation of RET with the activated mutation C634W in TT cells. These data demonstrate that lenvatinib provides antitumor activity mainly via angiogenesis inhibition but also inhibits FGFR and RET signaling pathway in preclinical human thyroid cancer models.

  2. Synthesis and antitumor activity evaluation of new 2-(4-aminophenyl)benzothiazole derivatives bearing different heterocyclic rings.

    PubMed

    Yurttaş, Leyla; Tay, Funda; Demirayak, Şeref

    2015-06-01

    Twenty-five new N-[4-(benzothiazole-2-yl)phenyl]acetamide derivatives bearing different heterocyclic ring systems were synthesized using 2-(4-aminophenyl)benzothiazole structure as a pharmacophoric group. Final compounds were screened for their potential antitumor activity in vitro against approximately 60 human tumor cell lines derived from nine neoplastic diseases at National Cancer Institute, USA. 2-(4-Aminophenyl)benzothiazole structure was prepared by the reaction of 4-aminobenzoic acid and 2-aminothiophenol in polyphosphoric acid using microwave irradiation. After acetylation reaction, amide compounds 2a and 2b were obtained, which were then reacted with 2-mercapto(benz)imidazole/benzothiazole/benzoxazole derivatives in acetone with the presence of potassium carbonate to gain final compounds (3-27). Among all tested compounds, compound 10, namely N-[4-(benzothiazole-2-yl)-3-chlorophenyl]-2-[(benzimidazole-2-yl)thio]acetamide, and compound 16, namely N-[4-(benzothiazole-2-yl)phenyl]-2-[(1,5-diphenyl-1H-imidazole-2-yl)thio]acetamide, were found to be of considerable anticancer activity against some cancer cell lines.

  3. Effects of nanoparticle size on antitumor activity of 10-hydroxycamptothecin-conjugated gold nanoparticles: in vitro and in vivo studies

    PubMed Central

    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. PMID:27022260

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

    PubMed

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

    2017-02-17

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

  5. Immunological mechanisms of antitumor activity of some kinds of Chinese herbs: Meth A-induced delayed type hypersensitivity.

    PubMed

    Mori, H; Xu, Q A; Sakamoto, O; Uesugi, Y; Ono, Y; Koda, A; Nishioka, I

    1988-09-01

    In the present paper, we confirmed that a delayed type hypersensitivity response can be elicited against Meth A tumor (Meth A-DTH) in BALB/c mice bearing the primary tumor. This response was augmented by lipopolysaccharide. We examined the effects of 4 kinds of Chinese herbs including A. capillaris, S. doederleinii, A. macrocephala and S. subprostrata on the Meth A-DTH, and the results were compared with that of the herbs on picryl chloride-induced delayed type hypersensitivity (PC-DTH). All of the herbs examined augmented the Meth A-DTH 10 days after the primary tumor transplantation, and S. doederleinii, A. macrocephala and S. subprostrata prevented the decay of the response on the 20th day, but A. capillaris did not. On the other hand, none of the herbs affected the PC-DTH. When both DTH responses were caused simultaneously in the same mouse, Meth A-DTH decayed 20 days after the transplantation but PC-DTH did not. In this case, the effects of these 4 herbs on Meth A-DTH and PC-DTH were essentially the same as those seen in the case of separate experiments. The previous and present results suggest that A. capillaris shows antitumor activity mainly through a direct cytotoxicity, although this herb might have certain components to enhance Meth A-DTH, and the other herbs display the activity through the enhancement of T cell-mediated tumor immunity, particularly tumor specific DTH.

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

    NASA Astrophysics Data System (ADS)

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

    2017-02-01

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

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

    PubMed

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

    1996-04-01

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

  8. Origin of anti-tumor activity of the cysteine-containing GO peptides and further optimization of their cytotoxic properties

    PubMed Central

    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. PMID:28091523

  9. Origin of anti-tumor activity of the cysteine-containing GO peptides and further optimization of their cytotoxic properties

    NASA Astrophysics Data System (ADS)

    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.

  10. Conservation of receptor antagonist anti-tumor activity by epidermal growth factor receptor antibody expressed in transgenic corn seed.

    PubMed

    Ludwig, Dale L; Witte, Larry; Hicklin, Daniel J; Prewett, Marie; Bassi, Rajiv; Burtrum, Douglas; Pereira, Daniel S; Jimenez, Xenia; Fox, Floyd; Saxena, Babita; Zhou, Qinwei; Ma, Yuemei; Kang, Xiaoqiang; Patel, Dipa; Barry, Michael; Kussie, Paul; Zhu, Zhenping; Russell, Douglas A; Petersen, William L; Jury, Thomas P; Gaitan-Gaitan, Fernando; Moran, Daniel L; Delannay, Xavier; Storrs, Bradley S; Tou, Jacob; Zupec, Mark E; Gustafson, Karen S; McIntyre, John; Tarnowski, S Joseph; Bohlen, Peter

    2004-01-01

    Recombinant protein production in plants such as corn is a promising means to generate high product yields at low comparable production cost. The anti-EGFR monoclonal antibody C225, cetuximab, is a well-characterized receptor antagonist antibody recently approved for the treatment of refractory colorectal cancer. We initiated a study to test and compare the functional activity of glycosylated and aglycosylated C225 produced in stable transgenic corn seed. Both corn antibodies were shown to be functionally indistinguishable from mammalian-derived C225 in demonstrating high-affinity binding to the EGF receptor, blocking of ligand-dependent signaling, and inhibiting cell proliferation. In addition, consistent with cetuximab, both corn antibodies possessed strong anti-tumor activity in vivo. Acute dose primate pharmacokinetic studies, however, revealed a marked increase in clearance for the glycosylated corn antibody, while the aglycosylated antibody possessed in vivo kinetics similar to cetuximab. This experimentation established that corn-derived receptor blocking monoclonal antibodies possess comparable efficacy to mammalian cell culture-derived antibody, and offer a cost effective alternative to large-scale mammalian cell culture production.

  11. Design, synthesis and structure-activity relationship study of novel pyrazole-based heterocycles as potential antitumor agents.

    PubMed

    Farag, Ahmad M; Ali, Korany A K; El-Debss, Taha M A; Mayhoub, Abdelrahman S; Amr, Abdel-Galil E; Abdel-Hafez, Naglaa A; Abdulla, Mohamed M

    2010-12-01

    The versatile hitherto unreported 3-[(E)-3-(dimethylamino)acryloyl]-1,5-diphenyl-1H-pyrazole-4-carbonitrile (3) was prepared via the reaction of 3-acetyl-1,5-diphenyl-1H-pyrazole-4-carbonitrile (1) with dimethylformamid-dimethylacetal (DMF-DMA). The latter product and 3-((E)-3-morpholin-4-yl-acryloyl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile (4) underwent regioselective 1,3-dipolar cycloaddition with nitrilimines to afford the corresponding pyrazole derivatives. In vivo anti-estrogenic activity and acute toxicity after single oral dose of the newly synthesized compounds were evaluated. In vitro disease-oriented primary antitumor screening utilizing 14 cell lines of breast and ovarian tumor subpanels has been also carried out. All tested compounds showed anti-estrogenic properties equipotent or superior to the reference drug, letrozole. 3-[3-(4-Cyano-1,5-diphenyl-1H-pyrazole-3-yl)-1-(4-methylphenyl)-1H-pyrazole-4-carbonyl]-1,5-diphenyl-1H-pyrazole-4-carbonitrile (27c) and 3-(3-acetyl-1-phenyl-1H-pyrazole-4-carbonyl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile (8a) showed a significant cytotoxic activity in a nanomolar range against certain types of breast and ovarian tumors with tolerable toxicity.

  12. Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma Models1

    PubMed Central

    Ulivi, Paola; Zoli, Wainer; Fabbri, Francesco; Brigliadori, Giovanni; Ricotti, Luca; Tesei, Anna; Rosetti, Marco; De Cesare, Michelandrea; Beretta, Giovanni L; Corna, Elisabetta; Supino, Rosanna; Zunino, Franco

    2005-01-01

    Abstract To investigate the cellular/molecular basis of the activity of a novel lipophilic camptothecin, gimatecan (ST1481), against slowly proliferating cells, we performed a comparative study of topotecan and gimatecan in human bladder cancer models (HT1376 and MCR). Gimatecan was significantly more effective than topotecan in inhibiting the growth of HT1376 tumor, thus reflecting antiproliferative potency. In both HT1376 and MCR cells, gimatecan caused a persistent S-phase arrest, indicating an efficient DNA damage checkpoint. This response was consistent with a cytostatic effect, because no evidence of apoptosis was detected. In contrast to gimatecan, topotecan at equitoxic concentrations caused an early and persistent downregulation of topoisomerase I. Modulation of protein level could not be solely ascribed to the proteasome-mediated degradation of the enzyme because the proteasome inhibitor PS341 sensitized MCR but not HT1376 cells to camptothecins, suggesting alternative mechanisms of drug-induced topoisomerase I downregulation. Indeed, the two camptothecins caused a differential inhibition of topoisomerase I transcription, which is more marked in topotecan-treated cells. The HT1376 model was more sensitive to this immediate decrease of mRNA level. Our data document a marked antitumor activity of gimatecan against a bladder carcinoma model. A limited downregulation of topoisomerase I by gimatecan provides additional insights into the cellular basis of drug potency. PMID:15802020

  13. Screening for genes coding for putative antitumor compounds, antimicrobial and enzymatic activities from haloalkalitolerant and haloalkaliphilic bacteria strains of Algerian Sahara Soils.

    PubMed

    Selama, Okba; Amos, Gregory C A; Djenane, Zahia; Borsetto, Chiara; Laidi, Rabah Forar; Porter, David; Nateche, Farida; Wellington, Elizabeth M H; Hacène, Hocine

    2014-01-01

    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.

  14. Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor.

    PubMed

    Meuillet, Emmanuelle J; Zuohe, Song; Lemos, Robert; Ihle, Nathan; Kingston, John; Watkins, Ryan; Moses, Sylvestor A; Zhang, Shuxing; Du-Cuny, Lei; Herbst, Roy; Jacoby, Jörg J; Zhou, Li Li; Ahad, Ali M; Mash, Eugene A; Kirkpatrick, D Lynn; Powis, Garth

    2010-03-01

    Phosphatidylinositol 3-kinase/phosphatidylinositide-dependent protein kinase 1 (PDPK1)/Akt signaling plays a critical role in activating proliferation and survival pathways within cancer cells. We report the molecular pharmacology and antitumor activity of PHT-427, a compound designed to bind to the pleckstrin homology (PH) binding domain of signaling molecules important in cancer. Although originally designed to bind the PH domain of Akt, we now report that PHT-427 also binds to the PH domain of PDPK1. A series of PHT-427 analogues with variable C-4 to C-16 alkyl chain length were synthesized and tested. PHT-427 itself (C-12 chain) bound with the highest affinity to the PH domains of both PDPK1 and Akt. PHT-427 inhibited Akt and PDPK1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. When given orally, PHT-427 inhibited the growth of human tumor xenografts in immunodeficient mice, with up to 80% inhibition in the most sensitive tumors, and showed greater activity than analogues with C4, C6, or C8 alkyl chains. Inhibition of PDPK1 was more closely correlated to antitumor activity than Akt inhibition. Tumors with PIK3CA mutation were the most sensitive, and K-Ras mutant tumors were the least sensitive. Combination studies showed that PHT-427 has greater than additive antitumor activity with paclitaxel in breast cancer and with erlotinib in non-small cell lung cancer. When given >5 days, PHT-427 caused no weight loss or change in blood chemistry. Thus, we report a novel PH domain binding inhibitor of PDPK1/Akt signaling with significant in vivo antitumor activity and minimal toxicity.

  15. Chemical and cellular investigations of trans-ammine-pyridine-dichlorido-platinum(II), the likely metabolite of the antitumor active cis-diammine-pyridine-chorido-platinum(II).

    PubMed

    Xu, Dechen; Min, Yuanzeng; Cheng, Qinqin; Shi, Hongdong; Wei, Kaiju; Arnesano, Fabio; Natile, Giovanni; Liu, Yangzhong

    2013-12-01

    It has been proposed that the well-studied monofunctional platinum complex cis-[PtCl(NH3)2(py)](+) (cDPCP) forms DNA adducts similar to those of the trans platinum complex trans-[PtCl2(NH3)(py)] (ampyplatin, py=pyridine). Thus this latter could be the active form of cDPCP. Detailed studies on the mechanism of ampyplatin action were performed in this work. Results indicate that ampyplatin has significantly higher antiproliferative activity than cDPCP and is comparable to cisplatin. Cellular uptake experiments indicate that ampyplatin can be efficiently accumulated in A549 cancer cells. Binding of ampyplatin to DNA mainly produces monofunctional adducts; remarkably, these adducts can be recognized by the HMGB1 protein. Kinetic studies on the reaction with GMP indicate that the reactivity of ampyplatin is much lower than that of transplatin and is more similar to that of trans-[PtCl2{E-HN=C(Me)OMe}2] (trans-EE), a widely investigated antitumor active trans-oriented platinum complex. In addition, the hydrolysis of ampyplatin is significantly suppressed, whereas the hydrolysis of the mono-GMP adduct is highly enhanced. These results indicate that the mechanism of ampyplatin differs not only from that of antitumor inactive transplatin but also from that of antitumor active trans-EE and this could account for the remarkable activity of parent cDPCP.

  16. Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety.

    PubMed

    Zhang, Kai; Wang, Peng; Xuan, Li-Na; Fu, Xiao-Yun; Jing, Fen; Li, Sha; Liu, Yu-Ming; Chen, Bao-Quan

    2014-11-15

    A series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC50 value of 2.84 μM. Compounds 8k and 8 n displayed highly effective antitumor activities against MCF-7 cells, with IC50 values of 4.56 and 4.25 μM, respectively. Compounds 8a and 8 n exhibited significant antiproliferative activity against A549 cells, with IC50 values of 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for modulating antiproliferative activities against various tumor cell lines.

  17. pH dependent unfolding characteristics of DLC8 dimer: Residue level details from NMR.

    PubMed

    Mohan, P M Krishna; Hosur, Ramakrishna V

    2008-11-01

    Environment dependence of folding and unfolding of a protein is central to its function. In the same vein, knowledge of pH dependence of stability and folding/unfolding is crucial for many biophysical equilibrium and kinetic studies designed to understand protein folding mechanisms. In the present study we investigated the guanidine induced unfolding transition of dynein light chain protein (DLC8), a cargo adaptor of the dynein complex in the pH range 7-10. It is observed that while the protein remains a dimer in the entire pH range, its stability is somewhat reduced at alkaline pH. Global unfolding features monitored using fluorescence spectroscopy revealed that the unfolding transition of DLC8 at pH 7 is best described by a three-state model, whereas, that at pH 10 is best described by a two-state model. Chemical shift perturbations due to pH change provided insights into the corresponding residue level structural perturbations in the DLC8 dimer. Likewise, backbone (15)N relaxation measurements threw light on the corresponding motional changes in the dimeric protein. These observations have been rationalized on the basis of expected changes with increasing pH in the protonation states of the titratable residues on the structure of the protein. These, in turn provide an explanation for the change from three-state to two-state guanidine induced unfolding transition as the pH is increased from 7 to 10. All these results exemplify and highlight the role of environment vis-à-vis the sequence and structure of a given protein in dictating its folding/unfolding characteristics.

  18. Toxicity evaluation of pH dependent stable Achyranthes aspera herbal gold nanoparticles

    NASA Astrophysics Data System (ADS)

    Tripathi, Alok; Kumari, Sarika; Kumar, Arvind

    2016-01-01

    Nanoparticles have gained substantial attention for the control of various diseases. However, any adverse effect of herbal gold nanoparticles (HGNPs) on animals including human being has not been investigated in details. The objectives of current study are to assess the cytotoxicity of HGNPs synthesized by using leaf extract of Achyranthes aspera, and long epoch stability. The protocol deals with stability of HGNPs in pH dependent manner. Visually, HGNPs formation is characterized by colour change of extract from dark brown to dark purple after adding gold chloride solution (1 mM). The 100 μg/ml HGNPs concentration has been found nontoxic to the cultured spleenocyte cells. Spectrophotometric analysis of nanoparticles solution gave a peak at 540 nm which corresponds to surface plasmon resonance absorption band. As per scanning electron microscopy and Transmission electron microscopy (TEM), size of HGNPs are in the range of 50-80 nm (average size 70 nm) with spherical morphology. TEM-selected area electron diffraction observation showed hexagonal texture. HGNPs showed substantial stability at higher temperature (85 °C), pH 10 and salt concentration (5 M). The zeta potential value of HGNPs is -35.9 mV at temperature 25 °C, pH 10 showing its good quality with better stability in comparison to pH 6 and pH 7. The findings advocate that the protocol for the synthesis of HGNPs is easy and quick with good quality and long epoch stability at pH 10. Moreover, non-toxic dose could be widely applicable for human health as a potential nano-medicine in the future to cure diseases.

  19. Combination of thymidine phosphorylase gene transfer and deoxyinosine treatment greatly enhances 5-fluorouracil antitumor activity in vitro and in vivo.

    PubMed

    Ciccolini, J; Cuq, P; Evrard, A; Giacometti, S; Pelegrin, A; Aubert, C; Cano, J P; Iliadis, A

    2001-12-01

    We reported previously that 5-fluorouracil (FUra) efficacy could be enhanced by increasing tumoral thymidine phosphorylase (TP) activity. Potentiated TP yield was achieved by either transfecting cells with human TP gene (A. Evrard et al., Br. J. Cancer, 80: 1726-1733, 1999) or associating FUra with 2'-deoxyinosine (d-Ino), a modulator providing the tumors with TP cofactor deoxyribose 1-phosphate (J. Ciccolini et al., Clin. Cancer Res., 6: 1529-1535, 2000). The purpose of the present work was to study the effects of a combined modulation (TP gene transfer + use of d-Ino) on the sensitivity to FUra of the LS174T human colorectal cell line. Results showed a near 4000 times increase of cell sensitivity in vitro after double (genetic + biochemical) modulation. This potentiation of tumor response was accompanied by a total change in the FUra anabolic pathway with a 5000% increase of cytosolic fluorodeoxyuridine monophosphate, a stronger and longer inhibition of thymidylate synthase, and 300% augmentation of DNA damage. Besides, whereas thymidine failed to inhibit FUra cytotoxicity in LS174T wild-type cells, the potentiation of the antitumor activity observed in the modulating regimen was partly reversed by thymidine, indicative of thymidylate synthase as the main drug target. The impact of this double modulation was next investigated in xenograft-bearing nude mice. Results showed that whereas FUra alone was completely ineffective on wild-type tumor growth, the size of TP-transfected tumors in animals treated with the FUra/d-Ino combination was reduced by 80% (P < 0.05). Our results suggest that FUra exhibits stronger antiproliferative activity when activated via TP through the DNA pathway and that high tumoral TP activity therefore leads to enhanced sensitivity to fluoropyrimidines.

  20. Co-delivery of paclitaxel and TOS-cisplatin via TAT-targeted solid lipid nanoparticles with synergistic antitumor activity against cervical cancer

    PubMed Central

    Liu, Bo; Han, Li; Liu, Junyan; Han, Shumei; Chen, Zhen; Jiang, Lixi

    2017-01-01

    Background Cervical cancer is a major world health problem for women. Currently, cancer research focuses on improving therapy for cervical cancer using various treatment options such as co-delivery of chemotherapeutic agents by nanocarriers. Purpose The aim of this study was to develop trans-activating transcriptional activator (TAT)-modified solid lipid nanoparticles (SLNs) for co-delivery of paclitaxel (PTX) and α-tocopherol succinate-cisplatin prodrug (TOS-CDDP) (TAT PTX/TOS-CDDP SLNs) in order to achieve synergistic antitumor activity against cervical cancer. Methods Lipid prodrug of CDDP (TOS-CDDP) and TAT-containing polyethylene glycol-distearoyl-phosphatidylethanolamine (TAT-PEG-DSPE) were synthesized. TAT PTX/TOS-CDDP SLNs were prepared by emulsification and solvent evaporation method. Physicochemical characteristics of SLNs such as size, morphology, and release profiles were explored. In vitro and in vivo studies were carried out to assess the efficacy of their antitumor activity in target cells. Results TAT PTX/TOS-CDDP SLNs could be successfully internalized by HeLa cells and showed a synergistic effect in the suppression of cervical tumor cell growth. They exhibited high tumor tissue accumulation, superior antitumor efficiency, and much lower toxicity in vivo. Conclusion The present study indicates that the co-delivery system provides a promising platform as a combination therapy for the treatment of cervical cancer, and possibly other types of cancer as well. PMID:28203075

  1. Coexpressed Catalase Protects Chimeric Antigen Receptor–Redirected T Cells as well as Bystander Cells from Oxidative Stress–Induced Loss of Antitumor Activity

    PubMed Central

    Ligtenberg, Maarten A.; Mougiakakos, Dimitrios; Mukhopadhyay, Madhura; Witt, Kristina; Lladser, Alvaro; Chmielewski, Markus; Riet, Tobias; Abken, Hinrich

    2016-01-01

    Treatment of cancer patients by adoptive T cell therapy has yielded promising results. In solid tumors, however, T cells encounter a hostile environment, in particular with increased inflammatory activity as a hallmark of the tumor milieu that goes along with abundant reactive oxygen species (ROS) that substantially impair antitumor activity. We present a strategy to render antitumor T cells more resilient toward ROS by coexpressing catalase along with a tumor specific chimeric Ag receptor (CAR) to increase their antioxidative capacity by metabolizing H2O2. In fact, T cells engineered with a bicistronic vector that concurrently expresses catalase, along with the CAR coexpressing catalase (CAR-CAT), performed superior over CAR T cells as they showed increased levels of intracellular catalase and had a reduced oxidative state with less ROS accumulation in both the basal state and upon activation while maintaining their antitumor activity despite high H2O2 levels. Moreover, CAR-CAT T cells exerted a substantial bystander protection of nontransfected immune effector cells as measured by CD3ζ chain expression in bystander T cells even in the presence of high H2O2 concentrations. Bystander NK cells, otherwise ROS sensitive, efficiently eliminate their K562 target cells under H2O2-induced oxidative stress when admixed with CAR-CAT T cells. This approach represents a novel means for protecting tumor-infiltrating cells from tumor-associated oxidative stress–mediated repression. PMID:26673145

  2. Coexpressed Catalase Protects Chimeric Antigen Receptor-Redirected T Cells as well as Bystander Cells from Oxidative Stress-Induced Loss of Antitumor Activity.

    PubMed

    Ligtenberg, Maarten A; Mougiakakos, Dimitrios; Mukhopadhyay, Madhura; Witt, Kristina; Lladser, Alvaro; Chmielewski, Markus; Riet, Tobias; Abken, Hinrich; Kiessling, Rolf

    2016-01-15

    Treatment of cancer patients by adoptive T cell therapy has yielded promising results. In solid tumors, however, T cells encounter a hostile environment, in particular with increased inflammatory activity as a hallmark of the tumor milieu that goes along with abundant reactive oxygen species (ROS) that substantially impair antitumor activity. We present a strategy to render antitumor T cells more resilient toward ROS by coexpressing catalase along with a tumor specific chimeric Ag receptor (CAR) to increase their antioxidative capacity by metabolizing H2O2. In fact, T cells engineered with a bicistronic vector that concurrently expresses catalase, along with the CAR coexpressing catalase (CAR-CAT), performed superior over CAR T cells as they showed increased levels of intracellular catalase and had a reduced oxidative state with less ROS accumulation in both the basal state and upon activation while maintaining their antitumor activity despite high H2O2 levels. Moreover, CAR-CAT T cells exerted a substantial bystander protection of nontransfected immune effector cells as measured by CD3ζ chain expression in bystander T cells even in the presence of high H2O2 concentrations. Bystander NK cells, otherwise ROS sensitive, efficiently eliminate their K562 target cells under H2O2-induced oxidative stress when admixed with CAR-CAT T cells. This approach represents a novel means for protecting tumor-infiltrating cells from tumor-associated oxidative stress-mediated repression.

  3. Structural studies of the protein endostatin in fusion with BAX BH3 death domain, a hybrid that presents enhanced antitumoral activity.

    PubMed

    Chura-Chambi, Rosa Maria; Arcuri, Helen Andrade; Lino, Felipe; Versati, Natan; Palma, Mario Sergio; Favaro, Denize C; Morganti, Ligia

    2016-05-04

    Endostatin (ES) is an antiangiogenic protein that exhibits antitumor activity in animal models. However, the activity observed in animals was not observed in human clinical trials. ES-BAX is a fusion protein composed of two functional domains: ES, which presents specificity and is internalized by activated endothelial cells and the proapoptotic BH3 domain of the protein BAX, a peptide inductor of cellular death when internalized. We have previously shown (Chura-Chambi et al., Cell Death Dis, 5, e1371, 2014) that ES-BAX presents improved antitumor activity in relation to wild-type ES. Secondary and tertiary structures of ES-BAX are similar to ES, as indicated by homology-modeling studies and molecular dynamics simulations. Tryptophan intrinsic fluorescence and circular dichroism spectroscopy corroborate these data. (15) N HSQC NMR indicates that ES-BAX is structured, but some ES residues have suffered chemical shift perturbations, suggesting that the BH3 peptide interacts with some parts of the ES protein. ES and ES-BAX present similar stability to thermal denaturation. The production of stable hybrid proteins can be a new approach to the development of therapeutic agents presenting specificity for tumoral endothelium and improved antitumor effect.

  4. Enhanced anti-tumor activity induced by adoptive T cell transfer and the adjunctive use of the HDAC Inhibitor LAQ824

    PubMed Central

    Vo, Dan D.; Prins, Robert M.; Begley, Jonathan L.; Donahue, Timothy R.; Morris, Lilah F.; Bruhn, Kevin W.; de la Rocha, Pilar; Yang, Meng-Yin; Mok, Stephen; Garban, Hermes J.; Craft, Noah; Economou, James S.; Marincola, Francesco M.; Wang, Ena; Ribas, Antoni

    2009-01-01

    Tumors grow in the presence of antigen-specific T cells, suggesting the existence of intrinsic cancer cell escape mechanisms. We hypothesized that a histone deacetylase (HDAC) inhibitor could sensitize tumor cells to immunotherapy because this class of agents has been reported to increase tumor antigen expression and shift gene expression to a pro-apoptotic milieu in cancer cells. To test this question, we treated B16 murine melanoma with the combination of the HDAC inhibitor LAQ824 together with the adoptive transfer (AT) of gp100 melanoma antigen-specific pmel-1 T cells. The combined therapy significantly improved antitumor activity through several mechanisms: 1) increase in MHC and tumor-associated antigen (TAA) expression by tumor cells; 2) decrease in competing endogenous lymphocytes in recipient mice, resulting in a proliferative advantage for the adoptively transferred cells; and 3) improvement in the functional activity of the adoptively transferred lymphocytes. We confirmed the beneficial effects of this HDAC inhibitor as sensitizer to immunotherapy in a different model of prophylactic prime-boost vaccination with the melanoma antigen tyrosinase-related protein-2 (TRP2), which also demonstrated a significant improvement in antitumor activity against B16 melanoma. In conclusion, the HDAC inhibitor LAQ824 significantly enhances tumor immunotherapy through effects on target tumor cells as well as improving the antitumor activity of tumor antigen-specific lymphocytes. PMID:19861533

  5. Linker stability influences the anti-tumor activity of acetazolamide-drug conjugates for the therapy of renal cell carcinoma

    PubMed Central

    Neri, Dario

    2016-01-01

    Small molecule-drug conjugates (SMDCs) are increasingly being considered as an alternative to antibody-drug conjugates (ADCs) for the selective delivery of anticancer agents to the tumor site, sparing normal tissues. Carbonic anhydrase IX (CAIX) is a membrane-bound enzyme, which is over-expressed in the majority of renal cell carcinomas and which can be efficiently targeted in vivo, using charged derivatives of acetazolamide, a small heteroaromatic sulfonamide. Here, we show that SMDC products, obtained by the coupling of acetazolamide with monomethyl auristatin E (MMAE) using dipeptide linkers, display a potent anti-tumoral activity in mice bearing xenografted SKRC-52 renal cell carcinomas. A comparative evaluation of four dipeptides revealed that SMDCs featuring valine-citrulline and valine-alanine linkers exhibited greater serum stability and superior therapeutic activity, compared to the counterparts with valine-lysine or valine-arginine linkers. The most active products substantially inhibited tumor growth over a prolonged period of time, in a tumor model for which sunitinib and sorafenib do not display therapeutic activity. However, complete tumor eradication was not possible even after ten intravenous injection. Macroscopic near-infrared imaging procedures confirmed that ligands had not lost the ability to selectively localize at the tumor site at the end of therapy and that the neoplastic masses continued to express CAIX. The findings are of mechanistic and of therapeutic significance, since CAIX is a non-internalizing membrane-associated antigen, which can be considered for targeted drug delivery applications in kidney cancer patients. PMID:27890855

  6. Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo☆

    PubMed Central

    Newell, Pippa; Toffanin, Sara; Villanueva, Augusto; Chiang, Derek Y.; Minguez, Beatriz; Cabellos, Laia; Savic, Radoslav; Hoshida, Yujin; Lim, Kiat Hon; Melgar-Lesmes, Pedro; Yea, Steven; Peix, Judit; Deniz, Kemal; Fiel, M. Isabel; Thung, Swan; Alsinet, Clara; Tovar, Victoria; Mazzaferro, Vincenzo; Bruix, Jordi; Roayaie, Sasan; Schwartz, Myron; Friedman, Scott L.; Llovet, Josep M.

    2010-01-01

    Background/Aims The success of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC) has focused interest on the role of Ras signaling in this malignancy. We investigated the molecular alterations of the Ras pathway in HCC and the antineoplastic effects of sorafenib in combination with rapamycin, an inhibitor of mTOR pathway, in experimental models. Methods Gene expression (qRT-PCR, oligonucleotide microarray), DNA copy number changes (SNP-array), methylation of tumor suppressor genes (methylation-specific PCR) and protein activation (immunohistochemistry) were analysed in 351 samples. Anti-tumoral effects of combined therapy targeting the Ras and mTOR pathways were evaluated in cell lines and HCC xenografts. Results Different mechanisms accounted for Ras pathway activation in HCC. H-ras was up-regulated during different steps of hepatocarcinogenesis. B-raf was overexpressed in advanced tumors and its expression was associated with genomic amplification. Partial methylation of RASSF1A and NORE1A was detected in 89% and 44% of tumors respectively, and complete methylation was found in 11 and 4% of HCCs. Activation of the pathway (pERK immunostaining) was identified in 10.3% of HCC. Blockade of Ras and mTOR pathways with sorafenib and rapamycin reduced cell proliferation and induced apoptosis in cell lines. In vivo, the combination of both compounds enhanced tumor necrosis and ulceration when compared with sorafenib alone. Conclusions Ras activation results from several molecular alterations, such as methylation of tumor suppressors and amplification of oncogenes (B-raf). Sorafenib blocks signaling and synergizes with rapamycin in vivo, preventing tumor progression. These data provide the rationale for testing this combination in clinical studies. PMID:19665249

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

    NASA Astrophysics Data System (ADS)

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

    2013-02-01

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

  8. Preparation of curcumin loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) nanofibers and their in vitro antitumor activity against Glioma 9L cells

    NASA Astrophysics Data System (ADS)

    Guo, Gang; Fu, Shaozhi; Zhou, Liangxue; Liang, Hang; Fan, Min; Luo, Feng; Qian, Zhiyong; Wei, Yuquan

    2011-09-01

    The purpose of this work was to develop implantable curcumin-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) nanofibers, which might have potential application in cancer therapy. Curcumin was incorporated into biodegradable PCEC nanofibers by electrospinning method. The surface morphology of the composite nanofibers was characterized on Scanning Electron Microscope (SEM). The average diameter of the nanofibers was 2.3-4.5μm. In vitro release behavior of curcumin from the fiber mats was also studied in detail. The in vitro cytotoxicity assay showed that the PCEC fibers themselves did not affect the growth of rat Glioma 9L cells. Antitumor activity of the curcumin-loaded fibers against the cells was kept over the whole experiment process, while the antitumor activity of pure curcumin disappeared within 48 h. These results strongly suggested that the curcumin/PCEC composite nanofibers might have potential application for postoperative chemotherapy of brain cancers.

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

    PubMed

    Elhusseiny, Amel F; Hassan, Hammed H A M

    2013-02-15

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

  10. Enhanced antitumor activity and mechanism of biodegradable polymeric micelles-encapsulated chetomin in both transgenic zebrafish and mouse models

    NASA Astrophysics Data System (ADS)

    Wu, Qinjie; Li, Guoyou; Deng, Senyi; Ouyang, Liang; Li, Ling; Liu, Lei; Luo, Na; Song, Xiangrong; He, Gu; Gong, Changyang; Wei, Yuquan

    2014-09-01

    Chetomin is a promising molecule with anti-tumor activities in the epipolythiodioxopiperazine family of fungal secondary metabolites; however, strong hydrophobicity has limited its further applications. In this work, chetomin was encapsulated into polymeric micelles to obtain an aqueous formulation, and the chetomin loaded micelles (Che-M) exhibited small particle size and high encapsulation efficiency. When the concentration of copolymer was higher than the critical gelation concentration, the Che-M could form a thermosensitive hydrogel (Che-H), which was free-flowing sol at ambient temperature and converted into a non-flowing gel at body temperature. The molecular modeling study has indicated that chetomin interacted with PCL as a core, which was embraced by PEG as a shell. Che-M showed equal cytotoxicity with free chetomin, but the apoptosis inducing effects of Che-M were more significant. Besides, Che-M could increase the GSSG level, decrease the GSH level, and increase the ROS in CT26 cells. Furthermore, stronger inhibitory effects of Che-M were observed on embryonic angiogenesis, tumor-induced angiogenesis and tumor growth in transgenic zebrafish models. In addition, Che-M was effective in inhibiting tumor growth and prolonging survival in a subcutaneous CT26 tumor model. In a colorectal peritoneal carcinomatosis model, both Che-M and Che-H showed excellent therapeutic effects, but Che-H was more effective. In conclusion, Che-M and Che-H may serve as candidates for cancer therapy.

  11. Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity.

    PubMed

    Eichner, Ruth; Heider, Michael; Fernández-Sáiz, Vanesa; van Bebber, Frauke; Garz, Anne-Kathrin; Lemeer, Simone; Rudelius, Martina; Targosz, Bianca-Sabrina; Jacobs, Laura; Knorn, Anna-Maria; Slawska, Jolanta; Platzbecker, Uwe; Germing, Ulrich; Langer, Christian; Knop, Stefan; Einsele, Herrmann; Peschel, Christian; Haass, Christian; Keller, Ulrich; Schmid, Bettina; Götze, Katharina S; Kuster, Bernhard; Bassermann, Florian

    2016-07-01

    Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.

  12. Effect of Tea Polyphenol Compounds on Anticancer Drugs in Terms of Anti-Tumor Activity, Toxicology, and Pharmacokinetics.

    PubMed

    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.

  13. Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via an apoptosis-independent pathway.

    PubMed

    An, Hyunsook; Kim, Ji Young; Lee, Nahyun; Cho, Youngkwan; Oh, Eunhye; Seo, Jae Hong

    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(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.

  14. Oroxylin A induced apoptosis of human hepatocellular carcinoma cell line HepG2 was involved in its antitumor activity

    SciTech Connect

    Hu Yang; Yang Yong; You Qidong . E-mail: qdyou@cpu.edu.cn; Liu Wei; Gu Hongyan; Zhao Li; Zhang Kun; Wang Wei; Wang Xiaotang; Guo Qinglong . E-mail: qinglongguo@hotmail.com

    2006-12-15

    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{sub 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.