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Sample records for ph-dependent antitumor activity

  1. Neuroserpin Differentiates Between Forms of Tissue Type Plasminogen Activator via pH Dependent Deacylation

    PubMed Central

    Carlson, Karen-Sue B.; Nguyen, Lan; Schwartz, Kat; Lawrence, Daniel A.; Schwartz, Bradford S.

    2016-01-01

    Tissue-type plasminogen activator (t-PA), initially characterized for its critical role in fibrinolysis, also has key functions in both physiologic and pathologic processes in the CNS. Neuroserpin (NSP) is a t-PA specific serine protease inhibitor (serpin) found almost exclusively in the CNS that regulates t-PA’s proteolytic activity and protects against t-PA mediated seizure propagation and blood–brain barrier disruption. This report demonstrates that NSP inhibition of t-PA varies profoundly as a function of pH within the biologically relevant pH range for the CNS, and reflects the stability, rather than the formation of NSP: t-PA acyl-enzyme complexes. Moreover, NSP differentiates between the zymogen-like single chain form (single chain t-PA, sct-PA) and the mature protease form (two chain t-PA, tct-PA) of t-PA, demonstrating different pH profiles for protease inhibition, different pH ranges over which catalytic deacylation occurs, and different pH dependent profiles of deacylation rates for each form of t-PA. NSP’s pH dependent inhibition of t-PA is not accounted for by differential acylation, and is specific for the NSP-t-PA serpin-protease pair. These results demonstrate a novel mechanism for the differential regulation of the two forms of t-PA in the CNS, and suggest a potential specific regulatory role for CNS pH in controlling t-PA proteolytic activity. PMID:27378851

  2. 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.

  3. 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.

  4. 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.

  5. pH dependence on functional activity of human and mouse flavin-containing monooxygenase 5.

    PubMed

    Motika, Meike S; Zhang, Jun; Ralph, Erik C; Dwyer, Mary A; Cashman, John R

    2012-04-01

    Flavin-containing monooxygenase (FMO) 5 belongs to a family of enzymes that catalyze the oxygenation of nucleophilic N- and S-containing compounds. The FMO enzyme family consists of five forms (FMOs1-5) that share about 50-60% sequence identity to each other. A comparison of FMOs showed that the pH-dependence profile for functional activity of FMO5 differed significantly from that of other FMO enzymes. The objective of this study was to examine the pH-dependence of FMO5 to gain insight into the mechanism of action of FMO5. Recombinant mouse and human FMO5 (mFMO5 and hFMO5, respectively) were expressed as maltose-binding fusion proteins from Escherichia coli, purified with affinity chromatography, and examined for their N-oxygenation functional activity at different pH values. hFMO5 showed a broader range and greater functional activity from pH 6 to 11 compared to mFMO5. mFMO5 lost almost all functional activity at pH 6, while hFMO5 maintained almost normal enzyme activity. In order to identify the amino acid residues involved in the effects of pH on hFMO5 and mFMO5 functional enzyme activity, pH-studies in the range of pH 6-9 were done with chimeras of recombinant mouse and human FMO5 and variants of both. Results of these studies and molecular modeling showed that residues responsible for the differences in the pH profile between mFMO5 and hFMO5 were located at positions 227 and 228 of the enzyme. Further variants were made to investigate the role of these amino acids. The results of this study may help to explain the mechanism of FMO function. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. 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.

  7. Effects of phencyclidine on cardiac action potential: pH dependence and structure-activity relationships.

    PubMed

    D'Amico, G A; Kline, R P; Maayani, S; Weinstein, H; Kupersmith, J

    1983-04-08

    The effects of phencyclidine [1-(1-phenylcyclohexyl)-piperidine; PCP] on cardiac action potential duration (APD) were compared to those of some of its derivatives, in strips of isolated frog ventricular muscle perfused with normal Ringer solution. We studied compounds with PCP-like behavioral actions (N-ethyl-1-phenyl-cyclohexylamine: PCE; and m-amino-PCP) as well as behaviorally inactive analogs (m-nitro-PCP; the quaternary derivative PCP-methyl iodide; and various fragments of the PCP molecule). Exposure to PCP, 3 microM to 1 mM, produced reversible, dose- and pH-dependent prolongations, of the APD to over 100% above control. The observed effects of the drugs are compatible with a mechanism of blockade of potassium conductance. An intracellular site for this action is suggested by: (i) the inactivity of the quaternary analog; (ii) the marked increase in the potency of the compounds when the external pH is changed in the region of their respective pKa values to increase the concentration of the unionized species; and (iii) the pronounced acceleration of the termination of the PCP effect by washout with a series of buffer solutions with decreasing pH values. The rank order of potency of the compounds in lengthening APD (PCE greater than m-amino PCP greater than PCP much much greater than m-nitro-PCP) is the same as reported from other pharmacological studies of specific PCP actions, and matches the rank of behavioral activity of the drugs.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. Immunologic mechanisms of antitumor activity.

    PubMed

    Foss, Francine M

    2002-06-01

    The growth and metastatic spread of tumors, to a large extent, depends on their capacity to evade host immune surveillance and overcome host defenses. All tumors express antigens that are recognized to a variable extent by the immune system, but in many cases an inadequate immune response is elicited because of partial antigen masking or ineffective activation of effector cells. Tumor antigens presented in the context of major histocompatability antigen (MHC) class I complexes on either the tumor cell itself or on antigen-presenting cells are capable of inducing tumor-specific cytotoxic T lymphocytes. The presence of costimulatory molecules, such as B7-1 and B7-2, on antigen-presenting cells and the secretion of IL-2 promote the differentiation of recruited CD8+ lymphocytes into cytotoxic T lymphocytes. Tumor escape from immune effectors is most often caused by weak immunogenicity of tumor antigens, antigen masking, or overall immunosuppression, a characteristic of advanced cancer. Failure of antigen processing or binding to MHC molecules, inadequate or low-affinity binding of MHC complexes to T-cell receptors, or inadequate expression of costimulatory adhesion molecules in conjunction with the antigen-presenting MHC complex may all lead to poor immunogenicity of tumor-associated peptides and impaired antitumor response. Therapeutic interventions to augment tumor antigenicity include vaccination with immunogenic peptides, administration of in vitro expanded and activated immune effector cells, in vivo effector cell expansion with cytokine therapies, or genetic modification of either immune effectors or tumor cells with cytokine genes or genes encoding costimulatory molecules to effectively activate the immune response. Copyright 2002, Elsevier Science (USA). All rights reserved.

  14. Antitumor and antimetastatic activity of IL-23.

    PubMed

    Lo, Chia-Hui; Lee, Shan-Chih; Wu, Pin-Yi; Pan, Wen-Yu; Su, Jui; Cheng, Chao-Wen; Roffler, Steve R; Chiang, Bor-Luen; Lee, Chun-Nan; Wu, Cheng-Wen; Tao, Mi-Hua

    2003-07-15

    The structure and T cell stimulatory effects of the recently discovered cytokine IL-23 are similar to, but distinct from, those of IL-12. Although the antitumor activities of IL-12 are well characterized, the effect of IL-23 on tumor growth is not known. In this study, murine CT26 colon adenocarcinoma and B16F1 melanoma cells were engineered using retroviral vectors to release single-chain IL-23 (scIL-23) to evaluate its antitumor activity. In BALB/c mice, scIL-23-transduced CT26 cells grew progressively until day 26 to an average size of 521 +/- 333 mm(3), then the tumors started to regress in most animals, resulting in a final 70% rate of complete tumor rejection. scIL-23 transduction also significantly suppressed lung metastases of CT26 and B16F1 tumor cells. In addition, mice that rejected scIL-23-transduced tumors developed a memory response against subsequent wild-type tumor challenge. Compared with scIL-12-expressing CT26 cells, scIL-23-transduced tumors lacked the early response, but achieved comparable antitumor and antimetastatic activity. These results demonstrated that IL-23, like IL-12, provided effective protection against malignant diseases, but it probably acted by different antitumor mechanisms. As a first step in identifying these antitumor mechanisms, tumor challenge studies were performed in immunocompromised hosts and in animals selectively depleted of various lymphocyte populations. The results showed that CD8(+) T cells, but not CD4(+) T cells or NK cells, were crucial for the antitumor activity of IL-23.

  15. 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.

  16. 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.

  17. Antitumor activity of Annona squamosa seed oil.

    PubMed

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

    2016-12-04

    Custard apple (Annona squamosa Linn.) is an edible tropical fruit, and its seeds have been used to treat "malignant sore" (cancer) and other usage as insecticide. A comparison of extraction processes, chemical composition analysis and antitumor activity of A. squamosa seed oil (ASO) were investigated. The optimal extraction parameters of ASO were established by comparing percolation, soxhlet, ultrasonic and SFE-CO2 extraction methods. The chemical composition of fatty acid and content of total annonaceous acetogenins (ACGs) of ASO was investigated by GC-MS and colorimetric assay, and anti-tumor activity of ASO was tested using H22 xenografts bearing mice. The optimal extraction parameters of ASO were obtained as follows: using soxhlet extraction method with extraction solvent of petroleum ether, temperature of 80°C, and extraction time of 90min. Under these conditions, the yield of ASO was 22.65%. GC-MS analysis results showed that the main chemical compositions of fatty acid of ASO were palmitic acid (9.92%), linoleic acid (20.49%), oleic acid (56.50%) and stearic acid (9.14%). The total ACGs content in ASO was 41.00mg/g. ASO inhibited the growth of H22 tumor cells in mice with a maximum inhibitory rate of 53.54% by oral administration. Furthermore, it was found that ASO exerted an antitumor effect via decreasing interleukin-6 (IL-6), janus kinase (Jak) and phosphorylated signal transducers and activators of transcription (p-Stat3) expression. The results demonstrated that ASO suppressed the H22 solid tumor development may due to its main chemical constituents unsaturated fatty acid and ACGs via IL-6/Jak/Stat3 pathway. ASO may be a potential candidate for the treatment of cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. 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.

  19. 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

  20. 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.

  1. Alocasia cucullata Exhibits Strong Antitumor Effect In Vivo by Activating Antitumor Immunity

    PubMed Central

    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. PMID:24086508

  2. 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.

  3. 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.

  4. 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%.

  5. 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

  6. 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.

  7. pH Dependent synthesis of two isomeric dinuclear Cerium(II) complexes: Structures, DNA interactions, cytotoxic activity and apoptotic study.

    PubMed

    Gao, En-Jun; Su, Jun-Qi; Jin, Hai-Tao; Liu, Si-Jia; Zhao, Fu-Chen; Meng, Yang; Ma, Xiao-Yu; Ge, Jing; Sun, Ya-Guang; Zhang, Wanzhong; Zhu, Ming-Chang

    2017-05-01

    Two isomeric dinuclear Cerium(II) complexes 1 and 2, formulated as Ce2(phen)2(NO3)2(L)4 [L=phenylacetic acid, phen=1,10-phenanthroline] was synthesized under solvothermal conditions at different pH values. The two complexes were characterized by elemental analysis, IR and single crystal X-ray diffraction. Complexes 1 and 2 were studied the binding with DNA and against cytotoxic activity. Fluorescence analysis indicated that the two complexes can bind to DNA. The changes with different gradient concentration of DNA added into the complexes in absorption spectra show a strongπ-stacking interaction between the complexes and DNA base pairs. The Cerium(II) complexes showed good cytotoxic activity against cancer cell lines, being 2 the most potent complex. Apoptotic studies of the two novel dinuclear complexes showed significant inhibitory rate on cancer cell growth line KB. Copyright © 2017. Published by Elsevier B.V.

  8. 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.

  9. 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.

  10. Immunostimulatory properties and antitumor activities of glucans

    PubMed Central

    VANNUCCI, LUCA; KRIZAN, JIRI; SIMA, PETR; STAKHEEV, DMITRY; CAJA, FABIAN; RAJSIGLOVA, LENKA; HORAK, VRATISLAV; SAIEH, MUSTAFA

    2013-01-01

    New foods and natural biological modulators have recently become of scientific interest in the investigation of the value of traditional medical therapeutics. Glucans have an important part in this renewed interest. These fungal wall components are claimed to be useful for various medical purposes and they are obtained from medicinal mushrooms commonly used in traditional Oriental medicine. The immunotherapeutic properties of fungi extracts have been reported, including the enhancement of anticancer immunity responses. These properties are principally related to the stimulation of cells of the innate immune system. The discovery of specific receptors for glucans on dendritic cells (dectin-1), as well as interactions with other receptors, mainly expressed by innate immune cells (e.g., Toll-like receptors, complement receptor-3), have raised new attention toward these products as suitable therapeutic agents. We briefly review the characteristics of the glucans from mycelial walls as modulators of the immunity and their possible use as antitumor treatments. PMID:23739801

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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

  17. Targeting macrophage anti-tumor activity to suppress melanoma progression

    PubMed Central

    Yang, Luhong; Liu, Chengfang; Zhang, Qi; Zhang, Linjing

    2017-01-01

    By phagocytosing cancer cells and their cellular debris, macrophages play a critical role in nonspecific defense (innate immunity) and, as antigen presenters, they help initiate specific defense mechanisms (adaptive immunity). Malignant melanoma is a lethal disease due to its aggressive capacity for metastasis and resistance to therapy. For decades, considerable effort has gone into development of an effective immunotherapy for treatment of metastatic melanoma. In this review, we focus on the anti-tumor activities of macrophages in melanoma and their potential as therapeutic targets in melanoma. Although macrophages can be re-educated through intercellular signaling to promote tumor survival owing to their plasticity, we expect that targeting the anti-tumor activity of macrophages remains a promising strategy for melanoma inhibition. The combination of tumoricidal macrophage activation and other treatments such as surgery, chemotherapy, and radiotherapy, may provide an effective and comprehensive anti-melanoma strategy. PMID:28060744

  18. 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.

  19. 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

  20. Synthesis and in vitro antitumor activity of novel scopoletin derivatives.

    PubMed

    Liu, Wukun; Hua, Jie; Zhou, Jinpei; Zhang, Huibin; Zhu, Haiyang; Cheng, Yanhua; Gust, Ronald

    2012-08-01

    Twenty scopoletin derivatives were developed by a systematic combinatorial chemical approach and their chemical structures were confirmed by MS, IR, (1)H NMR spectra and elemental analysis. Primary screening against mammary (MCF-7 and MDA-MB 231) and colon (HT-29) carcinoma cells indicated that five compounds (8d, 8g, 8j, 11b and 11g) displayed high antitumor potencies with IC(50) values below 20 μM whereas scopoletin showed IC(50) values above 100 μM. Moreover, the most promising compound 11g was more active than 5-fluorouracil. These results clearly indicated that the modification of the scopoletin structure could greatly increase its antitumor activity in vitro. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. 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.

  2. Immunomodulatory and antitumor activities of grape seed proanthocyanidins.

    PubMed

    Tong, Haibin; Song, Xiangfu; Sun, Xin; Sun, Guangren; Du, Fengfuo

    2011-11-09

    Proanthocyanidins are naturally occurring compounds that are widely available in many kinds of plants; particularly, the grape seeds are a rich source of proanthocyanidins. Grape seed proanthocyanidins (GSPs) have been demonstrated to possess a wide range of health beneficial properties. This study was carried out to elucidate the molecular mechanisms involved in the antitumor therapeutic and immunomodulating effects of GSPs through in vivo and in vitro models. The results showed that GSPs could significantly inhibit the growth of Sarcoma 180 tumor cells in vivo and remarkably increase thymus and spleen weight of Sarcoma 180-bearing mice and upgrade the secretion level of tumor necrosis factor-α (TNF-α) in serum. Moreover, GSPs could stimulate lymphocyte transformation, enhance lysosomal enzyme activity and phagocytic capability of peritoneal macrophages, and remarkably promote the production of TNF-α. These results suggested that GSPs could improve functional activation of the immune system, and the antitumor effects of GSPs were achieved by immunostimulating properties.

  3. Polysaccharides from Cymbopogon citratus with antitumor and immunomodulatory activity.

    PubMed

    Bao, Xiao-Li; Yuan, Hui-Hui; Wang, Cheng-Zhong; Fan, Wei; Lan, Min-Bo

    2015-01-01

    Abstract Context: Most of the present studies on the antitumor efficiency of Cymbopogon citratus (DC.) Stapf (Gramineae) are limited to its low-mass compounds, and little information about the antitumor activity of polysaccharides from this plant is available. This study focused on the potential antitumor and immunomodulatory activities of polysaccharides (CCPS) from C. citratus. CCPS was isolated using the water extraction-ethanol precipitation method. The sarcoma 180 (S180) cells-inoculated mice were intraperitoneally administrated with CCPS (30-200 mg/kg/d) for seven consecutive days. The effects of CCPS on tumor growth, thymus and spleen weights, splenocyte proliferation, and cytokine secretion in the tumor-bearing mice were measured. The cytotoxicity of CCPS (50-800 μg/mL) towards S180 cells was also studied. CCPS significantly inhibited the growth of the transplanted S180 tumors, with the inhibition rates ranging from 14.8 to 37.8%. Simultaneously, CCPS dose-dependently improved the immunity of the tumor-bearing mice. With the highest dose of 200 mg/kg/d, the thymus and spleen indices were increased by 21.9 and 91.9%, respectively; ConA- and LSP-induced splenocyte proliferations were increased by 32.7 and 35.3%, respectively. The secretions of interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 2 (IL-12), and tumor necrosis factor-α (TNF-α) were increased by 103.2, 40.2, 23.6, and 26.3%, respectively. Nevertheless, almost no toxicity of CCPS towards S180 cells was observed, with the maximal inhibition rate less than 15% at the CCPS concentration of 800 μg/mL. CCPS exhibited antitumor activity in vivo, and this activity might be achieved by immunoenhancement rather than direct cytotoxicity.

  4. 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.

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

    PubMed

    Wang, Xiaoqin; Zhang, Xuewu

    2013-01-01

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

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. Reovirus activates human dendritic cells to promote innate antitumor immunity.

    PubMed

    Errington, Fiona; Steele, Lynette; Prestwich, Robin; Harrington, Kevin J; Pandha, Hardev S; Vidal, Laura; de Bono, Johann; Selby, Peter; Coffey, Matt; Vile, Richard; Melcher, Alan

    2008-05-01

    Oncolytic viruses can exert their antitumor activity via direct oncolysis or activation of antitumor immunity. Although reovirus is currently under clinical investigation for the treatment of localized or disseminated cancer, any potential immune contribution to its efficacy has not been addressed. This is the first study to investigate the ability of reovirus to activate human dendritic cells (DC), key regulators of both innate and adaptive immune responses. Reovirus induced DC maturation and stimulated the production of the proinflammatory cytokines IFN-alpha, TNF-alpha, IL-12p70, and IL-6. Activation of DC by reovirus was not dependent on viral replication, while cytokine production (but not phenotypic maturation) was inhibited by blockade of PKR and NF-kappaB signaling. Upon coculture with autologous NK cells, reovirus-activated DC up-regulated IFN-gamma production and increased NK cytolytic activity. Moreover, short-term coculture of reovirus-activated DC with autologous T cells also enhanced T cell cytokine secretion (IL-2 and IFN-gamma) and induced non-Ag restricted tumor cell killing. These data demonstrate for the first time that reovirus directly activates human DC and that reovirus-activated DC stimulate innate killing by not only NK cells, but also T cells, suggesting a novel potential role for T cells in oncolytic virus-induced local tumor cell death. Hence reovirus recognition by DC may trigger innate effector mechanisms to complement the virus's direct cytotoxicity, potentially enhancing the efficacy of reovirus as a therapeutic agent.

  11. 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.

  12. 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.

  13. 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.

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

    PubMed

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

    2016-06-10

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

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. Leukaemomycin, in antibiotic with antitumor activity. II. Isolation and identification.

    PubMed

    Strauss, D; Fleck, W

    1975-01-01

    A Streptomyces strain belonging to Streptomyces griseus (Krainsky) Waksman et Henrici 1948 sensu Hütter (1967) was found to produce the red-pigment antibiotic leukaemomycin. The antitumor active antibiotic was isolated from the culture broth and purified by ion-exchange processes. The crude base of leukaemomycin mainly consists of 4 components with biological activity. The base-complex was separated by counter-current distribution into the biological active leukaemomycins B1, B2, C, and D. The single components of leukaemomycin were compared with the anthracycline antibiotics daunomycin, dihydrodaunomycin, and adriamycin. The analytical procedures allowed to state the identity of leukaemomycin B1 with rubomycin B, leukaemomycin C with daunomycin, leukaemomycin D with dihydrodaunomycin and allowed to suggest the identity of leukaemomycin B2 with daunosaminyldaunomycin. Formulas and physicochemical data are given. Bio-assay methods are described to determine leukaemomycin B complex beside leukaemomycin C.

  3. Antitumor activities of D-glucosamine and its derivatives*

    PubMed Central

    Zhang, Li; Liu, Wan-shun; Han, Bao-qin; Peng, Yan-fei; Wang, Dong-feng

    2006-01-01

    The growth inhibitory effects of D-glucosamine hydrochloride (GlcNH2·HCl), D-glucosamine (GlcNH2) and N-acetyl glucosamine (NAG) on human hepatoma SMMC-7721 cells in vitro were investigated. The results showed that GlcNH2·HCl and GlcNH2 resulted in a concentration-dependent reduction in hepatoma cell growth as measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. This effect was accompanied by a marked increase in the proportion of S cells as analyzed by flow cytometry. In addition, human hepatoma SMMC-7721 cells treated with GlcNH2·HCl resulted in the induction of apoptosis as assayed qualitatively by agarose gel electrophoresis. NAG could not inhibit the proliferation of SMMC-7721 cells. GlcNH2·HCl exhibited antitumor activity against Sarcoma 180 in Kunming mice at dosage of 125~500 mg/kg, dose of 250 mg/kg being the best. GlcNH2·HCl at dose of 250 mg/kg could enhance significantly the thymus index, and spleen index and could promote T lymphocyte proliferation induced by ConA. The antitumor effect of GlcNH2·HCl is probably host-mediated and cytocidal. PMID:16845712

  4. 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.

  5. 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.

  6. Melissa officinalis L. essential oil: antitumoral and antioxidant activities.

    PubMed

    de Sousa, Allyne Carvalho; Alviano, Daniela Sales; Blank, Arie Fitzgerald; Alves, Péricles Barreto; Alviano, Celuta Sales; Gattass, Cerli Rocha

    2004-05-01

    Melissa officinalis L (lemon balm) is a traditional herbal medicine used widely as a mild sedative, spasmolytic and antibacterial agent. This paper focuses on the analysis of the chemical composition and the biological activities of M. officinalis essential oil obtained under controlled harvesting and drying conditions. An in-vitro cytotoxicity assay using MTT indicated that this oil was very effective against a series of human cancer cell lines (A549, MCF-7, Caco-2, HL-60, K562) and a mouse cell line (B16F10). This oil possessed antioxidant activity, as evidenced by reduction of 1,1-diphenyl-2-picryl-hydrazyl (DPPH). These results pointed to the potential use of M. officinalis essential oil as an antitumoral agent.

  7. 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.

  8. IL-37 mediates the antitumor activity in renal cell carcinoma.

    PubMed

    Jiang, Yazhuo; Wang, Yili; Liang, Liang; Gao, Yang; Chen, Juan; Sun, Yi; Cheng, Yongyi; Xu, Yonggang

    2015-11-01

    Interleukin (IL)-37 is a natural suppressor of innate inflammatory and immune responses. IL-37 plays an important role in renal function and antitumor activity. The aim of this study was to investigate the role of IL-37 in renal cell carcinoma (Rcc). Serum IL-37 levels in 120 Rcc patients and 50 healthy controls were measured by enzyme-linked immunosorbent assay (ELISA). The Rcc cell lines A498 and Caki-1 were cultured with 0-100 ng/mL of recombinant human IL-37 protein (rhIL-37). Cancer cells were transfected with or without pcDNA3.1-IL-6 to alter IL-6 expression. Cell migration, proliferation, and apoptosis were tested by wound-healing assay, MTT, and flow cytometry, respectively. Levels of IL-6, pSTAT3 Y705, Bcl-2, cyclin D1, and HIF-1α were detected by qRT-PCR, ELISA, or western blot. Additionally, therapeutic effect of rhIL-37 was also confirmed in SCID mice. The expression of IL-37 was decreased in Rcc patients and was negatively correlated with tumor progression. In vitro, IL-37 markedly inhibited the migration and proliferation, and promoted apoptosis in Rcc cells. Furthermore, the expressions of IL-6, pSTAT3 Y705, HIF-1α, Bcl-2, and cyclin D1 were decreased by IL-37. However, these effects were reversed by the transfection of pcDNA3.1-IL-6. In vivo, tumor growth and gene expressions of IL-6 and HIF-1α were suppressed by IL-37. In conclusion, IL-37 might serve as a novel tumor suppressor in Rcc and exert its antitumor activity through inhibiting IL-6/STAT3 signaling.

  9. Antitumor and antiviral activity of Colombian medicinal plant extracts.

    PubMed

    Betancur-Galvis, L; Saez, J; Granados, H; Salazar, A; Ossa, J

    1999-01-01

    Extracts of nine species of plants traditionally used in Colombia for the treatment of a variety of diseases were tested in vitro for their potential antitumor (cytotoxicity) and antiherpetic activity. MTT (Tetrazolium blue) and Neutral Red colorimetric assays were used to evaluate the reduction of viability of cell cultures in presence and absence of the extracts. MTT was also used to evaluate the effects of the extracts on the lytic activity of herpes simplex virus type 2 (HSV-2). The 50% cytotoxic concentration (CC50) and the 50% inhibitory concentration of the viral effect (EC50) for each extract were calculated by linear regression analysis. Extracts from Annona muricata, A. cherimolia and Rollinia membranacea, known for their cytotoxicity were used as positive controls. Likewise, acyclovir and heparin were used as positive controls of antiherpetic activity. Methanolic extract from Annona sp. on HEp-2 cells presented a CC50 value at 72 hr of 49.6x10(3)mg/ml. Neither of the other extracts examined showed a significant cytotoxicity. The aqueous extract from Beta vulgaris, the ethanol extract from Callisia grasilis and the methanol extract Annona sp. showed some antiherpetic activity with acceptable therapeutic indexes (the ratio of CC50 to EC50). These species are good candidates for further activity-monitored fractionation to identify active principles.

  10. 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. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. 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.

  12. 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.

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

    PubMed Central

    Li, Hui

    2017-01-01

    Microbial transformation can strengthen the antioxidant and antitumor activities of polyphenols. Polyphenols contents, antioxidant and antitumor activities of pine polyphenols and its biotransformation extracts by Aspergillus niger, Aspergillus oryzae, Aspergillus carbonarius, Aspergillus candidus, Trichodermas viride, Mucor wutungkiao and Rhizopus sp were studied. Significant differences were noted in antioxidant and antitumor activities. The highest antioxidant activities in Trolox equivalent antioxidant capacity (TEAC), DPPH radical scavenging activity, superoxide anion radical scavenging activity, hydroxyl radical scavenging activity, reducing power assay and antitumor activity against LoVo cells were biotransformation extract of Aspergillus carbonarius (BAC), biotransformation extract of Mucor wutungkiao (BMW), biotransformation extract of Aspergillus carbonarius (BAC), biotransformation extract of Aspergillus niger (BAN), biotransformation extract of Aspergillus oryzae (BAO) and BMW, respectively. Correlation analysis found that antioxidant and antitumor activities were associated with polyphenols contents and types of free radicals and tumors. A. carbonarius can make polyphenol oxidation, hydroxylation and methylation, and form new polyphenols. In conclusion, A. carbonarius, A. niger and M. wutungkiao are valuable microorganisms used for polyphenols biotransformation and enhance the antioxidant and antitumor activities of polyphenols. PMID:28560092

  14. Immunomodulating and Antitumor Activities of Panellus serotinus Polysaccharides

    PubMed Central

    Kim, Jeong Hwa; Lee, Jae Seong; Lee, Kyung Rim; Shim, Mi Ja; Lee, Min Woong; Shin, Pyung Gyun; Cheong, Jong Chun; Yoo, Young Bok

    2012-01-01

    This study was initiated in order to investigate the anticancer and immunomodulating activities of crude polysaccharides extracted in methanol, neutral saline, and hot water (hereinafter referred to as Fr. MeOH, Fr. NaCl, and Fr. HW, respectively) from the fruiting bodies of Panellus serotinus. Content of β-glucan and protein in Fr. MeOH, Fr. NaCl, and Fr. HW extracts of P. serotinus ranged from 22.92~28.52 g/100 g and 3.24~3.68 g/100 g, respectively. In vitro cytotoxicity tests, none of the various fractions of crude polysaccharides were cytotoxic against sarcoma 180, HT-29, NIH3T3, and RAW 264.7 cell lines at the tested concentration. Intraperitoneal injection with crude polysaccharides resulted in a life prolongation effect of 23.53~44.71% in mice previously inoculated with sarcoma 180. Treatment with Fr. HW resulted in an increase in the numbers of spleen cells by 1.3 fold at the concentration of 50 µg/mL compared with control. Treatment with Fr. NaCl resulted in improvement of the immuno-potentiating activity of B lymphocytes by increasing the alkaline phosphatase activity by 1.4 fold, compared with control, at the concentration of 200 µg/mL. Among the three fractions, maximum nitric oxide (13.48 µM) was recorded at 500 µg/mL in Fr. HW. Production of tumor necrosis factor alpha, interleukin-1β, and interleukin-6 was significantly higher, compared to the positive control, concanavalin A, at the tested concentration. Therefore, treatment with crude polysaccharides extracted from the fruiting body of P. serotinus could result in improvement of antitumor activity. PMID:23115511

  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. 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.

  17. 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.

  18. 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.

  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. 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

  1. Study of Antitumor Activity of Sodium Phenylbutyrate, Histon Deacetylase Inhibitor, on Ehrlich Carcinoma Model.

    PubMed

    Fadeev, N P; Kharisov, R I; Kovan'ko, E G; Pustovalov, Yu I

    2015-09-01

    Antitumor activity of sodium phenylbutyrate was studied on 120 outbred female mice with transplanted Ehrlich ascites carcinoma. The animals received the drug in doses of 400, 800, and 1200 mg/kg with drinking water daily for 21 days. The antitumor effect was evaluated by tumor growth inhibition and lifespan prolongation. Phenylbutyrate in the dose of 800 mg/kg was most effective. The drug inhibited the tumor growth by 71%, prolonged the lifespan of animals by 28, and was low-toxic.

  2. 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.

  3. 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.

  4. PH Dependent Interactions between Aqueous Iodide Ion and Selected Oxidizers.

    DTIC Science & Technology

    1985-12-06

    between the oxidizers oeroxydisultte, peroxide. percarbonate, and perborate ions and aqueous iodide have been measured at pH 1. 4. 7, 9. Reactions were... Perborate and percarbonate are salts with "hydrogen peroxide of crystallization" (see formulae listed in Table i). These salts appear to release this...between hydrogen peroxide and iodide are highly pH dependent. These materials react very slowly, or not at all, at pH 49. 2). Perborate and percarbonate are

  5. CRISPR knock out CTLA-4 enhances the anti-tumor activity of cytotoxic T lymphocytes.

    PubMed

    Shi, Long; Meng, Tongyu; Zhao, Zhilong; Han, Jinsheng; Zhang, Wei; Gao, Fei; Cai, Jianhui

    2017-09-06

    T cell-mediated anti-tumor immunity plays a pivotal role in cancer immune surveillance. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a protein receptor mainly expressed in activated T cells and regulatory T cells. CTLA-4 competes with CD28 for ligand binding and generates inhibitory signals to attenuate T cell activation. The blockade of CTLA-4 mediated immune inhibitory checkpoint has been associated with enhanced anti-tumor immunity. In this study, we use CRISPR-Cas9 system to knock out (KO) CTLA-4 from cytotoxic T lymphocytes (CTLs) and evaluate its effect on the anti-tumor activity of the CTLs. CTLA-4 KO CTLs robustly enhanced tumor cell death by 40% compared to the control and facilitated apoptosis and caspase activities in tumor cells. The knockout of CTLA-4 also increased TNF-α and IFN-γ secretion of the CTLs by approximately 2-fold. The effectiveness of CTLA-4 KO in enhancing anti-tumor activity of the CTLs was verified in vivo using mouse xenograft model. The xenografted mice treated with CTLA-4 KO CTLs demonstrated repressed tumor growth and prolonged survival compared to the control group. Our data suggest that CRISPR targeting CTLA-4 immune checkpoint could significantly improve the anti-tumor activity of CTLs. Copyright © 2017. Published by Elsevier B.V.

  6. Cytotoxic and antitumor activities of a polypore macrofungus, Phellinus rimosus (Berk) Pilat.

    PubMed

    Ajith, T A; Janardhanan, K K

    2003-02-01

    Cytotoxic and antitumor activities of ethyl acetate, methanol and aqueous extracts of a wood inhabiting polypore macrofungus, Phellinus rimosus (Berk) Pilat. were studied. Ethyl acetate and methanol extracts showed in vitro cytotoxic activity against Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines. The aqueous extract did not exhibit cytotoxicity against the tested cell lines. All the three extracts were highly effective in inhibiting growth of solid tumor induced by DLA cell line in mice. However, the antitumor activity of ethyl acetate extract was higher than that of methanol and aqueous extracts. The ethyl acetate extract was also effective in preventing the EAC induced ascites tumor development in mice. The antitumor activity of all the three extracts against solid tumor at a dose of 50 mg/kg (p.o.) was comparable to the clinically used standard reference drug, cisplatin (4 mg/kg, i.p.). Pre-treatment of the extracts was also effective in inhibiting the tumor growth induced by DLA cell lines. The experimental results revealed that ethyl acetate extract of P. rimosus possessed significant antitumor activity. The findings thus suggest the potential use of this mushroom as antitumor agent. Copyright 2002 Elsevier Science Ireland Ltd.

  7. Isolation and characterization of polysaccharides with the antitumor activity from Tuber fruiting bodies and fermentation system.

    PubMed

    Zhao, Wei; Wang, Xiao-Hua; Li, Hong-Mei; Wang, Shi-Hua; Chen, Tao; Yuan, Zhan-Peng; Tang, Ya-Jie

    2014-03-01

    Fifty-two polysaccharides were isolated from the fermentation systems of Tuber melanosporum, Tuber indicum, Tuber sinense, Tuber aestivum and the fruiting bodies of Tuber indicum, Tuber himalayense, Tuber sinense by elution with an activated carbon column. Polysaccharides from Tuber fermentation system exhibited relatively higher in vitro antitumor activity against HepG2, A549, HCT-116, SK-BR-3, and HL-60 cells than those from Tuber fruiting bodies. All polysaccharides were mainly composed of D-mannose, D-glucose, and D-galactose, which suggested that the polysaccharides from Tuber fruiting bodies and fermentation system have identical chemical compositions. The results of antitumor activity and structural identification indicated that the polysaccharide fractions could promote antitumor activity. Tuber polysaccharides from Tuber fermentation system exhibited relatively higher than that from Tuber fruiting bodies. These results confirm the potential of Tuber fermentation mycelia for use as an alternative resource for its fruiting bodies.

  8. 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.

  9. Isatin-β-thiocarbohydrazones: Microwave-assisted synthesis, antitumor activity and structure-activity relationship.

    PubMed

    Gabr, Moustafa T; El-Gohary, Nadia S; El-Bendary, Eman R; El-Kerdawy, Mohamed M; Ni, Nanting

    2017-03-10

    A new series of isatin-β-thiocarbohydrazones was synthesized based on the pharmacophoric features of triapine required for metal chelation. Our strategy involved the modifications of triapine basic skeleton by replacing pyridinyl moiety with isatin which retains the tridentate feature of triapine needed for metal chelation. The new compounds were esteemed for their antitumor efficacy against cervical cancer (Hela) and kidney fibroblast cancer (COS-7) cell lines. Compounds 4c, 4d, 5c and 5e exhibited remarkable efficacy against Hela cell line. In addition, compounds 4c, 4k, 4e, 5c and 5e displayed an outstanding efficacy against COS-7 cell line. Compounds 4c, 4k, 4e, 5c and 5e were examined for their in vivo antitumor efficacy against Ehrlich ascites carcinoma (EAC) in mice. Pharmacophore mapping was performed to study the structural features of the synthesized compounds compared to triapine and to identify the essential moieties required for potent and selective antitumor activity. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. 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

  11. 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.

  12. 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.

  13. Antitumor activity in mice of orally administered polysaccharide from Kefir grain.

    PubMed

    Shiomi, M; Sasaki, K; Murofushi, M; Aibara, K

    1982-04-01

    The antitumor activity of a water-soluble polysaccharide (KGF-C), isolated from the Kefir grain, was studied in the mice subcutaneously inoculated with Ehrlich carcinoma (EC) or Sarcoma 180 (S-180). The growth of EC and S-180 solid tumor was inhibited by 40-59% and 21-81%, respectively, by oral administration of KGF-C as compared with the unadministered mice. The tumor growth was similarly inhibited by intraperitoneal administration. The mechanism of the antitumor activity of KGF-C was considered to be host-mediated because of the lack of direct in vitro effect on tumor cells.

  14. Chemical analyses and antitumor activity of hydrosoluble substances from Mycobacterium bovis, strain BCG.

    PubMed

    Sato, H; Arai, H; Nagai, H; Ito, M; Satoh, K; Kumano, N; Motomiya, M; Konno, K

    1983-05-01

    Hydrosoluble substances from BCG were prepared by cold water extraction and by hot phenol-water extraction. Chemical analyses revealed that both of them were derived from cytoplasm. The cold water extract (CWE) was effective in the treatment of C3H/He mice which had received an intraperitoneal inoculation of a syngeneic ascites hepatoma, MH134. The growth of a graft in footpad of mastocytoma P815 in CDF1 mice was retarded by intraperitoneal injections of CWE. A peptidoglycan from cell wall prepared by digestion with lysozyme exerted no antitumor activity in the same experimental condition as for the evaluation of antitumor effect of CWE. These results indicate that the antitumor activity of CWE was not due to the presence of a cell wall component.

  15. 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

  16. 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

  17. 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

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

    PubMed

    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.

  19. 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.

  20. Antitumor and Antimicrobial Activity of Some Cyclic Tetrapeptides and Tripeptides Derived from Marine Bacteria

    PubMed Central

    Chakraborty, Subrata; Tai, Dar-Fu; Lin, Yi-Chun; Chiou, Tzyy-Wen

    2015-01-01

    Marine derived cyclo(Gly-l-Ser-l-Pro-l-Glu) was selected as a lead to evaluate antitumor-antibiotic activity. Histidine was chosen to replace the serine residue to form cyclo(Gly-l-His-l-Pro-l-Glu). Cyclic tetrapeptides (CtetPs) were then synthesized using a solution phase method, and subjected to antitumor and antibiotic assays. The benzyl group protected CtetPs derivatives, showed better activity against antibiotic-resistant Staphylococcus aureus in the range of 60–120 μM. Benzyl group protected CtetPs 3 and 4, exhibited antitumor activity against several cell lines at a concentration of 80–108 μM. However, shortening the size of the ring to the cyclic tripeptide (CtriP) scaffold, cyclo(Gly-l-Ser-l-Pro), cyclo(Ser-l-Pro-l-Glu) and their analogues showed no antibiotic or antitumor activity. This phenomenon can be explained from their backbone structures. PMID:25988520

  1. 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

  2. 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.

  3. 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.

  4. [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.

  5. Synergistic antitumor activity of immune strategies combined with radiation.

    PubMed

    Sharp, Hadley J; Wansley, Elizabeth K; Garnett, Charlie T; Chakraborty, Mala; Camphausen, Kevin; Schlom, Jeffrey; Hodge, James W

    2007-09-01

    Since its discovery more than a hundred years ago, radiation has been used to treat cancer. In recent decades, advances in radiation technology have expanded the role and value of radiation in imaging and treating many forms of cancer. Currently, there is a growing interest in combining radiation with other modalities, such as immunotherapy, to treat a broad range of malignancies. This article reviews the use of standard and novel combinations of radiation therapy and immunotherapy to eradicate tumor cells. The combination of radiation therapy and immunotherapy holds particular promise as a strategy for cancer therapeutics for a variety of reasons. First, there is evidence that immunotherapy is most beneficial when employed early in the disease process and in combination with standard therapies. In addition, radiation may act synergistically with immunotherapy to enhance immune responses, inhibit immunosuppression, and/or alter the phenotype of tumor cells, thus rendering them more susceptible to immune-mediated killing. Finally, as monotherapies, both immunotherapy and radiation may be insufficient to eliminate tumor masses. However, following immunization with a cancer vaccine, the destruction of even a small percentage of tumor cells by radiation could result in cross-priming and presentation of tumor antigens to the immune system, thereby potentiating antitumor responses.

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

    PubMed

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

    2017-06-21

    Psidium guajava L., a species native to South America, has been widely cultivated in the tropical and subtropical areas of China for its popular fruits. The preliminary analysis by liquid chromatography-ultraviolet (LC-UV) indicated the presence of meroterpenoids in the fruits of P. guajava (guava). Subsequent fractionation of the petroleum ether extract resulted in the identification of two new meroterpenoids, psiguajavadials A (1) and B (2), together with 14 previously described meroterpenoids (3-16). Their structures were fully elucidated by comprehensive spectroscopic techniques and theoretical calculations. All of the meroterpenoids showed cytotoxicities against five human cancer cell lines, with guajadial B (12) being the most effective having an IC50 value of 150 nM toward A549 cells. Furthermore, biochemical topoisomerase I (Top1) assay revealed that psiguajavadial A (1), psiguajavadial B (2), guajadial B (12), guajadial C (14), and guajadial F (16) acted as Top1 catalytic inhibitors and delayed Top1 poison-mediated DNA damage. The flow cytometric analysis indicated that the new meroterpenoids psiguajavadials A (1) and B (2) could induce apoptosis of HCT116 cells. These data suggest that meroterpenoids from guava fruit could be used for the development of antitumor agents.

  7. [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).

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

    PubMed

    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.

  9. 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

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. Leukaemomycin, an antibiotic with antitumor activity. I. Screening, fermentation, and biological activity.

    PubMed

    Fleck, W; Strauss, D

    1975-01-01

    A Streptomyces strain belonging to S. griseus (Krainski) Waksman et Henrici 1948 sensu Hütter (1967) was found to produce an antibiotic designated as leukaemomycin. The red-pigment antibiotic, having antimicrobial and antitumor activity in vitro and in vivo, was isolated from C-, N-, and Fe-containing cultures of the strains IMET JA 3933, IMET JA 5570, IMET JA 10086, and IMET JA 10431. Leukaemomycin has indicator properties and is produced by the classic procedures of submerged fermentation. The crude base of leukaemomycin consists of 4 main components, designated as leukaemomycin A, B, C, and D. The biological activity of the main components leukaemomycin B and C was compared. The biological activity and the physicochemical properties of leukaemomycin C are identical with known properties of the anthracycline antibiotic daunorubicin.

  16. 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

  17. 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.

  18. [Pharmacological study on kefir--a fermented milk product in Caucasus. I. On antitumor activity (1)].

    PubMed

    Kubo, M; Odani, T; Nakamura, S; Tokumaru, S; Matsuda, H

    1992-07-01

    The antitumor activity of kefir (YK-1), a fermented milk product in Caucasus, was investigated. YK-1 at oral doses of 100 or 500 mg/kg inhibited the proliferation of solid tumor of Ehrlich ascites carcinoma transplanted subcutaneously in mice. YK-1 did not show an inhibitory effect on the ear swelling induced contact dermatitis caused by picryl chloride (PC-CD). However, YK-1 inhibited the immunosuppression in Ehrlich carcinoma-bearing mice and with the frozen and dried ascites of the tumor-bearing mice containing immunosuppressive substances (EC-sup) in PC-CD-induced mice. And also, YK-1 activated the immunosuppressive activity of spleen cells of mouse treated with EC-sup. These results suggest that YK-1 may have antitumor activity against Ehrlich carcinoma and activate the immunosuppression with it.

  19. A novel cationic lipid with intrinsic antitumor activity to facilitate gene therapy of TRAIL DNA.

    PubMed

    Luo, Cong; Miao, Lei; Zhao, Yi; Musetti, Sara; Wang, Yuhua; Shi, Kai; Huang, Leaf

    2016-09-01

    Metformin (dimethylbiguanide) has been found to be effective for the treatment of a wide range of cancer. Herein, a novel lipid (1,2-di-(9Z-octadecenoyl)-3-biguanide-propane (DOBP)) was elaborately designed by utilizing biguanide as the cationic head group. This novel cationic lipid was intended to act as a gene carrier with intrinsic antitumor activity. When compared with 1,2-di-(9Z-octadecenoyl)-3-trimethylammonium-propane (DOTAP), a commercially available cationic lipid with a similar structure, the blank liposomes consisting of DOBP showed much more potent antitumor effects than DOTAP in human lung tumor xenografts, following an antitumor mechanism similar to metformin. Given its cationic head group, biguanide, DOBP could encapsulate TNF-related apoptosis-inducing ligand (TRAIL) plasmids into Lipid-Protamine-DNA (LPD) nanoparticles (NPs) for systemic gene delivery. DOBP-LPD-TRAIL NPs demonstrated distinct superiority in delaying tumor progression over DOTAP-LPD-TRAIL NPs, due to the intrinsic antitumor activity combined with TRAIL-induced apoptosis in the tumor. These results indicate that DOBP could be used as a versatile and promising cationic lipid for improving the therapeutic index of gene therapy in cancer treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. Design, synthesis and antitumor activity of Novel Sorafenib derivatives bearing pyrazole scaffold.

    PubMed

    Wang, Min; Xu, Shan; Lei, Huajun; Wang, Caolin; Xiao, Zhen; Jia, Shuang; Zhi, Jia; Zheng, Pengwu; Zhu, Wufu

    2017-09-06

    Four series of Sorafenib derivatives bearing pyrazole scaffold (8a-m, 9a-c, 10a-e and 11a) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR, BRAF, CRAF, c-Met, EGFR and Flt-3 kinases. Compounds 8b and 8i were more active than that of compounds 8h, 9a, especially the IC50 value of compounds 8b on VEGFR-2 kinase was 0.56μM. And compound 8b exhibited moderate to good activity toward c-Met and showed moderate to no activity against CRAF, c-Met, EGFR, Flt-3 kinases. Eleven of the target compounds exhibited moderate to good antitumor activities. The most promising compound 8b showed strong antitumor activities against A549, HepG2 and MCF-7 cell lines with IC50 values of 2.84±0.78μM, 1.85±0.03μM and 1.96±0.28μM, which were equivalent to Sorafenib (2.92±0.68μM, 3.44±0.50μM and 3.18±0.18μM). Structure-activity relationships (SARs) and docking studies indicated that the pyrazole scaffolds exerted key effect on antitumor activities of target compounds. Substitutions of aryl group at C-3 positions had a significant impact on the antitumor activities, and 3-Br substitution produced the best potency. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Icariin potentiates the antitumor activity of gemcitabine in gallbladder cancer by suppressing NF-κB

    PubMed Central

    Zhang, Dian-cai; Liu, Jin-long; Ding, Yong-bin; Xia, Jian-guo; Chen, Guo-yu

    2013-01-01

    Aim: Gemcitabine has been increasingly prescribed for the treatment of gallbladder cancer. However, the response rate is low. The aim of this study is to determine whether icariin, a flavonoid isolated from Epimedi herba, could potentiate the antitumor activity of gemcitabine in gallbladder cancer. Methods: Human gallbladder carcinoma cell lines GBC-SD and SGC-996 were tested. Cell proliferation and apoptosis were analyzed using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related molecules was detected with Western blotting. Caspase-3 activity was analyzed using colorimetric assay, and NF-κB activity was measured with ELISA. A gallbladder cancer xenograft model was established in female BALB/c (nu/nu) mice. The mice were intraperitoneally administered gemcitabine (125 mg/kg) in combination with icariin (40 mg/kg) for 2 weeks. Results: Icariin (40–160 μg/mL) dose-dependently suppressed cell proliferation and induced apoptosis in both GBC-SD and SGC-996 cells, with SGC-996 cells being less sensitive to the drug. Icariin (40 μg/mL) significantly enhanced the antitumor activity of gemcitabine (0.5 μmol/L) in both GBC-SD and SGC-996 cells. The mice bearing gallbladder cancer xenograft treated with gemcitabine in combination with icariin exhibited significantly smaller tumor size than the mice treated with either drug alone. In GBC-SD cells, icariin significantly inhibited both the constitutive and gemcitabine-induced NF-κB activity, enhanced caspase-3 activity, induced G0-G1 phase arrest, and suppressed the expression of Bcl-2, Bcl-xL and surviving proteins. Conclusion: Icariin, by suppressing NF-κB activity, exerts antitumor activity, and potentiates the antitumor activity of gemcitabine in gallbladder cancer. Combined administration of gemcitabine and icariin may offer a better therapeutic option for the patients with gallbladder cancer. PMID:23274410

  6. 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.

  7. Antitumor effect of synergistic contribution of nitrite and hydrogen peroxide in the plasma activated medium

    NASA Astrophysics Data System (ADS)

    Kurake, Naoyuki; Tanaka, Hiromasa; Ishikawa, Kenji; Nakamura, Kae; Kajiyama, Hiroaki; Kikkawa, Fumiaki; Kondo, Takashi; Mizuno, Masaaki; Takeda, Keigo; Kondo, Hiroki; Sekine, Makoto; Hori, Masaru

    2015-09-01

    Non-equilibrium atmospheric pressure plasmas (NEAPP) have been attracted attention in the noble application of cancer therapy. Although good effects of the Plasma-Activated-Medium (PAM) such as the selective antitumor effect and killing effect for the anticancer agent resistant cells were reported, a mechanism of this effect has not been still clarified yet. In this study, we have investigated a contribution of the reactive nitrogen and oxygen species (RNOS) generated in PAM such as hydrogen peroxide and nitrite. Those species generated in the PAM quantitatively measured by light absorbance of commercial regent. Moreover, viable cell count after cell culture with those RNOS intentionally added medium or PAM were also measured by MTS assay. Our NEAPP source generated hydrogen peroxide and nitrite with the generation ratio of 0.35 μM/s and 9.8 μM/s. In those RNOS, hydrogen peroxide has respective antitumor effect. On the other hands, nitrite has no antitumor effect singly. But, synergistically enhance the antitumor effect of hydrogen peroxide. Moreover, this effect of those RNOS also contribute for the selectively cancer killing effect of PAM.

  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. In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide: mechanisms of action.

    PubMed

    Xu, X; Shen, J; Mall, J W; Myers, J A; Huang, W; Blinder, L; Saclarides, T J; Williams, J W; Chong, A S

    1999-11-01

    Leflunomide, a novel immunomodulatory drug, has two biochemical activities: inhibition of tyrosine phosphorylation and inhibition of pyrimidine nucleotide synthesis. In the present study, we first showed that A77 1726 [N-(4-trifluoromethylphenyl-2-cyano-3-hydroxycrotoamide)], the active metabolite of leflunomide, was more effective at inhibiting the tyrosine kinase activity of platelet-derived growth factor (PDGF) receptor than that of epidermal growth factor (EGF) receptor, and had no effect on the tyrosine kinase activity of the fibroblast growth factor receptor. In the presence of exogenous uridine, A77 1726 was more effective at inhibiting the PDGF-stimulated proliferation of PDGF receptor-overexpressing C6 glioma than the EGF-stimulated proliferation of EGF receptor-overexpressing A431 cells. In vivo studies demonstrated that leflunomide treatment strongly inhibited the growth of the C6 glioma but had only a modest effect on the growth of the A431 tumor. Uridine co-administered with leflunomide did not reverse the antitumor activity of leflunomide on C6 and A431 tumors significantly. Quantitation of nucleotide levels in the tumor tissue revealed that leflunomide treatment significantly reduced pyrimidine nucleotide levels in the fast-growing C6 glioma but had no effect on the relatively slow-growing A431 tumor. Whereas uridine co-administration normalized pyrimidine nucleotide levels, it had minimal effects on the antitumor activity of leflunomide in both tumor models. Immunohistochemical analysis revealed that leflunomide treatment significantly reduced the number of proliferating cell nuclear antigen-positive cells in C6 glioma, and that uridine only partially reversed this inhibition. These results collectively suggest that the in vivo antitumor effect of leflunomide is largely independent of its inhibitory effect on pyrimidine nucleotide synthesis. The possibility that leflunomide exerts its antitumor activity by inhibition of tyrosine phosphorylation or

  10. 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.

  11. 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.

  12. 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

  13. Reorientations in the bacteriorhodopsin photoscycle are pH dependent.

    PubMed Central

    Harms, G S; Song, Q; Johnson, C K

    1996-01-01

    Chromophore reorientations during the bacteriorhodopsin photocycle in the purple membrane of Halobacterium salinarium have been detected by time-resolved linear dichroism measurements of the optical anisotropy over the pH range from 4 to 10 and at ionic strengths from 10 mM to 1 M. The results show that reorientations in the L and M states of bacteriorhodopsin are pH dependent, reaching their largest amplitude when the membrane is at pH 6-8. Reorientations on the millisecond time scale of unexcited spectator proteins in the native purple membrane also depend on pH, consistent with the suggestion that spectator reorientations are triggered by reorientation of the photoexcited protein. The results imply that a group with a PK(a) of 5 to 6 enables reorientations, and that the deprotonation of a site at pH values above 9 restricts reorientational motion. This suggests that reorientations in M may be correlated with proton release. PMID:9172759

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. Shaping of Natural Killer Cell Antitumor Activity by Ex Vivo Cultivation.

    PubMed

    Granzin, Markus; Wagner, Juliane; Köhl, Ulrike; Cerwenka, Adelheid; Huppert, Volker; Ullrich, Evelyn

    2017-01-01

    Natural killer (NK) cells are a promising tool for the use in adoptive immunotherapy, since they efficiently recognize and kill tumor cells. In this context, ex vivo cultivation is an attractive option to increase NK cells in numbers and to improve their antitumor potential prior to clinical applications. Consequently, various strategies to generate NK cells for adoptive immunotherapy have been developed. Here, we give an overview of different NK cell cultivation approaches and their impact on shaping the NK cell antitumor activity. So far, the cytokines interleukin (IL)-2, IL-12, IL-15, IL-18, and IL-21 are used to culture and expand NK cells. The selection of the respective cytokine combination is an important factor that directly affects NK cell maturation, proliferation, survival, distribution of NK cell subpopulations, activation, and function in terms of cytokine production and cytotoxic potential. Importantly, cytokines can upregulate the expression of certain activating receptors on NK cells, thereby increasing their responsiveness against tumor cells that express the corresponding ligands. Apart from using cytokines, cocultivation with autologous accessory non-NK cells or addition of growth-inactivated feeder cells are approaches for NK cell cultivation with pronounced effects on NK cell activation and expansion. Furthermore, ex vivo cultivation was reported to prime NK cells for the killing of tumor cells that were previously resistant to NK cell attack. In general, NK cells become frequently dysfunctional in cancer patients, for instance, by downregulation of NK cell activating receptors, disabling them in their antitumor response. In such scenario, ex vivo cultivation can be helpful to arm NK cells with enhanced antitumor properties to overcome immunosuppression. In this review, we summarize the current knowledge on NK cell modulation by different ex vivo cultivation strategies focused on increasing NK cytotoxicity for clinical application in malignant

  19. Shaping of Natural Killer Cell Antitumor Activity by Ex Vivo Cultivation

    PubMed Central

    Granzin, Markus; Wagner, Juliane; Köhl, Ulrike; Cerwenka, Adelheid; Huppert, Volker; Ullrich, Evelyn

    2017-01-01

    Natural killer (NK) cells are a promising tool for the use in adoptive immunotherapy, since they efficiently recognize and kill tumor cells. In this context, ex vivo cultivation is an attractive option to increase NK cells in numbers and to improve their antitumor potential prior to clinical applications. Consequently, various strategies to generate NK cells for adoptive immunotherapy have been developed. Here, we give an overview of different NK cell cultivation approaches and their impact on shaping the NK cell antitumor activity. So far, the cytokines interleukin (IL)-2, IL-12, IL-15, IL-18, and IL-21 are used to culture and expand NK cells. The selection of the respective cytokine combination is an important factor that directly affects NK cell maturation, proliferation, survival, distribution of NK cell subpopulations, activation, and function in terms of cytokine production and cytotoxic potential. Importantly, cytokines can upregulate the expression of certain activating receptors on NK cells, thereby increasing their responsiveness against tumor cells that express the corresponding ligands. Apart from using cytokines, cocultivation with autologous accessory non-NK cells or addition of growth-inactivated feeder cells are approaches for NK cell cultivation with pronounced effects on NK cell activation and expansion. Furthermore, ex vivo cultivation was reported to prime NK cells for the killing of tumor cells that were previously resistant to NK cell attack. In general, NK cells become frequently dysfunctional in cancer patients, for instance, by downregulation of NK cell activating receptors, disabling them in their antitumor response. In such scenario, ex vivo cultivation can be helpful to arm NK cells with enhanced antitumor properties to overcome immunosuppression. In this review, we summarize the current knowledge on NK cell modulation by different ex vivo cultivation strategies focused on increasing NK cytotoxicity for clinical application in malignant

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

    PubMed

    Vaupel, Peter; Multhoff, Gabriele

    2016-05-01

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

  1. Synthesis, antimicrobial, antiquorum-sensing and antitumor activities of new benzimidazole analogs.

    PubMed

    El-Gohary, N S; Shaaban, M I

    2017-09-08

    New benzimidazole analogs were prepared and tested for antimicrobial efficacy toward Escherichia coli ATCC 12435, Bacillus cereus UW 85, Staphylococcus aureus ATCC 29213, Candida albicans and Aspergillus fumigatus 293. Results indicated that compound 10 has potent and broad spectrum antimicrobial activity. In addition, 4b and 5c showed eminent antimicrobial efficacy toward B. cereus, S. aureus, C. albicans and A. fumigatus. Furthermore, 12 and 14 demonstrated interesting antifungal activity toward C. albicans. Antiquorum-sensing efficacy of the new compounds toward Chromobacterium violacium ATCC 12472 was also examined. In vitro antitumor screening of the new benzimidazoles toward HepG2, HCT-116 and MCF-7 cancer cell lines demonstrated that 4b and 5b,c are the most potent analogs toward all tested cell lines. The three potent in vitro antitumor analogs were further assessed for in vivo antitumor activity toward EAC in mice, and in vitro cytotoxicity toward W138 normal cell line. Results revealed that 4b has the highest in vivo activity, and that the three tested analogs are less cytotoxic than 5-FU toward W138 normal cell line. The most active antimicrobial and antitumor analogs were examined for DNA-binding affinity, whereas 4b and 5c displayed the highest affinity. The in silico studies illustrated that all of the new benzimidazoles meet the optimal requirements for good oral absorption and bioavailability. Moreover, in silico toxicity assessment has been reported. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Antitumor and immunomodulatory activity of polysaccharides from the roots of Actinidia eriantha.

    PubMed

    Xu, Hai-Shun; Wu, Yuan-Wen; Xu, Shi-Fang; Sun, Hong-Xiang; Chen, Feng-Yang; Yao, Li

    2009-09-07

    The roots of Actinidia eriantha Benth (Actinidiaceae) have been used for cancers in the Chinese folk medicine. The present study aimed at evaluating the antitumor potentials of the polysaccharides from the roots of Actinidia eriantha and elucidating their immunological mechanisms by determining the effects on the growth of tumor transplanted in mice and the immune response in tumor-bearing mice. The total polysaccharide AEP and fours purified polysaccharides AEPA, AEPB, AEPC and AEPD were isolated and purified from the roots of Actinidia eriantha by hot water extraction, ethanol precipitation, dialysis and gel filtration. Their effects on the growth of mouse transplantable tumor, splenocyte proliferation, the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), production of cytokines from splenocytes, and serum antigen-specific antibody levels in tumor-bearing mice were measured. AEP and four purified polysaccharides could not only significantly inhibit the growth of mouse transplantable tumor, but also remarkably promote splenocytes proliferation, NK cell and CTL activity, IL-2 and IFN-gamma production from splenocytes, and serum antigen-specific antibody levels in tumor-bearing mice. The antitumor activity of AEP and four purified polysaccharides might be achieved by improving immune response, and the composition of the monosaccharides, uronic acid contents and molecular weight could affect their antitumor and immunomodulatory activity.

  4. Immunomodulatory and antitumor activity of triterpenoid fractions from the rhizomes of Astilbe chinensis.

    PubMed

    Tu, Jue; Sun, Hong-Xiang; Ye, Yi-Ping

    2008-09-26

    The objectives of this study were to evaluate the in vivo antitumor potential of the triterpenoid fraction from the rhizomes of Astilbe chinensis (Saxifragaceae) (Saxifragaceae) (ATF) and to elucidate its immunological mechanisms by determining its effects on the growth of mouse transplanted tumors and the immune response in naïve and tumor-bearing mice. The mice inoculated with mouse tumor cell lines were treated per os with ATF at the doses of 20, 40, 60 mg/kg for 10 days. The effects of ATF on the growth of transplantable tumor, splenocyte proliferation, the activity of natural killer (NK) cells, and production of interleukin-2 (IL-2) from splenocytes in tumor-bearing mice were measured. Meanwhile, the effects of ATF on 2,4-dinitrofluorobenzene (DNFB)-induced delayed type hypersensitivity (DTH) reaction and the sheep red blood cell (SRBC)-induced antibody response in naïve mice were also studied. ATF could not only significantly inhibit the growth of mice transplantable tumor, but also remarkably increase splenocytes proliferation, NK cells activity, and the level of IL-2 secreted by splenocytes in tumor-bearing mice, promote the DTH reaction and enhance anti-SRBC antibody level in naïve mice, which indicated that the ATF could improve both specific and non-specific cellular and humoral immune response. The antitumor activity of ATF might be achieved by improving immune response, and ATF could act as antitumor agent with immunomodulatory activity.

  5. Failure in antitumor activity by overdose of an immunomodulating beta-glucan preparation, sonifilan.

    PubMed

    Miura, T; Miura, N N; Ohno, N; Adachi, Y; Shimada, S; Yadomae, T

    2000-02-01

    Schizophyllan (SPG, Sonifilan) is a soluble (1-->3)-beta-D-glucan, used as a biological response modifier (BRM) with radiation therapy for cancer treatment in Japan. The mechanism of SPG mediated antitumor activity is thought to be via immune stimulation, which includes cytokine production, hematopoietic response, and so on. In this paper, we found that the activity of SPG was quite long-lived and an overdose significantly failed to display the antitumor activity. To demonstrate the mechanism several parameters were examined using a high dose of SPG administration as follows: i) the effect on vascular permeability in vivo, ii) the priming effect on tumor necrosis factor (TNF-alpha) production in vivo, iii) the effect on macrophage adherence to plastic plate in vitro, and iv) anti-Sarcoma 180 antibody production in vivo. It was evident that vascular permeability and anti-Sarcoma 180 antibody production remained unchanged, but TNF-alpha production and adherence to a plastic plate was significantly reduced by a high dose of SPG. These facts strongly suggested that modulation of the cytokine syntheses and the leukocyte traffic would be the causative mechanisms of the failure of antitumor activity by an overdose of SPG.

  6. Biological activity of Pityrosporum. II. Antitumor and immune stimulating effect of Pityrosporum in mice.

    PubMed

    Takahashi, M; Ushijima, T; Ozaki, Y

    1986-11-01

    The antitumor activity of Pityrosporum (P. orbiculare, P. ovale, P. pachydermatis, and Pityrosporum sp.) on Ehrlich ascites carcinomas (EACs) implanted into outbred ICR mice was studied. Pityrosporum significantly prolonged the survival of mice, regardless of the administration mode. In the case of P. orbiculare, the maximum survival time was 32.3 days on the mean and was obtained by injection ip of 1 mg (dry weight) P. orbiculare for 7 consecutive days following inoculation of the tumor cells. In contrast, the mean survival time of the nontreated mice was 14.9 days. For the investigation of the mechanisms of this antitumor activity, an examination was done on the ability of intracellular killing of Salmonella typhimurium and oxygen intermediate release by Pityrosporum, as elicited by mouse peritoneal exudate cells (PEC) or mouse peritoneal macrophages (PM). With about 40-minute incubation, 60-80% of S. typhimurium phagocytized by Pityrosporum elicited PEC or PM or were killed. The amounts of superoxide released from Pityrosporum-elicited cells were 1.5 times higher than those of P. acnes-elicited ones. Furthermore, three serum proteins (LA, LB, and LC), which closely related to the anti-tumor activity of immunomodulators, increased in the mice given Pityrosporum. These results indicated that the better survival rate seen in the case of Pityrosporum administration to mice with an implanted EAC may relate to the potent activation of phagocytes and to the increase in serum proteins LA, LB, and LC.

  7. Fermented Noni exudate (fNE): a mediator between immune system and anti-tumor activity.

    PubMed

    Li, Jinhua; Stickel, Sara L; Bouton-Verville, Hilary; Burgin, Kelly E; Yu, Xianzhong; Wong, Desmond K W; Wagner, Thomas E; Wei, Yanzhang

    2008-12-01

    The anti-tumor activity of Morinda citrifolia fruit juice (Noni) has been previously reported. However, the mechanism behind this activity remains unknown. In the present study, we studied the anti-tumor activity of fermented Noni exudate (fNE) and demonstrated that intraperitoneal injection of this material significantly increased the percentages of granulocytes and NK cells in the peripheral blood, peritoneum, and spleen. Furthermore, in preventive and treatment settings, fNE injection induced complete tumor rejection in normal C57BL/6J mice, partial tumor rejection in C57 nude mice lacking functional lymphocytes, and no tumor rejection in NK cell deficient beige mice. Over 85% of the C57BL/6J mice that received fNE survived the first tumor injection and rejected up to 5 x 10(6) tumor cells when re-challenged. The anti-tumor activity remains in the heat-inactivated and filtrated supernatant of fNE. These data demonstrate that fNE appears to be able to stimulate the innate immune system and the adaptive immune system to reject tumor cells. NK cells respond quickly and appear to be among the major players of the innate immune system, while the adaptive immune system reacts later with a retained memory.

  8. 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.

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

    PubMed Central

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

    2015-01-01

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

  10. 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.

  11. 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.

  12. Degalactosylated/desialylated human serum containing GcMAF induces macrophage phagocytic activity and in vivo antitumor activity.

    PubMed

    Kuchiike, Daisuke; Uto, Yoshihiro; Mukai, Hirotaka; Ishiyama, Noriko; Abe, Chiaki; Tanaka, Daichi; Kawai, Tomohito; Kubo, Kentaro; Mette, Martin; Inui, Toshio; Endo, Yoshio; Hori, Hitoshi

    2013-07-01

    The group-specific component protein-derived macrophage-activating factor (GcMAF) has various biological activities, such as macrophage activation and antitumor activity. Clinical trials of GcMAF have been carried out for metastatic breast cancer, prostate cancer, and metastatic colorectal cancer. In this study, despite the complicated purification process of GcMAF, we used enzymatically-treated human serum containing GcMAF with a considerable macrophage-stimulating activity and antitumor activity. We detected GcMAF in degalactosylated/desialylated human serum by western blotting using an anti-human Gc globulin antibody, and Helix pomatia agglutinin lectin. We also found that GcMAF-containing human serum significantly enhanced the phagocytic activity of mouse peritoneal macrophages and extended the survival time of mice bearing Ehrlich ascites tumors. We demonstrated that GcMAF-containing human serum can be used as a potential macrophage activator for cancer immunotherapy.

  13. Triterpenoid saponins from the seeds of Celosia argentea and their anti-inflammatory and antitumor activities.

    PubMed

    Wu, Qingbin; Wang, Yan; Guo, Meili

    2011-01-01

    Three new triterpenoid saponins, named celosin E (1), celosin F (2) and celosin G (3), together with a known compound cristatain (4), were isolated from the seeds of Celosia argentea L. (Amaranthaceae). All the isolated compounds were obtained for the first time from this plant. The structures of new compounds were characterized on the basis of extensive NMR experiments and mass spectrometry data. The antitumor and anti-inflammatory activities of the four compounds were tested in vitro.

  14. 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.

  15. [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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. Antitumor Activity of Citrus maxima (Burm.) Merr. Leaves in Ehrlich's Ascites Carcinoma Cell-Treated Mice

    PubMed Central

    KunduSen, Sriparna; Gupta, Malaya; Mazumder, Upal K.; Haldar, Pallab K.; Saha, Prerona; Bala, Asis

    2011-01-01

    Context. The plant Citrus maxima Merr. (Rutaceae), commonly known as shaddock or pomelo is indigenous to tropical parts of Asia. The objective of present study is to evaluate the methanol extract of Citrus maxima leaves for its antitumor activity against Ehrlich's Ascites Carcinoma cell in Swiss albino mice. Experimental design. The antitumor activity of methanol extract of Citrus maxima leaves (MECM) was evaluated against Ehrlich Ascites Carcinoma (EAC) cell line in Swiss albino mice. 2 × 106 cells were inoculated in different groups of animals. MECM (200 and 400 mg/kg BW i.p.) was administered for nine consecutive days. On day 10th half the animals of different groups were sacrificed for determination of tumor and haematological parameters and the rest half were kept with sufficient food and water ad libitum for determination of increase in life span. Result and Discussions. Oral administration of the extract at the doses of 200 and 400 mg/kg significantly decreased tumor parameters such as tumor volume, viable tumor cell count and increased body weight, hematological parameters and life span in respect of the EAC control mice. Conclusion. Experimental design exhibits significant antitumor activity of the extract (MECM) in a dose dependant manner. PMID:22084708

  1. Antitumor Activity of Citrus maxima (Burm.) Merr. Leaves in Ehrlich's Ascites Carcinoma Cell-Treated Mice.

    PubMed

    Kundusen, Sriparna; Gupta, Malaya; Mazumder, Upal K; Haldar, Pallab K; Saha, Prerona; Bala, Asis

    2011-01-01

    Context. The plant Citrus maxima Merr. (Rutaceae), commonly known as shaddock or pomelo is indigenous to tropical parts of Asia. The objective of present study is to evaluate the methanol extract of Citrus maxima leaves for its antitumor activity against Ehrlich's Ascites Carcinoma cell in Swiss albino mice. Experimental design. The antitumor activity of methanol extract of Citrus maxima leaves (MECM) was evaluated against Ehrlich Ascites Carcinoma (EAC) cell line in Swiss albino mice. 2 × 10(6) cells were inoculated in different groups of animals. MECM (200 and 400 mg/kg BW i.p.) was administered for nine consecutive days. On day 10th half the animals of different groups were sacrificed for determination of tumor and haematological parameters and the rest half were kept with sufficient food and water ad libitum for determination of increase in life span. Result and Discussions. Oral administration of the extract at the doses of 200 and 400 mg/kg significantly decreased tumor parameters such as tumor volume, viable tumor cell count and increased body weight, hematological parameters and life span in respect of the EAC control mice. Conclusion. Experimental design exhibits significant antitumor activity of the extract (MECM) in a dose dependant manner.

  2. 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

  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. 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.

  5. Synthesis, antiviral and antitumor activity of 2-substituted-5-amidino-benzimidazoles.

    PubMed

    Starcević, Kristina; Kralj, Marijeta; Ester, Katja; Sabol, Ivan; Grce, Magdalena; Pavelić, Kresimir; Karminski-Zamola, Grace

    2007-07-01

    We have prepared a set of heterocyclic benzimidazole derivatives bearing amidino substituents at C-5 of benzimidazole ring, by introducing various heterocyclic nuclei (pyridine, N-methyl-pyrrole or imidazole) at C-2, and evaluated their antitumor and antiviral activities. The most pronounced antiproliferative activity was shown with compounds 6 and 9, having imidazolinylamidino-substituent. Interestingly, all compounds show noticeable selectivity toward breast cancer cell line MCF-7. The most distinct and selective antiviral activity toward coxsackieviruses and echoviruses was observed with compounds having pyridine ring at C-2. Especially interesting was fairly strong activity of 4 and 8 toward adenoviruses, which could be considered as leads against adenoviral replication.

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

    PubMed

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

    2015-09-01

    Five novel ruthenium(II)-arene complexes with polycyclic aromatic ligands were synthesized, comprising three compounds of the formula [RuCl(η(6)-p-cym)(L)][PF6], where p-cym = 1-isopropyl-4-methylbenzene and L are the bidentate aromatic ligands 1,10-phenanthroline-5,6-dione, 1, 5-amine-1,10-phenanthroline, 4, or 5,6-epoxy-5,6-dihydro-phenanthroline, 5. In the other two complexes [RuCl2(η(6)-p-cym)(L')], the metal is coordinated to a monodentate ligand L', where L' is phenanthridine, 2, or 9-carbonylanthracene, 3. All compounds were fully characterized by mass spectrometry and elemental analysis, as well as NMR and IR spectroscopic techniques. Obtained ruthenium compounds as well as their respective ligands were tested for their antiparasitic and antitumoral activities. Even though all compounds showed lower Trypanosoma brucei activity than the free ligands, they also resulted less toxic on mammalian cells. Cytotoxicity assays on HL60 cells showed a moderate antitumoral activity for all ruthenium compounds. Compound 1 was the most potent antitumoral (IC50 = 1.26±0.78 μM) and antiparasitic (IC50 = 0.19 ± 0.05 μM) agent, showing high selectivity towards the parasites (selectivity index >100). As complex 1 was the most promising antitumoral compound, its interaction with ubiquitin as potential target was also studied. In addition, obtained ruthenium compounds were found to bind DNA, and they are thought to interact with this macromolecule mainly through intercalation of the aromatic ligand. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Improved antitumor activity and reduced myocardial toxicity of doxorubicin encapsulated in MPEG-PCL nanoparticles.

    PubMed

    Sun, Chuntang; Zhou, Le; Gou, Maling; Shi, Shuai; Li, Tao; Lang, Jinyi

    2016-06-01

    Doxorubicin (Dox) is a broad-spectrum antitumor drug used for the treatment of many types of malignant tumors. Although it possesses powerful antitumor activity, its clinical application is seriously encumbered by its unselective distribution and systemic toxicities, particularly myocardial toxicity. Thus, it is imperative to modify Dox to decrease its systemic toxicities and improve its therapeutic index. In the present study, we adopted a novel type of monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles to encapsulate Dox to prepare Dox-loaded MPEG-PCL (Dox/MPEG-PCL) nanoparticles by a controllable self-assembly process. The cellular uptake efficiency and cell proliferation inhibition of the Dox/MPEG-PCL nanoparticles were examined. The antitumor activity of the Dox/MPEG-PCL nanoparticles was tested on a multiple pulmonary metastasis model of melanoma on C57BL/6 mice. Systemic toxicities and survival time were compared between the mice treated with the Dox/MPEG-PCL nanoparticles and free Dox. The potential myocardial toxicity of the Dox/MPEG-PCL nanoparticles was investigated using a prolonged observation period. Encapsulation of Dox in MPEG-PCL nanoparticles significantly improved the cellular uptake and cell proliferation inhibition of Dox in vivo. Intravenous injection of Dox/MPEG-PCL nanoparticles obtained significant inhibition of the growth and metastasis of melanoma in the lung and prolonged survival time compared with free Dox (P<0.05). The Dox/MPEG-PCL nanoparticles did not show obvious additional systemic toxicities compared with free Dox during the treatment time. During the prolonged observation period, obvious decreased cardiac toxicity was observed in the Dox/MPEG-PCL nanoparticle-treated mice compared with that observed in the free Dox-treated mice. These results indicated that encapsulating Dox with MPEG-PCL micelles could significantly promote its antitumor activity and reduce its toxicity to the myocardium.

  8. Chalcogen containing heterocyclic scaffolds: New hybrids with antitumoral activity.

    PubMed

    Alcolea, Verónica; Plano, Daniel; Encío, Ignacio; Palop, Juan Antonio; Sharma, Arun K; Sanmartín, Carmen

    2016-11-10

    In this work, 27 novel hybrid derivatives containing diverse substituents with chalcogen atoms (selenium or sulfur) and several active heterocyclic scaffolds have been synthesized. Compounds were tested against two human cancer cells lines (MCF7 and PC-3) and a normal human mammary epithelial cell line (184B5) in order to determine their activity and selectivity against malignant cells. Ten compounds showed GI50 values below 10 μM in at least one of the cancer cell lines and six of them exhibited a selectivity index higher than 9. In general, selenium-containing compounds were more active than their corresponding sulfur analogs but we found some thiocyanate derivatives with comparable or higher activity and selectivity. Among the different substituents, the seleno- and thio-cyanate groups showed the most promising results. On the basis of their potent activity and high selectivity index, compounds 7e and 8f (containing a thiocyanate and a selenocyanate group, respectively) were selected for further biological evaluation. Both the compounds induced caspase-dependent cell death and cell cycle arrest in G2/M phase. In addition, these compounds do not violate any of the Lipinski's Rule of Five and thus possess good potential to become drugs, compound 7e being particularly promising. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Cisplatin pretreatment enhances anti-tumor activity of cytokine-induced killer cells

    PubMed Central

    Huang, Xiang; Chen, Yi-Tian; Song, Hai-Zhu; Huang, Gui-Chun; Chen, Long-Bang

    2011-01-01

    AIM: To investigate whether cisplatin (DDP) enhances the anti-tumor activity of cytokine- induced killer (CIK) cells in a murine colon adenocarcinoma model. METHODS: Tumor size and weight served as indicators of therapeutic response. Immunohistochemistry was performed to observe intratumoral lymphocyte infiltration and tumor microvessel density. Changes in the percentage of regulatory T (Treg) cells within the spleens of tumor-bearing mice preconditioned with DDP were monitored using flow cytometry. RESULTS: A marked T cell-dependent, synergistic anti-tumor effect of the combined therapy was observed (1968 ± 491 mm3 vs 3872 ± 216 mm3; P = 0.003). Preconditioning chemotherapy with DDP augmented the infiltration of CD3+ T lymphocytes into the tumor mass and reduced the percentage of both intratumoral and splenic Treg cells. CONCLUSION: Preconditioning with DDP markedly enhances the efficacy of adoptively transferred CIK cells, providing a potential clinical modality for the treatment of patients with colorectal cancer. PMID:21799646

  10. 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.

  11. 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.

  12. 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

  13. Eclipta prostrata L. phytochemicals: isolation, structure elucidation, and their antitumor activity.

    PubMed

    Liu, Qi-Mei; Zhao, Hai-Yan; Zhong, Xian-Ke; Jiang, Jian-Guo

    2012-11-01

    Eclipta prostrata L., (Asteraceae), is used in China for both food and medicine purposes. This research is concerned with the isolation and purification of phytochemical constituents from the aerial parts of E. prostrata, using gradient solvent fractionation, macroporous resin, silica gel, Sephadex LH-20 and ODS columns, and TLC analyses. Four fractions (water, 30% ethanol, 60% ethanol and 90% ethanol) were obtained. Four compounds, wedelolactone (I), eclalbasaponin I (II), luteolin (III) and luteolin-7-O-glucoside (IV) were purified and their structures were identified by the interpretation of spectroscopic analyses including MS, (1)H and (13)C NMR. Antitumor activities of extracts (total fraction), four fractions and the isolated compounds were assessed using hepatoma cell smmc-7721 as an in vitro assay system. The 30% ethanol fraction and eclalbasaponin I dose-dependently inhibited the proliferation of hepatoma cell smmc-7721 with IC(50) values of 74.2399 and 111.1703 μg/ml, respectively, more strongly compared with 5-fluorouracil positive control group with the IC(50) value of 195.3131 μg/ml. Antitumor activities of other fractions and compounds were lower than positive control. These results suggested that some specific compounds or extracts from E. prostrata are potential sources of natural anti-tumor materials and worthy of further study. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Evaluation of antitumor activity of Mimusops elengi leaves on Ehrlich's ascites carcinoma-treated mice.

    PubMed

    Kar, Biswakanth; Kumar, R B Suresh; Bala, Asis; Dolai, Narayan; Mazumder, Upal Kanti; Haldar, Pallab Kanti

    2012-09-01

    Mimusops elengi (M. elengi) Linn. (Sapotaceae) has been used as a folk medicine in wound healing, and the treatment of pain, and inflammation in many parts of India. The purpose of this investigation was to explore the antitumor activity of methanol extract of M. elengi (MEME) in Swiss albino mice against Ehrlich ascites carcinoma (EAC) cell line. Twenty-four hours after intraperitoneal (i.p.) inoculation of tumor (EAC) cells in mice (n = 12), MEME was administered at 200 and 300 mg/kg body weight daily for 9 consecutive days. On day 10, half of the mice were dissected and the rest were kept alive for assessment of increase in life span. The antitumor effect of MEME was assessed by evaluating tumor volume, viable and nonviable tumor cell count, tumor weight, hematological parameter, and biochemical estimations. In vivo antioxidant parameters were assayed by estimating liver tissue enzyme. In vitro cytotoxicity assay of MEME was measured by using trypan blue exclusion method. MEME showed significant (p < .001) decrease in tumor volume, packed cell volume, and viable cell count, and increased the life span of EAC bearing mice. Hematological, biochemical profile, and in vivo antioxidant parameters were significantly restored toward normal levels in MEME-treated mice as compared to EAC control. MEME also showed direct cytotoxicity on EAC cell line in a dose-dependent manner. The present study demonstrates that M. elengi leaves exhibited antitumor activity in Swiss mice, which may be due to its cytotoxic effect and antioxidant properties.

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

    PubMed Central

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

    2017-01-01

    A Ficus umbellata is used to treat cancer. The present work was therefore designed to assess antitumor potentials of F. umbellata extracts in nine different cell lines. Cell cycle, apoptosis, cell migration/invasion, levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), caspases activities as well as Bcl-2 and Bcl-xL protein content were assessed in MDA-MB-231 cells. The 7,12-dimethylbenz(a)anthracene (DMBA)-induced carcinogenesis in rats were also used to investigate antitumor potential of F. umbellata extracts. The F. umbellata methanol extract exhibited a CC50 of 180 μg/mL in MDA-MB-231 cells after 24 h. It induced apoptosis in MCF-7 and MDA-MB-231 cells, while it did not alter their cell cycle phases. Further, it induced a decrease in MMP, an increase in ROS levels and caspases activities as well as a downregulation in Bcl-2 and Bcl-xL protein contents in MDA-MB-231 cells. In vivo, F. umbellata aqueous (200 mg/kg) and methanol (50 mg/kg) extracts significantly (p < 0.001) reduced ovarian tumor incidence (10%), total tumor burden (58% and 46%, respectively), average tumor weight (57.8% and 45.6%, respectively) as compared to DMBA control group. These results suggest antitumor potential of F. umbellata constituents possibly due to apoptosis induction mediated through ROS-dependent mitochondrial pathway. PMID:28545243

  16. 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.

  17. Anti-tumor and immunomodulatory activity of peptide fraction from the larvae of Musca domestica.

    PubMed

    Sun, Hong-Xiang; Chen, Li-Qing; Zhang, Juan; Chen, Feng-Yang

    2014-05-14

    The larvae of Musca domestica (Diptera: Muscidae) have been used traditionally for malnutritional stagnation, decubital necrosis, osteomyelitis, ecthyma and lip scald and also to treat coma and gastric cancer in the traditional Chinese medicine. Its in vitro antitumor activity and immunomodulatory effect in naïve mice in relation to the traditional uses were also reported. However, the in vivo antitumor effect of this insect and its mechanism of action have not yet been well studied. The objectives of this study were to evaluate the in vivo antitumor potential of the peptide fraction from Musca domestica larvae (MDPF) and to elucidate its immunological mechanisms. The mice inoculated with sarcoma S180 cells were orally administered with MDPF at three doses for 10 days. The effects of MDPF on the growth of mouse S180 sarcoma, splenocyte proliferation, the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), production and mRNA expression of cytokines from splenocytes, and serum antigen-specific antibody levels in tumor-bearing mice were measured. MDPF could significantly not only inhibit the growth of mouse transplanted S180 sarcoma, but also promote splenocytes proliferation, NK cell and CTL activity from splenocytes, and enhance serum antigen-specific IgG, IgG2a and IgG2b antibody levels in S180-bearing mice. MDPF also significantly promoted the production of IFN-γ and up-regulated the mRNA expression levels of IFN-γ and Th1 transcription factors T-bet and STAT-4 in splenocytes from the S180-bearing mice. However, Th2 cytokine IL-10 and transcription factors GATA-3 and STAT-6 were not significantly changed both at transcriptional and protein levels following MDPF treatment. MDPF significantly inhibit the growth of transplantable tumor in mice and its in vivo antitumor activity might be achieved by switching-on of Th1-based protective cell-mediated immunity. MDPF could act as antitumor agent with immunomodulatory activity. Copyright © 2014

  18. 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

  19. 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.

  20. 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.

  1. In vitro antibacterial and antitumor activities of some medicinal plant extracts, growing in Turkey.

    PubMed

    Yildirim, Arzu Birinci; Karakas, Fatma Pehlivan; Turker, Arzu Ucar

    2013-08-01

    To investigate antibacterial and antitumor activities of 51 different extracts prepared with 3 types of solvents (water, ethanol and methanol) of 16 different plant species (Ajuga reptans (A. reptans) L., Phlomis pungens (P. pungens) Willd., Marrubium astracanicum (M. astracanicum) Jacq., Nepeta nuda (N. nuda) L., Stachys annua (S. annua) L., Genista lydia (G. lydia) Boiss., Nuphar lutea (N. lutea) L., Nymphaea alba (N. alba) L., Vinca minor (V. minor) L., Stellaria media (S. media) L., Capsella bursa-pastoris (C. bursa-pastoris) L., Galium spurium (G. spurium) L., Onosma heterophyllum (O. heterophyllum) Griseb., Reseda luteola (R. luteola) L., Viburnum lantana (V. lantana) L. and Mercurialis annua (M. annua) L.) grown in Turkey was conducted. Antibacterial activity was evaluated with 10 bacteria including Streptococcus pyogenes (S. pyogenes), Staphylococcus aureus (S. aureus), Staphylococcus epidermidis (S. epidermidis), Escheria coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Salmonella typhimurium (S. typhimurium), Serratia marcescens (S. marcescens), Proteus vulgaris (P. vulgaris), Enterobacter cloacae (E. cloacea), and Klebsiella pneumoniae (K. pneumoniae) by using disc diffusion method. Antitumor activity was evaluated with Agrobacterium tumefaciens (A. tumefaciens)-induced potato disc tumor assay. Best antibacterial activity was obtained with ethanolic extract of P. pungens against S. pyogenes. Ethanolic and methanolic extract of N. alba and ethanolic extract of G. lydia also showed strong antibacterial activities. Results indicated that alcoholic extracts especially ethanolic extracts exhibited strong antibacterial activity against both gram-positive and gram-negative bacteria. Best antitumor activity was obtained with methanolic extracts of N. alba and V. lantana (100% tumor inhibition). Ethanolic extract of N. alba, alcoholic extracts of N. lutea, A. reptans and V. minor flowers, methanolic extracts of G. lydia and O. heterophyllum and ethanolic

  2. Synthesis of novel chromene derivatives of expected antitumor activity.

    PubMed

    Kandeel, Manal M; Kamal, Aliaa M; Abdelall, Eman K A; Elshemy, Heba A H

    2013-01-01

    Inhibition of tubulin polymerization is one of the important tactics in cancer therapy. Since 4-aryl-4H-chromene derivatives are found to be microtubule-binding agents via interfering with tubulin polymerization so we decide to concentrate our exploration efforts on the combination of this nucleus with 5-, 6-, and/or 7-memebered heterocyclic moieties in a novel series of compounds to explore the effect that might result from this combination. Ten novel compounds were selected for anticancer screening assay against MCF-7 breast cancer cell line in comparison to colchicine as positive control and most of them showed excellent activity. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  3. Aconitine-containing agent enhances antitumor activity of dichloroacetate against Ehrlich carcinoma.

    PubMed

    Pyaskovskaya, O N; Boychuk, I V; Fedorchuk, A G; Kolesnik, D L; Dasyukevich, O I; Solyanik, G I

    2015-09-01

    Significant variability of anticancer efficacy of dichloroacetate (DCA) stimulated an active search for the agents capable to enhance it antitumor action. Therefore, the aim of this work is the study of capability of aconitine-containing antiangiogenic agent BC1 to enhance anticancer activity of DCA against Ehrlich carcinoma. DCA (total dose was 1.3 g/kg of b.w.) and BC1 (total dose was 0.9 mg/kg of b.w.) were administered per os starting from the 2(nd) and 3(rd) days, respectively (8 admini-strations for each agent). Antitumor efficacy of agents was estimated. Lactate level, LDH activity and the state of mitochondrial electron transport chain in tumor cells as well as phagocytic activity and reactive oxygen species (ROS) production of tumor-associated macrophages (TAM) were studied. Combined administration of DCA and ВС1 resulted in 89.8% tumor growth inhibition (p < 0.001), what is by 22.5% (p < 0.05) higher that that of DCA alone. This combined treatment was accompanied with a decrease of lactate level in tumor tissue by 30% (p < 0.05) and significant elevation of LDH activity by 70% (p < 0.01). Increased level of NO-Fe-S clusters and 2-fold reduction of Fe-S cluster content were revealed in tumor tissue of mice after DCA and BC1 administration. It was shown that combined therapy did not effect TAM quantity and their phagocytic activity but stimulated ROS production by TAMs by 78% (p < 0.05) compared to this index in control animals. Antiangiogenic agent ВС1 in combination with DCA considerably enhances antitumor activity of DCA via significant decrease of Fe-S-containing protein level resulted from substantial elevation of nitrosylation of these proteins.

  4. Anti-tumor activities of triterpenes from Syzygium kusukusense.

    PubMed

    Bai, Li-Yuan; Lin, Wei-Yu; Chiu, Chang-Fang; Weng, Jing-Ru

    2014-11-01

    In this study, we report the isolation from the stem of Syzygium kusukusense of five triterpenes, 2α-hydroxybetulinic acid (1), betulinic acid (2), platanic acid (3), ursolic acid (4), and hyptatic acid A (5). All were identified for the first time from this indigenous plant of Taiwan. Assessment of the cytotoxic activities of these compounds against a panel of human tumor cell lines, including MCF-7 breast, PC-3 prostate, and SCC2095 oral squamous cell cancers, revealed the high potency of compounds 1 (IC50, 5.7 - 7.6 μM) and, especially, 4 (IC50, 1.7 - 3.7 μM) in suppressing cell viability, which warrants further mechanistic investigations.

  5. 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.

  6. 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

  7. 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.

  8. 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.

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

    PubMed

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

    2009-09-01

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

  10. Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts

    PubMed Central

    Beljanski, Vladimir; Lewis, Clayton S

    2011-01-01

    The balance between the pro-apoptotic lipids ceramide and sphingosine and the pro-survival lipid sphingosine 1-phosphate (S1P) is termed the “sphingosine rheostat”. Two isozymes, sphingosine kinase 1 and 2 (SK1 and SK2), are responsible for phosphorylation of pro-apoptotic sphingosine to form pro-survival S1P. We have previously reported the antitumor properties of an SK2 selective inhibitor, ABC294640, alone or in combination with the multikinase inhibitor sorafenib in mouse models of kidney carcinoma and pancreatic adenocarcinoma. Here, we evaluated the combined antitumor effects of the aforementioned drug combination in two mouse models of hepatocellular carcinoma. Although combining the SK2 inhibitor, ABC294640 and sorafenib in vitro only afforded additive drug-drug effects, their combined antitumor properties in the mouse model bearing HepG2 cells mirrored effects previously observed in animals bearing kidney carcinoma and pancreatic adenocarcinoma cells. Combining ABC294640 and sorafenib led to a decrease in the levels of phosphorylated ERK in SK-HEP -1 cells, indicating that the antitumor effect of this drug combination is likely mediated through a suppression of the MAPK pathway in hepatocellular models. We also measured levels of S1P in the plasma of mice treated with two different doses of ABC294640 and sorafenib. We found decreases in the levels of S1P in plasma of mice treated daily with 100 mg/kg of ABC294640 for 5 weeks, and this decrease was not affected by coadministration of sorafenib. Taken together, these data support combining ABC294640 and sorafenib in clinical trials in HCC patients. Furthermore, monitoring levels of S1P may provide a pharmacodynamic marker of ABC294640 activity. PMID:21258214

  11. 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.

  12. 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

  13. Novel structural insights for imidoselenocarbamates with antitumoral activity related to their ability to generate methylselenol.

    PubMed

    Font, María; Zuazo, Alicia; Ansó, Elena; Plano, Daniel; Sanmartín, Carmen; Palop, Juan-Antonio; Martínez-Irujo, Juan-José

    2012-09-01

    In the search for molecules with potential antiangiogenic activity we found that several imidoselenocarbamate derivatives, which have pro-apoptotic and antiproliferative activities, under hypoxic conditions release methylselenol, a volatile and highly reactive gas that was considered to be responsible for the observed biological activity. The kinetic for the liberation of methylselenol is highly dependent on the nature of the overall structure and correlate with their proven pro-apoptotic activity in lung cancer cell line H157. The preliminary structure-activity relationships allow us to select as the basic structural element a scaffold constructed with an imidoselenocarbamate fragment decorated with a methyl residue on the Se central atom and two heteroaromatic lateral rings. These imidoselenocarbamate derivatives may be of interest both for their antitumoral activities and because they have a structure that can be considered as a template for the design of new derivatives with apoptotic activity. This activity is related to the controlled delivery of methylselenol and makes this an interesting approach to develop new antitumoral agents. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. 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

  15. Selective antitumor activity of roscovitine in head and neck cancer.

    PubMed

    Gary, Cyril; Hajek, Michael; Biktasova, Asel; Bellinger, Gary; Yarbrough, Wendell G; Issaeva, Natalia

    2016-06-21

    Radiation and chemotherapy that are commonly used to treat human cancers damage cellular DNA. DNA damage appears to be more toxic to cancer cells than normal cells, most likely due to deregulated checkpoint activation and/or deficiency in DNA repair pathways that are characteristics of many tumors. However, unwanted side effects arise as a result of DNA damage to normal cells during the treatment.Here, we show that roscovitine, a cyclin-dependent kinase (CDK) inhibitor that inhibits CDK-1, CDK-2, CDK-5, CDK-7, and CDK-9 due to competitive binding to the ATP site on the kinases, causes significant DNA damage followed by p53-dependent cell death in human papilloma virus (HPV)-positive, but not in HPV-negative, head and neck cancer cells. Since HPV positivity was a molecular marker for increased sensitivity of cells to roscovitine, we reasoned that systemic roscovitine administration would not be toxic to healthy HPV-negative tissue. Indeed, low roscovitine doses significantly inhibited the growth of HPV-associated xenografted tumors in mice without causing any detectable side effects.Given that inhibition of CDKs has been shown to inhibit replication of several viruses, we suggest that roscovitine treatment may represent a selective and safe targeted therapeutic option against HPV-positive head and neck cancer.

  16. 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.

  17. In vivo antitumor and immunomodulation activities of different molecular weight lambda-carrageenans from Chondrus ocellatus.

    PubMed

    Zhou, Gefei; Sun, YuePing; Xin, Hua; Zhang, Yuna; Li, Zhien; Xu, Zuhong

    2004-07-01

    lambda-Carrageenan is a sulfated galactan isolated from some red algae and have been reported to have many kinds of biological activities. lambda-Carrageenan from Chondrus ocellatus, an important economic alga in China and many other parts of the world, was degraded by microwave, and obtained five products that have different molecular weight: 650, 240, 140, 15, 9.3 kDa. Analytical results confirmed that microwave degradation might not change the chemical components and structure of polysaccharides under certain condition. In this study, tumor-inhibiting activities, weight of immune organ, nature killer cells activity, lymphocyte proliferation ratio and pathological slice of spleen and tumor cells from the control group and lambda-carrageenan-treated mice of transplanted S180 and H22 tumor were investigated. The results indicated that the five lambda-carrageenan samples all showed antitumor and immunomodulation activities in different degree. Molecular weight of polysaccharides had notable effect on the activities. In addition, their antitumor and immunomodulation have some relevance and the five lambda-carrageenans probably inhibited tumor by means of activating the immunocompetence of the body. Among all the experiment results, samples with the highest activities are PC4 and PC5 whose molecular weight are 15 and 9.3 kDa.

  18. 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.

  19. Design of antitumor agents containing carbohydrate based on GLUT1, and evaluation of antiproliferative activity.

    PubMed

    Zhang, Renshuai; Song, Lairong; Jiang, Bo; Wang, Lijun; Wu, Ning; Guo, Shuju; Shi, Dayong

    2017-06-01

    A series of novel carbohydrate-modified antitumor compounds were designed based on glucose transporter 1 (GLUT1), and evaluated for their anticancer activities against four cancer cell lines. The ribose derivatives (compound 9 and 10) exhibited modest inhibitory activity. The compound 9 significantly inhibited the migration of A549 cell and induced A549 cell apoptosis in a concentration-dependent manner. Moreover, compound 9 blocked A549 cells at the G0/G1 phase. The cellular uptake studies suggested that ribose-modified compound 9 could be taken through GLUT1 in A549 cell line. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Antitumor activity of Aponogeton undulatus against Ehrilich ascites carcinoma in Swiss albino mice.

    PubMed

    Islam, Md Reyazul; Alam, Md Badrul; Tamima, Umme; Jenny, Shayla Islam

    2015-06-01

    To investigate in vitro antioxidant and in vivo antitumor activity of the crude methanolic extract of Aponogeton undulatus (A. undulatus) (MAU) along with its various organic fractions. A. undulatus leaves were successively extracted using methanol (MAU) and then fractionated by chloroform, ethyl acetate (EAU) and water. The total antioxidant capacity, lipid peroxidation inhibition assay, 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay and ferrous reducing power assessment were used to evaluate the antioxidant potential of the crude extract and its organic fractions. The in vivo antitumor activity is evaluated against Ehrlich ascites carcinoma (EAC) cell bearing in Swiss albino mice. EAU showed the highest antioxidant capacity as (175.80 ± 0.41) mg/g, IC50 value of DPPH scavenging activity was (38.84 ± 0.02) μg/mL and also exhibited maximum lipid peroxidation inhibition activity with the IC50 value of (42.52 ± 0.32) μg/mL than other fractions. The results demonstrate that reducing power of the extract was concentration dependent. In addition, EAU was administered at 50, 100 and 200 mg/kg body weight respectively to EAC cell bearing mice and a significant (P < 0.05) decrease in tumor volume, packed cell volume and viable cell count and also increased the life span (17.52%, 42.53% and 62.05%). Hematological profiles were restored to normal levels in MAU treated mice as compared to EAC control mice. The results were found to be significant and confirmed that the A. undulatus has remarkable antitumor activity with antioxidant potential. Copyright © 2015 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

  1. 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

  2. Antioxidant activity, antitumor effect, and antiaging property of proanthocyanidins extracted from Kunlun Chrysanthemum flowers.

    PubMed

    Jing, Siqun; Zhang, Xiaoming; Yan, Liang-Jun

    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.

  3. 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

  4. Evaluation of antitumoral and antimicrobial activity of Morinda lcitrifolia L. grown in Southeast Brazil.

    PubMed

    Candida, Thamyris; França, Jerônimo Pereira de; Chaves, Alba Lucilvânia Fonseca; Lopes, Fernanda Andrade Rodrigues; Gaiba, Silvana; Sacramento, Celio Kersul do; Ferreira, Lydia Masako; França, Lucimar Pereira de

    2014-01-01

    To evaluate the antitumor and antimicrobial activity of ethanolic extract of Morinda citrifolia L. fruit cultivated in southeastern Brazil. Preparation ethanolic extract of the fruit of Morinda citrifolia L. Culture of melanoma cells B16-F10 for treatment with ethanolic extract of Morinda citrifolia L. fruit to determine cell viability by MTT and determination temporal effect of ethanolic extract fruit on the cell growth B16-F10 for 8 days. Evaluation of antimicrobial activity of ethanolic extract fruit against Staphylococcus aureus and Escherichia coli by determination of Minimum Inhibitory Concentration (MIC). The ethanolic extract of Morinda citrifolia L. fruit (10mg/mL) decreased cellular activity and inhibited 45% the rate of cell proliferation of B16-F10 melanoma treated during period studied. The ethanolic extract of Morinda citrifolia L. fruit demonstrated antimicrobial activity inhibiting the growth of both microorganisms studied. Staphylococcus aureus was less resistant to ethanolic extract of Morinda citrifolia L. fruit than Escherichia coli, 1 mg/mL and 10 mg/mL, respectively. What these results indicate that the ethanolic extract of the fruit of Morinda citrifolia L. showed antitumor activity with inhibition of viability and growth of B16-F10 cells and also showed antibacterial activity as induced inhibition of growth of Staphylococcus aureus and Escherichia coli.

  5. Preparation and Characterization of Gelonin-Melittin Fusion Biotoxin for Synergistically Enhanced Anti-Tumor Activity

    PubMed Central

    Cheong, Heesun; Moon, Cheol; Huang, Yongzhuo; He, Huining; Yang, Victor C.

    2016-01-01

    Purpose To investigate the applicability of fusion biotoxins combining pore-forming toxins (PFTs) and ribosome-inactivating proteins (RIPs) for the anti-cancer treatment. Methods Membrane active PFTs tend to destabilize cell membranes of tumor cells, but lack a warhead inducing significant cause of cell death. Cell-impermeable RIPs possess a powerful warhead, yet not able to enter the tumor cells. To address these challenges for anti-tumor effects, we introduced a fusion strategy of conjugating melittin (a PFT) and gelonin (a type 1 RIP) via chemical and recombinant methods, followed by in vitro assays and in vivo animal studies. Results In vitro characterization results confirmed that the chimeric gelonin-melittin fusion proteins retained equivalent intrinsic activity to that of unmodified gelonin in inhibiting protein translation. However, chemically conjugated gelonin-melittin (cGel-Mel) and recombinant chimeric gelonin-melittin fusion (rGel-Mel) exhibited greater cell uptake, yielding a significantly enhanced cytotoxic activity over treatment of gelonin, melittin or physical mixture of gelonin and melittin. Remarkably, cGel-Mel and rGel-Mel displayed 32- and 10-fold lower IC50 than gelonin in the cell lines. The superior anti-tumor efficacy of multivalent cGel-Mel to monovalent rGel-Mel suggested that valency could be a crucial factor for the extent of melittin-mediated cell uptake. Tumoricidal effects observed from animal studies were in good accordance with our findings from the cellular assays. Conclusions This study successfully demonstrated that fusion of biotoxins could provide a simple yet effective way to synergistically augment their anti-tumor activity. PMID:27251414

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome.

    PubMed

    Demo, Susan D; Kirk, Christopher J; Aujay, Monette A; Buchholz, Tonia J; Dajee, Maya; Ho, Mark N; Jiang, Jing; Laidig, Guy J; Lewis, Evan R; Parlati, Francesco; Shenk, Kevin D; Smyth, Mark S; Sun, Congcong M; Vallone, Marcy K; Woo, Tina M; Molineaux, Christopher J; Bennett, Mark K

    2007-07-01

    Clinical studies with bortezomib have validated the proteasome as a therapeutic target for the treatment of multiple myeloma and non-Hodgkin's lymphoma. However, significant toxicities have restricted the intensity of bortezomib dosing. Here we describe the antitumor activity of PR-171, a novel epoxyketone-based irreversible proteasome inhibitor that is currently in clinical development. In comparison to bortezomib, PR-171 exhibits equal potency but greater selectivity for the chymotrypsin-like activity of the proteasome. In cell culture, PR-171 is more cytotoxic than bortezomib following brief treatments that mimic the in vivo pharmacokinetics of both molecules. Hematologic tumor cells exhibit the greatest sensitivity to brief exposure, whereas solid tumor cells and nontransformed cell types are less sensitive to such treatments. Cellular consequences of PR-171 treatment include the accumulation of proteasome substrates and induction of cell cycle arrest and/or apoptosis. Administration of PR-171 to animals results in the dose-dependent inhibition of the chymotrypsin-like proteasome activity in all tissues examined with the exception of the brain. PR-171 is well tolerated when administered for either 2 or 5 consecutive days at doses resulting in >80% proteasome inhibition in blood and most tissues. In human tumor xenograft models, PR-171 mediates an antitumor response that is both dose and schedule dependent. The antitumor efficacy of PR-171 delivered on 2 consecutive days is stronger than that of bortezomib administered on its clinical dosing schedule. These studies show the tolerability, efficacy, and dosing flexibility of PR-171 and provide validation for the clinical testing of PR-171 in the treatment of hematologic malignancies using dose-intensive schedules.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. Antitumor activities and pharmacokinetics of silatecans DB-67 and DB-91.

    PubMed

    Yeh, Teng-Kuang; Li, Chien-Ming; Chen, Ching-Ping; Chuu, Jiuun-Jye; Huang, Chen-Lung; Wang, Hsin-Sheng; Shen, Chien-Chang; Lee, Tien-Yi; Chang, Chi-Yen; Chang, Chung-Ming; Chao, Yu-Sheng; Lin, Chin-Tarng; Chang, Jang-Yang; Chen, Chiung-Tong

    2010-02-01

    DB-67 and its lactone homolog DB-91 are derivatives of topoisomerase I inhibitor camptothecin (CPT) with silyl moiety, which may exhibit a slower inactivation process by changed kinetics of protein binding and/or hydrolysis of its lactone ring and result in increased antitumor activity and decreased toxicity. Pharmacokinetic properties and antitumor activities of the two silatecans were studied and compared. The lactone ring of DB-91 is more stable than those of all the other CPT derivatives in mouse plasma. Both silatecans were metabolized faster than CPT in mouse and human liver microsomes. Pharmacokinetic study revealed a plasma elimination half-life (t(1/2)) of 33 and 94min for DB-67 and DB-91, respectively; similar systemic exposure in plasma between DB-67 and DB-91; and similar volume of distribution at the steady state between DB-67 and DB-91, approximately 15-fold smaller than that of CPT. While DB-91 showed limited activities, DB-67 exhibited activities against the growth of in vivo-like histocultured human tumors and s.c. xenografted human tumors in nude mice. In conclusion, DB-67 is more effective, compared to DB-91, against human tumor growth in in vitro, in vivo-like and in vivo systems. Further pre-clinical and clinical investigations of DB-67 are warranted. Copyright 2009 Elsevier Ltd. All rights reserved.

  20. Evaluation of antimicrobial and antitumoral activity of Garcinia mangostana L. (mangosteen) grown in Southeast Brazil.

    PubMed

    Cunha, Bruna Lais Almeida; França, Jerônimo Pereira de; Moraes, Andrea Aparecida de Fátima Souza; Chaves, Alba Lucilvânia Fonseca; Gaiba, Silvana; Fontana, Renato; Sacramento, Celio Kersul do; Ferreira, Lydia Masako; França, Lucimar Pereira de

    2014-01-01

    To characterize the anatomy of the fruit and leaf and the presence of phytocompounds. To evaluate the antitumor and antimicrobial activity of ethanolic extract of Garcinia mangostana L. (mangosteen) cultivated in southeastern Brazil. Anatomical characterization and histochemical reactions were performed for structural identification and the presence of phytocompounds. Preparation of ethanolic extract of the fruit, leaf and resin of mangosteen. Culture B16-F10 melanoma cells for treatment with mangosteen ethanolic extract to determine cell viability by MTT and genotoxic effect by comet assay. Evaluation by antimicrobial activity against Staphylococcus aureus and Escherichia coli by agar diffusion test and by determination of Minimum Inhibitory Concentration (MIC). Our results showed many secretory canals in resin fruit and leaf; identifying lipids, starch, lignin and phenolic compounds. The leaf extract induced genotoxicity and apoptosis in B16-F10 cells, since the fragmentation of DNA in the comet assay. The ethanolic extract of mangosteen obtained in the resin, leaf and fruit showed antimicrobial activity against Staphylococcus aureus and Escherichia coli with a MIC at 0.1 mg/mL. In conclusion, we have demonstrated both antimicrobial and antitumor activity of ethanol extract of mangosteen emphasizing its therapeutic potential in infectious diseases and in cancer, such as melanoma.

  1. 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.

  2. 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

  3. Design, synthesis and antitumor activity of triterpenoid pyrazine derivatives from 23-hydroxybetulinic acid.

    PubMed

    Zhang, Hengyuan; Wang, Yiwei; Zhu, Peiqing; Liu, Jie; Xu, Shengtao; Yao, Hequan; Jiang, Jieyun; Ye, Wencai; Wu, Xiaoming; Xu, Jinyi

    2015-06-05

    Pyrazine-fused 23-hydroxybetulinic acid was synthesized by introducing a pyrazine ring between C-2 and C-3 position and further modifications were carried out by substitution of C-28 carboxyl group by ester and amide linkage to enhance the antitumor activity. The biological screening results showed that all of the derivatives exhibited more significant antiproliferative activity than the parent compound. In particular compound 12a exhibited the most potent activity with IC50 values of 3.53 μM, 4.42 μM and 5.13 μM against cell lines SF-763, B16 and Hela, respectively. In the preliminary mechanism study, 12a caused cell arrest in G1 phase and significantly induced apoptosis of B16 cells in a dose-dependent manner. Furthermore, the in vivo antitumor activity of 12a was validated (tumor inhibitory ratio of 55.6% and 62.7%, respectively) in mice with H22 liver cancer and B16 melanoma. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  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. 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.

  11. 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.

  12. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. 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.

  14. 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

  15. 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

  16. Antitumor Activity of Alloy and Core-Shell-Type Bimetallic AgAu Nanoparticles.

    PubMed

    Shmarakov, Igor; Mukha, Iuliia; Vityuk, Nadiia; Borschovetska, Vira; Zhyshchynska, Nelya; Grodzyuk, Galyna; Eremenko, Anna

    2017-12-01

    Nanoparticles (NPs) of noble metals, namely gold and silver, remain promising anticancer agents capable of enhancing current surgery- and chemotherapeutic-based approaches in cancer treatment. Bimetallic AgAu composition can be used as a more effective agent due to the synergetic effect. Among the physicochemical parameters affecting gold and silver nanoparticle biological activity, a primary concern relates to their size, shape, composition, charge, etc. However, the impact of metal components/composition as well as metal topological distribution within NPs is incompletely characterized and remains to be further elucidated and clarified. In the present work, we tested a series of colloidal solutions of AgAu NPs of alloy and core-shell type for an antitumor activity depending on metal molar ratios (Ag:Au = 1:1; 1:3; 3:1) and topological distribution of gold and silver within NPs (AucoreAgshell; AgcoreAushell). The efficacy at which an administration of the gold and silver NPs inhibits mouse Lewis lung carcinoma (LLC) growth in vivo was compared. The data suggest that in vivo antitumor activity of the studied NPs strongly depends on gold and silver interaction arising from their ordered topological distribution. NPs with Ag core covered by Au shell were the most effective among the NPs tested towards LLC tumor growth and metastasizing inhibition. Our data show that among the NPs tested in this study, AgcoreAushell NPs may serve as a suitable anticancerous prototype.

  17. Antitumor Activity of Alloy and Core-Shell-Type Bimetallic AgAu Nanoparticles

    NASA Astrophysics Data System (ADS)

    Shmarakov, Igor; Mukha, Iuliia; Vityuk, Nadiia; Borschovetska, Vira; Zhyshchynska, Nelya; Grodzyuk, Galyna; Eremenko, Anna

    2017-05-01

    Nanoparticles (NPs) of noble metals, namely gold and silver, remain promising anticancer agents capable of enhancing current surgery- and chemotherapeutic-based approaches in cancer treatment. Bimetallic AgAu composition can be used as a more effective agent due to the synergetic effect. Among the physicochemical parameters affecting gold and silver nanoparticle biological activity, a primary concern relates to their size, shape, composition, charge, etc. However, the impact of metal components/composition as well as metal topological distribution within NPs is incompletely characterized and remains to be further elucidated and clarified. In the present work, we tested a series of colloidal solutions of AgAu NPs of alloy and core-shell type for an antitumor activity depending on metal molar ratios (Ag:Au = 1:1; 1:3; 3:1) and topological distribution of gold and silver within NPs (AucoreAgshell; AgcoreAushell). The efficacy at which an administration of the gold and silver NPs inhibits mouse Lewis lung carcinoma (LLC) growth in vivo was compared. The data suggest that in vivo antitumor activity of the studied NPs strongly depends on gold and silver interaction arising from their ordered topological distribution. NPs with Ag core covered by Au shell were the most effective among the NPs tested towards LLC tumor growth and metastasizing inhibition. Our data show that among the NPs tested in this study, AgcoreAushell NPs may serve as a suitable anticancerous prototype.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. Assessment of antitumor activity and acute peripheral neuropathy of 1,2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016).

    PubMed

    Ueno, Takayoshi; Endo, Kazuhira; Hori, Kiyomi; Ozaki, Noriyuki; Tsuji, Akira; Kondo, Satoru; Wakisaka, Naohiro; Murono, Shigeyuki; Kataoka, Kazunori; Kato, Yasuki; Yoshizaki, Tomokazu

    2014-01-01

    Oxaliplatin, a third-generation platinum compound incorporating oxalate and 1,2-diaminocyclohexane platinum, has been widely used in chemotherapy regimens for the treatment of metastatic colorectal cancer. Because of its wide spectrum of antitumor activity, oxaliplatin has been applied for the treatment of other carcinomas. However, the antitumor activity of single-agent oxaliplatin is insufficient. To increase its antitumor effects, polymeric micellar nanoparticles incorporating 1,2-diaminocyclohexane platinum (NC-4016) have been developed. The present study was designed to evaluate the efficacy of NC-4016 and its association with peripheral neuropathy, which is a primary dose-limiting factor in oxaliplatin therapy. The in vitro antitumor activity of NC-4016 was investigated using human carcinoma cell lines. To investigate the antitumor effects of NC-4016 in vivo, nude mice bearing the human carcinoma cell line KB were administered NC-4016 or oxaliplatin. The in vitro growth-inhibiting effect of NC-4016 was significantly weaker than that of oxaliplatin. However, the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in vivo. Moreover, we compared the severity of peripheral neuropathy induced by oxaliplatin and NC-4016 in a rat model. Oxaliplatin, NC-4016, or 5% glucose (control) were administered by a single tail vein injection. In the oxaliplatin-treated rats, neither mechanical nor heat allodynia was observed during the experimental period, whereas cold hyperalgesia/allodynia was observed from day 1 to 7. Conversely, cold hyperalgesia/allodynia was not observed in the NC-4016-treated rats. The present study demonstrated that the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in a mouse model of human carcinoma cell line KB. In addition, NC-4016-treated rats did not develop acute cold hypersensitivity, which is frequently experienced by patients after oxaliplatin administration.

  5. 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

  6. Optimization for production of exopolysaccharides with antitumor activity in vitro from Paecilomyces hepiali.

    PubMed

    Wu, Zhongwei; Lu, Junwen; Wang, Xiaoqing; Hu, Bing; Ye, Hong; Fan, Jialong; Abid, Muhammad; Zeng, Xiaoxiong

    2014-01-01

    In the present study, optimal medium for the growth of mycelia and the production of exopolysaccharides from Paecilomyces hepiali HN1 (PHEPS) in submerged culture was investigated. As a result, the maximum production of mycelia (12.98 ± 0.14 g/L) and PHEPS (5.33 ± 0.11 g/L) were achieved under the optimal medium of sucrose 46.08 g/L, yeast extract 4.71 g/L, (NH₄)₂SO₄ 5.72 g/L, KH₂PO₄ 1.70 g/L, CaCl₂ 0.50 g/L, MgSO₄ 0.50 g/L, potato extract 1% and malt extract 1%. Furthermore, the antitumor activity of PHEPS in vitro was evaluated by using three cell lines of human liver tumor HepG2 cells, breast cancer MCF-7 cells and cervical cancer Hela cells. It was found that PHEPS exhibited relative higher anti-proliferative activity against HepG2 cells than MCF-7 cells and Hela cells. At a concentration of 500 μg/mL and 72 h treatment, the inhibition rate of PHEPS on HepG2 cells reached to 62.58%. All these results suggested that PHEPS could be explored as novel natural antitumor agent with great potential application. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. 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.

  8. Anti-tumor and macrophage activation induced by alkali-extracted polysaccharide from Pleurotus ostreatus.

    PubMed

    Kong, Fanli; Li, Feng-E; He, Zhongmei; Jiang, Yong; Hao, Ruoyi; Sun, Xin; Tong, Haibin

    2014-08-01

    Pleurotus ostreatus is popularly consumed as traditional medicine and health food for enhancing immune function in China. Polysaccharides from mushroom have been demonstrated to possess a wide range of health beneficial properties. This study was carried out to elucidate the immunomodulating effects and molecular mechanism involved in the in vivo and in vitro anti-tumor activities of alkali-extracted polysaccharide (WPOP-N1) from the fruiting bodies of P. ostreatus. The results showed that WPOP-N1 significantly inhibited the tumor growth of Sarcoma 180 tumor-bearing mice, and markedly increased the secretion level of TNF-α in serum. In addition, WPOP-N1 enhanced the phagocytic capability of peritoneal macrophages in vitro. Furthermore, the secretion of TNF-α and NO and the amount of TNF-α and iNOS transcript were increased significantly when the peritoneal macrophages were exposed to WPOP-N1. Meanwhile, Western blot analysis revealed that the stimulation of peritoneal macrophages by WPOP-N1 induced the phosphorylation of p65 and a marked decrease of IκB expression. These results suggest that WPOP-N1 could activate macrophages through NF-κB signaling pathway, and the anti-tumor effects of WPOP-N1 can be achieved by its immunostimulating property. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. 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.

  10. 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. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  11. 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

  12. Oncolytic Adenovirus Loaded with L-carnosine as Novel Strategy to Enhance the Antitumor Activity.

    PubMed

    Garofalo, Mariangela; Iovine, Barbara; Kuryk, Lukasz; Capasso, Cristian; Hirvinen, Mari; Vitale, Andrea; Yliperttula, Marjo; Bevilacqua, Maria Assunta; Cerullo, Vincenzo

    2016-04-01

    Oncolytic viruses are able to specifically replicate, infect, and kill only cancer cells. Their combination with chemotherapeutic drugs has shown promising results due to the synergistic action of virus and drugs; the combinatorial therapy is considered a potential clinically relevant approach for cancer. In this study, we optimized a strategy to absorb peptides on the viral capsid, based on electrostatic interaction, and used this strategy to deliver an active antitumor drug. We used L-carnosine, a naturally occurring histidine dipeptide with a significant antiproliferative activity. An ad hoc modified, positively charged L-carnosine was combined with the capsid of an oncolytic adenovirus to generate an electrostatic virus-carnosine complex. This complex showed enhanced antitumor efficacy in vitro and in vivo in different tumor models. In HCT-116 colorectal and A549 lung cancer cell lines, the complex showed higher transduction ratio and infectious titer compared with an uncoated oncolytic adenovirus. The in vivo efficacy of the complex was tested in lung and colon cancer xenograft models, showing a significant reduction in tumor growth. Importantly, we investigated the molecular mechanisms underlying the effects of complex on tumor growth reduction. We found that complex induces apoptosis in both cell lines, by using two different mechanisms, enhancing viral replication and affecting the expression of Hsp27. Our system could be used in future studies also for delivery of other bioactive drugs. Mol Cancer Ther; 15(4); 651-60. ©2016 AACR. ©2016 American Association for Cancer Research.

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

    PubMed

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

    1999-11-15

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

  14. Putative mechanisms of antitumor activity of cyano-substituted heteroaryles in HeLa cells.

    PubMed

    Ester, Katja; Supek, Fran; Majsec, Kristina; Marjanović, Marko; Lembo, David; Donalisio, Manuela; Šmuc, Tomislav; Jarak, Ivana; Karminski-Zamola, Grace; Kralj, Marijeta

    2012-04-01

    Six recently synthesized cyano-substituted heteroaryles, which do not bind to DNA but are highly cytotoxic against the human tumor cell line HeLa, were analyzed for their antitumor mechanisms of action (MOA). They did not interfere with the expression of human papillomavirus oncogenes integrated in the HeLa cell genome, but they did induce strong G1 arrest and result in the activation of caspase-3 and apoptosis. A computational analysis was performed that compared the antiproliferative activities of our compounds in 13 different tumor cell lines with those of compounds listed in the National Cancer Institute database. The results indicate that interference with cytoskeletal function and inhibition of mitosis are the likely antitumor MOA. Furthermore, a second in silico investigation revealed that the tumor cells that are sensitive to the cyano-substituted compounds show differences in their expression of locomotion genes compared with that of insensitive cell lines, thus corroborating the involvement of the cytoskeleton. This MOA was also confirmed experimentally: the cyano-substituted heteroaryles disrupted the actin and the tubulin networks in HeLa cells and inhibited cellular migration. However, further analysis indicated that multiple MOA may exist that depend on the position of the cyano-group; while cyano-substituted naphthiophene reduced the expression of cytoskeletal proteins, cyano-substituted thieno-thiophene-carboxanilide inhibited the formation of cellular reactive oxygen species.

  15. 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.

  16. Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo

    PubMed Central

    Li, Fubin; Ravetch, Jeffrey V.

    2013-01-01

    Agonistic anti-TNF receptor (TNFR) superfamily member antibodies are a class of promising antitumor therapies in active clinical investigation. An unexpected requirement for inhibitory Fcγ receptor FcγRIIB coengagement has recently been described for their in vivo antitumor activities. Although these findings have informed the design of more potent antitumor agonistic, anti-TNFR therapies, the underlying mechanism has remained obscure. Through detailed genetic analysis of strains conditionally deleted for FcγRIIB on defined cellular populations or mutated in specific signaling components, we now demonstrate that different agonistic anti-TNFR antibodies have specific requirements for FcγRIIB expression on defined cellular populations and function in trans in the absence of FcγRIIB signaling components, thus supporting a general mechanism of FcγRIIB cross-linking in vivo for the activities of these antibodies. PMID:24218606

  17. 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.

  18. Solid lipid nanoparticles containing tamoxifen characterization and in vitro antitumoral activity.

    PubMed

    Fontana, Giacomo; Maniscalco, Laura; Schillaci, Domenico; Cavallaro, Gennara; Giammona, Gaetano

    2005-01-01

    Solid lipid nanoparticles (SLNs) containing tamoxifen, a nonsteroidal antiestrogen used in breast cancer therapy, were prepared by microemulsion and precipitation techniques. Tamoxifen loaded SLNs seem to have dimensional properties useful for parenteral administration, and in vitro plasmatic drug release studies demonstrated that these systems are able to give a prolonged release of the drug in the intact form. Preliminary study of antiproliferative activity in vitro, carried out on MCF-7 cell line (human breast cancer cells), demonstrated that SLNs, containing tamoxifen showed an antitumoral activity comparable to free drug. The results of characterization studies and of in vitro antiproliferative activity strongly support the potential application of tamoxifen-loaded SLNs as a carrier system at prolonged release useful for intravenous administration in breast cancer therapy.

  19. 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.

  20. 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.

  1. 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.

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

    PubMed

    Zhu, Weili; Xue, Xiaoping; Zhang, Zhanjun

    2016-10-01

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

  3. 5-Aminolevulinic Acid Enhances Ultrasound-mediated Antitumor Activity via Mitochondrial Oxidative Damage in Breast Cancer.

    PubMed

    Shimamura, Yoshiki; Tamatani, Dai; Kuniyasu, Syota; Mizuki, Yusuke; Suzuki, Takuma; Katsura, Hanayo; Yamada, Hisatsugu; Endo, Yoshio; Osaki, Tomohiro; Ishizuka, Masahiro; Tanaka, Tohru; Yamanaka, Nobuyasu; Kurahashi, Tsukasa; Uto, Yoshihiro

    2016-07-01

    5-Aminolevulinic acid (5-ALA), a precursor of protoporphyrin IX (PpIX), is now used for photodynamic therapy (PDT) of pre-cancers of the skin and photodynamic diagnosis (PDD) of brain tumors. Sonodynamic therapy (SDT) of cancers with ultrasound has been studied using 5-ALA as a sonosensitizer. In this article, we evaluated the sonosensitizing activity and mode of action of 5-ALA/PpIX by using mouse mammary tumor EMT6 cells. 5-ALA-SDT showed significant antitumor effects toward EMT6 cells in vitro and in vivo. The fluorescence of MitoSOX Red, an indicator specific for mitochondrial superoxide, was significantly increased by 5-ALA-SDT. Moreover, the fluorescence derived from JC-1, an indicator of mitochondrial membrane potential, was also significantly increased by 5-ALA-SDT. These findings suggest that mitochondria are one of the target organelles of 5-ALA-SDT. PpIX enhanced reactive oxygen species (ROS) production from tert-butyl hydroperoxide (tBHP), suggesting that PpIX might stabilize or promote ROS generation from tBHP. 5-ALA-SDT showed an antitumor effect in mouse mammary tumor EMT6 cells through oxidation of the mitochondrial membrane via ROS production. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  4. 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.

  5. 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.

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

    PubMed

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

    2009-04-01

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

  7. Chitin extraction from shrimp shell using enzymatic treatment. Antitumor, antioxidant and antimicrobial activities of chitosan.

    PubMed

    Younes, Islem; Hajji, Sawssen; Frachet, Véronique; Rinaudo, Marguerite; Jellouli, Kemel; Nasri, Moncef

    2014-08-01

    Chitin was recovered through enzymatic deproteinization of the shrimp processing by-products. Different microbial and fish viscera proteases were tested for their deproteinization efficiency. High levels of protein removal of about 77±3% and 78±2% were recorded using Bacillus mojavensis A21 and Balistes capriscus proteases, respectively, after 3h of hydrolysis at 45°C using an enzyme/substrate ratio of 20U/mg. Therefore, these two crude proteases were used separately for chitin extraction and then chitosan preparation by N-deacetylation. Chitin and chitosan samples were then characterized by 13 Cross polarization magic angle spinning nuclear magnetic resonance (CP/MAS)-NMR spectroscopy and compared to samples prepared through chemical deproteinization. All chitins and chitosans showed identical spectra. Chitosans prepared through enzymatic deproteinization have practically the same acetylation degree but higher molecular weights compared to that obtained through chemical process. Antimicobial, antioxidant and antitumoral activitities of chitosan-M obtained by treatment with A21 proteases and chitosan-C obtained by alkaline treatment were investigated. Results showed that both chitosans inhibited the growth of most Gram-negative, Gram-positive bacteria and fungi tested. Furthermore, both chitosans exhibited antioxidant and antitumor activities which was dependent on the molecular weight. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. [Chemical Components from Leaves of Fatsia japonica and Their Antitumor Activities in vitro].

    PubMed

    Wei, Qiang; Qiu, Zhen; Xu, Fei; Li, Qian-rong; Yin, Hao

    2015-04-01

    To study the chemical components from the leaves of Fatsia japonica and their antitumor activities in vitro. All compounds were separated and purified by column chromatography over silica gel, Sephadex LH-20 and preparative HPLC. Their structures were identified by physical and chemical properties and spectral methods including 1H-NMR and 13C-NMR. Antitumor assay was measured by MTT method. 18 compounds were isolated and identified as palmitic acid (1), β-hydroxypropiovanillone (2), adenosine (3), β-sitosterol (4), daucosterol (5), oleanolic acid (6), echinocystic acid (7), betulinic acid (8), hederagenin(9), hederagenin-3-O-α-L-rhamnopyranosyl(1-->2)-α-L-arabinopyranoside(10), acacetin(11), quercetin(12), quercetin-3-O-β-D-glucopyranoside(13), isovitexin(14), isovitexin-7-O-glucoside(15), astragalin(16), methylpluviatolide(17), and syringaresinol-4-O-β-D-glucopyranoside(18). All compounds are isolated from the leaves of Fatsia japonica for the first time except compound 1. The ethyl acetate extract and compounds 6, 10, 12 and 18 at the concentration of 0. 5 mg/mL showed inhibitory effect against the proliferation of colon cell line A549 with the inhibitory rate over 90% in vitro.

  9. 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

  10. 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.

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

    PubMed Central

    2014-01-01

    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. PMID:24685243

  12. 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

  13. 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.

  14. Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models

    PubMed Central

    TANAKA, NOZOMU; SAKAMOTO, KAZUKI; OKABE, HIROYUKI; FUJIOKA, AKIO; YAMAMURA, KEISUKE; NAKAGAWA, FUMIO; NAGASE, HIDEKI; YOKOGAWA, TATSUSHI; OGUCHI, KEI; ISHIDA, KEIJI; OSADA, AKIKO; KAZUNO, HIROMI; YAMADA, YUKARI; MATSUO, KENICHI

    2014-01-01

    TAS-102 is a novel oral nucleoside antitumor agent containing trifluridine (FTD) and tipiracil hydrochloride (TPI). The compound improves overall survival of colorectal cancer (CRC) patients who are insensitive to standard chemotherapies. FTD possesses direct antitumor activity since it inhibits thymidylate synthase (TS) and is itself incorporated into DNA. However, the precise mechanisms underlying the incorporation into DNA and the inhibition of TS remain unclear. We found that FTD-dependent inhibition of TS was similar to that elicited by fluorodeoxyuridine (FdUrd), another clinically used nucleoside analog. However, washout experiments revealed that FTD-dependent inhibition of TS declined rapidly, whereas FdUrd activity persisted. The incorporation of FTD into DNA was significantly higher than that of other antitumor nucleosides. Additionally, orally administered FTD had increased antitumor activity and was incorporated into DNA more effectively than continuously infused FTD. When TAS-102 was administered, FTD gradually accumulated in tumor cell DNA, in a TPI-independent manner, and significantly delayed tumor growth and prolonged survival, compared to treatment with 5-FU derivatives. TAS-102 reduced the Ki-67-positive cell fraction, and swollen nuclei were observed in treated tumor tissue. The amount of FTD incorporation in DNA and the antitumor activity of TAS-102 in xenograft models were positively and significantly correlated. These results suggest that TAS-102 exerts its antitumor activity predominantly due to its DNA incorporation, rather than as a result of TS inhibition. The persistence of FTD in the DNA of tumor cells treated with TAS-102 may underlie its ability to prolong survival in cancer patients. PMID:25230742

  15. Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models.

    PubMed

    Tanaka, Nozomu; Sakamoto, Kazuki; Okabe, Hiroyuki; Fujioka, Akio; Yamamura, Keisuke; Nakagawa, Fumio; Nagase, Hideki; Yokogawa, Tatsushi; Oguchi, Kei; Ishida, Keiji; Osada, Akiko; Kazuno, Hiromi; Yamada, Yukari; Matsuo, Kenichi

    2014-12-01

    TAS-102 is a novel oral nucleoside antitumor agent containing trifluridine (FTD) and tipiracil hydrochloride (TPI). The compound improves overall survival of colorectal cancer (CRC) patients who are insensitive to standard chemotherapies. FTD possesses direct antitumor activity since it inhibits thymidylate synthase (TS) and is itself incorporated into DNA. However, the precise mechanisms underlying the incorporation into DNA and the inhibition of TS remain unclear. We found that FTD-dependent inhibition of TS was similar to that elicited by fluorodeoxyuridine (FdUrd), another clinically used nucleoside analog. However, washout experiments revealed that FTD-dependent inhibition of TS declined rapidly, whereas FdUrd activity persisted. The incorporation of FTD into DNA was significantly higher than that of other antitumor nucleosides. Additionally, orally administered FTD had increased antitumor activity and was incorporated into DNA more effectively than continuously infused FTD. When TAS-102 was administered, FTD gradually accumulated in tumor cell DNA, in a TPI-independent manner, and significantly delayed tumor growth and prolonged survival, compared to treatment with 5-FU derivatives. TAS-102 reduced the Ki-67-positive cell fraction, and swollen nuclei were observed in treated tumor tissue. The amount of FTD incorporation in DNA and the antitumor activity of TAS-102 in xenograft models were positively and significantly correlated. These results suggest that TAS-102 exerts its antitumor activity predominantly due to its DNA incorporation, rather than as a result of TS inhibition. The persistence of FTD in the DNA of tumor cells treated with TAS-102 may underlie its ability to prolong survival in cancer patients.

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

    PubMed

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

    2016-01-01

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

  17. 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.

  18. Macrophage antitumor activity induced by the antigenic lymphoma L5178Y/DTIC subline.

    PubMed

    Marelli, O; Mantovani, A; Franco, P; Nicolin, A

    1982-10-31

    Murine leukemic cells, after in vivo treatment with antineoplastic drugs, have been shown to express new antigenic specificities that were not detectable on parental cells and that were heritable after the withdrawal of drug treatment. A study was conducted of macrophage antitumor activity triggered by LY/DTIC cells, a subline of LY murine lymphoma, antigenically altered by the drug DTIC. In vitro non-specific inhibition of tumor cell growth was exhibited by spleen and peritoneal macrophages from mice previously challenged with viable LY/DTIC. Peritoneal macrophages from LY/DTIC immune animals showed moderate, although significant lytic activity against unrelated tumor target cells. Supernatants from mixed lymphocyte-tumor cell cultures, in which LY/DTIC immune lymphocytes and LY/DTIC tumor cells had been cultured, rendered normal macrophages non-specifically growth inhibitory for tumor cells.

  19. 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.

  20. Antitumoral activity of 1,2-diaminocyclohexane derivatives in breast, colon and skin human cancer cells.

    PubMed

    Morales, Fátima; Ramírez, Alberto; Morata-Tarifa, Cynthia; Navarro, Saúl A; Marchal, Juan A; Campos, Joaquín M; Conejo-García, Ana

    2017-03-01

    Cancer is among the leading causes of death worldwide. Medical interest has focused on macrocyclic polyamines because of their properties as antitumor agents. Results/Methodology: We have designed and synthesized a series of 1,2-diaminocyclohexane derivatives with notable in vitro antiproliferative activities against the MCF-7, HCT-116 and A375 cancer cell lines. Cell cycle and apoptosis analyses were also carried out. Our results show that all the compounds are potent cytotoxic agents, especially against the A375 cell line. The selective activity of the macrocyclic derivative against A375, via apoptosis, supposes a great advantage for future therapeutic use. This exemplifies the potential of 1,2-diaminocyclohexane derivatives to qualify as lead structures for future anticancer drug development due to their easy syntheses and noteworthy bioactivity.

  1. Evaluation of antitumor activity and development of solid lipid nanoparticles of metronidazole analogue.

    PubMed

    Lages, Eduardo Burgarelli; de Freitas, Maria Betânia; Gonçalves, Isadora Marques Brum; Alves, Ricardo José; Vianna-Soares, Cristina Duarte; Ferreira, Lucas Antônio Miranda; de Oliveira, Mônica Cristina; de Oliveira, Renata Barbosa

    2013-11-01

    Nitroheterocyclic compounds have received considerable interest as hypoxia-selective cytotoxins (HSC) for cancer treatment. In the present study, we investigated antitumor activity of an iodide analogue of metronidazole, 1-(2-iodoethyl)-2-methyl-5-nitroimidazole (MTZ-I), using Swiss mice bearing solid Ehrlich tumor. MTZ-I showed potent anti-cancer activity at a dose of 40 mg/kg. MTZ-I loaded solid lipid nanoparticles (SLN) were developed as an alternative colloidal carrier system to enhance tumor drug uptake. SLN were characterized for particle size, polydispersity index, zeta potential and entrapment efficiency. In addition, the influence of presence of the cationic lipid stearylamine (STE) on stability of formulation was assessed. The results of DSC study showed that MTZ-I exhibited interaction with STE.

  2. 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.

  3. 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

  4. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma.

    PubMed

    Wang, Jin; Liu, Xiaoyang; Hong, Yongzhi; Wang, Songtao; Chen, Pin; Gu, Aihua; Guo, Xiaoyuan; Zhao, Peng

    2017-07-17

    Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM. Cell proliferation was determined by using cell viability, colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell cycle and cell apoptosis were analyzed by flow cytometry. Cell migratory ability was evaluated by wound healing assays and trans-well migration assays. ATG7 expression was knocked-down by transfection with Atg7-specific small interfering RNA. Overexpression of active Akt protein was achieved by transfecting the cells with a plasmid expressing constitutively active Akt (CA-Akt). Transmission electron microscopy was performed to examine the formation of autophagosomes in cells. Immunofluorescence and western blot analyses were used to analyze protein expression. Tumor xenografts in nude mice and immunohistochemistry were performed to evaluate the effect of ibrutinib on tumor growth in vivo. Ibrutinib inhibited cellular proliferation and migration, and induced apoptosis and autophagy in LN229 and U87 cells. Overexpression of the active Akt protein decreased ibrutinib-induced autophagy, while inhibiting Akt by LY294002 treatment enhanced ibrutinib-induced autophagy. Specific inhibition of autophagy by 3-methyladenine (3MA) or Atg7 targeting with small interfering RNA (si-Atg7) enhanced the anti-GBM effect of ibrutinib in vitro and in vivo. Our results indicate that ibrutinib exerts a profound antitumor effect and induces autophagy through Akt/mTOR signaling pathway in GBM cells. Autophagy inhibition promotes the antitumor activity of ibrutinib in GBM. Our findings provide important insights into the action of an anticancer agent combining with autophagy inhibitor for malignant glioma.

  5. [Correlation of antitumor effect of recombinant sea snake basic phospholipase A2 to its enzymatic activity].

    PubMed

    Liang, Yong-Ju; Yang, Xiao-Ping; Wei, Jian-Wen; Fu, Li-Wu; Jiang, Xiao-Yu; Chen, Shang-Wu; Yang, Wen-Li

    2005-12-01

    Snake venom phospolipase A2 (PLA(2)), a large family of homologous (14 ku) soluble proteins, exerts diverse pharmacologic activities as well as enzymatic activities. So far, the structure and function of terrestrial snake PLA(2), especially the relationship of its enzymatic and pharmacologic activities have been studied extensively, but the investigation of sea snake PLA(2) are limited. This study was to investigate the in vitro and in vivo antitumor effects of recombinant sea snake basic PLA(2) (rSSBPLA(2)) and its mutants rN48 and rK4 from sea snake Lapemis hardwickii venom, and to explore the influence of 2 residues related with the enzymatic activity on the antitumor effects. Site-directed mutagenesis of the 2 conserved residues related with enzymatic activity (His48 mutated to Asn and Asp49 mutated to Lys) was performed. The inhibitory effects of rSSBPLA(2), rN48 and rK49 on proliferation of human myeloid leukemia cell line HL-60, human neuroblastoma cell line SK-N-SH, human gastric cancer cell line MGC-803, and human liver cancer cell line HepG2 were assessed by MTT assay. Their antitumor effects on sarcoma cell line S180 xenograft and EAC ascites cancer model in mice were detected. The relative enzymatic activities of rN48 and rK49 were 0 and 5% of that of rSSBPLA(2). The 50% inhibitory concentration (IC(50)) of rSSBPLA(2) for HL60, SK-N-SH, and MGC-803 cells were (45.28+/-0.09) microg/ml, (57.07+/-0.12) microg/ml, and (69.34+/-0.35) microg/ml, respectively, but it had no inhibitory effect on proliferation of HepG2 cells. rSSBPLA(2) obviously inhibited growth of S180 xenograft in miceû the inhibitory rates were 50.8%, 43.2%, 38.2%, and 55.5%, respectively, under the dose of 2 mg/kg (qd x 10), 2 mg/kg (q2d x 5), 4 mg/kg (qd x 1) and 4 mg/kg (q5d x 2). The inhibitory rate of EAC model was 33.5% under the dose of 4 mg/kg (q5d x 2). The inhibitory rates were significantly higher in test groups than in control groups (P<0.01). rN48 and rK49 had no inhibitory

  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. 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.

  8. G-quadruplex ligand RHPS4 potentiates the antitumor activity of camptothecins in preclinical models of solid tumors.

    PubMed

    Leonetti, Carlo; Scarsella, Marco; Riggio, Giuseppe; Rizzo, Angela; Salvati, Erica; D'Incalci, Maurizio; Staszewsky, Lidia; Frapolli, Roberta; Stevens, Malcolm F; Stoppacciaro, Antonella; Mottolese, Marcella; Antoniani, Barbara; Gilson, Eric; Zupi, Gabriella; Biroccio, Annamaria

    2008-11-15

    The formation of G-quadruplex structures at telomeric DNA sequences blocks telomerase activity, offering an original strategy to design and develop new antitumor agents. The pentacyclic acridinium salt RHPS4 is one of the most effective and selective G4 ligands able to rapidly disrupt telomere architecture, resulting in apoptosis of cancer cells. Here, we studied the therapeutic index of RHPS4 and its integration with chemotherapeutics in preclinical model of solid tumors. The antitumoral activity of RHPS4 was evaluated on human xenografts of different histotypes and compared with that of standard antineoplastic agents. Moreover, the effect of RHPS4/chemotherapeutics combinations on cell survival was studied and the most favorable combination was evaluated on tumor-bearing mice. RHPS4 was active in vivo as single agent and showed a high therapeutic efficacy when compared with conventional drugs. Moreover, RHPS4 had antitumoral activity in human melanoma xenografts inherently resistant to chemotherapy and exhibited antimetastatic activity. RHPS4 also showed a strong synergistic interaction with camptothecins and this effect was strictly dependent on the drug sequence employed. Treatment of mice with irinotecan followed by RHPS4 was able to inhibit and delay tumor growth and to increase mice survival. Our data show that RHPS4 has a good pharmacodynamic profile and in combination therapy produces a strong antitumoral activity, identifying this drug as promising agent for clinical development.

  9. 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.

  10. 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.

  11. 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

  12. Interleukin-21 activates cytotoxic T lymphocytes and natural killer cells to generate antitumor response in mouse renal cell carcinoma.

    PubMed

    Kumano, Masafumi; Hara, Isao; Furukawa, Junya; Oniki, Shuntaro; Nagai, Hiroshi; Miyake, Hideaki; Fujisawa, Masato

    2007-10-01

    We evaluated the antitumor effects of IL-21 gene transfer into mouse RenCa renal cell carcinoma cells, so that cells could spontaneously secrete IL-21. We also investigated the mechanisms underlying this antitumor effect. The IL-21 gene was introduced into RenCa cells by the liposome mediated method using Lipofectamine. The in vivo antitumor effect of IL-21 secreting RenCa cells was assessed by subcutaneous injection into syngeneic BALB/c mice. Mechanisms underlying the antitumor effects were investigated in syngeneic mice in which CD8 T, CD4 T or natural killer cells had been depleted using the corresponding antibody. The cytotoxic activity of splenocytes in mice injected with IL-21 secreting RenCa cells was determined using the CytoTox 96 nonradioactive cytotoxicity assay. Immunohistochemical examinations were performed to investigate infiltrating cells around tumor sites in vivo. Tumor vaccine study was also performed. IL-21 secreting RenCa cells were almost all rejected following subcutaneous injection into syngeneic mice. The antitumor effect of IL-21 secreting RenCa cells remained in mice in which CD4 T cells had been depleted but it was totally abrogated in mice depleted of CD8 T cells or natural killer cells. Cytotoxic activities of splenocytes were higher in IL-21 secreting RenCa cell rejected mice than in parental RenCa mice. Immunohistochemical study also supported the involvement of CD8 T cells and natural killer cells in the antitumor effect of IL-21 secreting RenCa cells. Moreover, mitomycin C treated IL-21 secreting RenCa cells inhibited the growth of parental RenCa at distant site. IL-21 secreting RenCa could be rejected in syngeneic mice by the activation of CD8 T cells and natural killer cells. Moreover, mitomycin C treated IL-21 secreting RenCa cells could work as a tumor vaccine for parental RenCa.

  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. Preparation and characterization of water-soluble albumin-bound curcumin nanoparticles with improved antitumor activity.

    PubMed

    Kim, Tae Hyung; Jiang, Hai Hua; Youn, Yu Seok; Park, Chan Woong; Tak, Kyung Kook; Lee, Seulki; Kim, Hyungjun; Jon, Sangyong; Chen, Xiaoyuan; Lee, Kang Choon

    2011-01-17

    Curcumin (CCM), a yellow natural polyphenol extracted from turmeric (Curcuma longa), has potent anti-cancer properties as has been demonstrated in various human cancer cells. However, the widespread clinical application of this efficient agent in cancer and other diseases has been limited by its poor aqueous solubility and bioavailability. In this study, we prepared novel CCM-loaded human serum albumin (HSA) nanoparticles (CCM-HSA-NPs) for intravenous administration using albumin bound technology. Field emission scanning electron microscopy (FE-SEM) and dynamic light scattering (DLS) investigation confirmed a narrow size distribution in the 130-150nm range. Furthermore, CCM-HSA-NPs showed much greater water solubility (300-fold) than free CCM, and on storage, the biological activity of CCM-HSA-NPs was preserved with negligible activity loss. In vivo distributions and vascular endothelial cells transport studies demonstrated the superiority of CCM-HSA-NPs over CCM. Amounts of CCM in tumors after treatment with CCM-HSA-NPs were about 14 times higher at 1h after injection than that achieved by CCM. Furthermore, vascular endothelial cell binding of CCM increased 5.5-fold, and transport of CCM across a vascular endothelial cell monolayer by Transwell testing was 7.7-fold greater for CCM-HSA-NPs than CCM. Finally, in vivo antitumor tests revealed that CCM-HSA-NPs (10 or 20mg/kg) had a greater therapeutic effect (50% or 66% tumor growth inhibition vs. PBS-treated controls) than CCM (18% inhibition vs. controls) in tumor xenograft HCT116 models without inducing toxicity. We attribute this potent antitumor activity of CCM-HSA-NPs to enhanced water solubility, increased accumulation in tumors, and an ability to traverse vascular endothelial cell. Copyright © 2010 Elsevier B.V. All rights reserved.

  15. 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. Copyright © 2016, American Association for the Advancement of Science.

  16. 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

  17. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer.

    PubMed

    Yang, Hong; Higgins, Brian; Kolinsky, Kenneth; Packman, Kathryn; Bradley, William D; Lee, Richard J; Schostack, Kathleen; Simcox, Mary Ellen; Kopetz, Scott; Heimbrook, David; Lestini, Brian; Bollag, Gideon; Su, Fei

    2012-02-01

    The protein kinase BRAF is a key component of the RAS-RAF signaling pathway which plays an important role in regulating cell proliferation, differentiation, and survival. Mutations in BRAF at codon 600 promote catalytic activity and are associated with 8% of all human (solid) tumors, including 8% to 10% of colorectal cancers (CRC). Here, we report the preclinical characterization of vemurafenib (RG7204; PLX4032; RO5185426), a first-in-class, specific small molecule inhibitor of BRAF(V600E) in BRAF-mutated CRC cell lines and tumor xenograft models. As a single agent, vemurafenib shows dose-dependent inhibition of ERK and MEK phosphorylation, thereby arresting cell proliferation in BRAF(V600)-expressing cell lines and inhibiting tumor growth in BRAF(V600E) bearing xenograft models. Because vemurafenib has shown limited single-agent clinical activity in BRAF(V600E)-mutant metastatic CRC, we therefore explored a range of combination therapies, with both standard agents and targeted inhibitors in preclinical xenograft models. In a BRAF-mutant CRC xenograft model with de novo resistance to vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced by combining with an AKT inhibitor (MK-2206). The addition of vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or irinotecan, or erlotinib resulted in increased antitumor activity and improved survival in xenograft models. Together, our findings suggest that the administration of vemurafenib in combination with standard-of-care or novel targeted therapies may lead to enhanced and sustained clinical antitumor efficacy in CRCs harboring the BRAF(V600E) mutation. ©2011 AACR.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. Antitumor Activity of the Methanol Extract of Hypericum hookerianum Stem Against Ehrlich Ascites Carcinoma in Swiss Albino Mice.

    PubMed

    Dongre, Santoshkumar H; Badami, Shrishailappa; Natesan, Senthilkumar; H, Raghu Chandrashekhar

    2007-04-01

    A large number of plants belonging to the Hypericum family are known to possess strong antitumor properties. The methanol extract of H. hookerianum Wight and Arnott stem (MEHH) exhibited potent in vitro cytotoxic activity against various cancerous cell lines. In the present study, the high performance liquid chromatography (HPLC) standardized MEHH was tested for in vivo antitumor properties against Ehrlich ascites carcinoma (EAC) tumor bearing mice at 100, 200, and 400 mg/kg body weight doses given orally once daily for 14 days. The results indicate that administration of the extract not only increased the survival of animals with ascites tumor, decreased the body weight induced by the tumor burden, and reduced packed cell volume and viable tissue cell count, but also altered many hematological parameters changed during tumor progression, indicating the potent antitumor nature of the extract. Among the three doses tested, the 200 mg/kg body weight dose was found to be the most potent.

  4. 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

  5. The potential molecular effects of bursal septpeptide II on immune induction and antitumor activity

    PubMed Central

    Zhou, Guang Fang; Liu, Qing Tao; Zhou, Bin; Qiu, Ya Feng; Liu, Xiao Dong; Ma, Zhi Yong; Chen, Pu Yan

    2015-01-01

    The bursa of Fabricius (BF) is the acknowledged central humoral immune organ in birds. Bursal septpeptide II (BSP-II) is an immunomodulatory bioactive peptide isolated from BF. To understand the effects of BSP-II on immune induction, gene expression profiles of hybridoma cells treated with BSP-II were evaluated. Pathway analysis showed that regulated genes were involved in cytokine-cytokine receptor interactions, T cell receptor signaling pathway, and pathway in cancer. It was observed that BSP-II reduced tumor cells proliferation and stimulated p53 expression. These results indicate potential mechanisms underlying the effects of the humoral immune system on immune induction, including antitumor activities. Our study has provided a novel insight into immunotherapeutic strategies for treating human tumors. PMID:25643804

  6. 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

  7. 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.

  8. Flavored black ginseng exhibited antitumor activity via improving immune function and inducing apoptosis.

    PubMed

    Chen, Guilin; Li, Haijun; Gao, Yugang; Zhang, Lianxue; Zhao, Yan

    2017-05-24

    The objective of this project was to examine saponin and carbohydrate conversion, and to evaluate the antitumor activity of a novel ready-to-eat flavored black ginseng (FBG). The results of chemical experiments showed that common saponins in ginseng such as ginsenoside Re, Rg1, Rb1, etc., are almost completely converted to rare saponins and aglycones such as ginsenoside Rg5, protopanaxadiol (PPD), etc., and non-reducing sugars such as starch are almost completely degraded into reducing sugars as affected by garlic juice and high temperature processing. Furthermore, pharmacological experimental results showed that this novel FBG could inhibit the growth of tumors in H22 tumor-bearing mice dose-dependently at the dosage of 250, 500 and 1000 mg kg(-1); meanwhile, the results of ELISA, H&E staining, western blotting and qRT-PCR show that FBG could improve immune function and induce tumor cell apoptosis.

  9. 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

  10. Polaprezinc reduces paclitaxel-induced peripheral neuropathy in rats without affecting anti-tumor activity.

    PubMed

    Tsutsumi, Kuniaki; Kaname, Takanori; Shiraishi, Haruka; Kawashiri, Takehiro; Egashira, Nobuaki

    2016-06-01

    Paclitaxel, an anticancer drug, frequently causes painful peripheral neuropathy. In this study, we investigated the preventive effect of polaprezinc on paclitaxel-induced peripheral neuropathy in rats. Polaprezinc (3 mg/kg, p.o., once daily) inhibited the development of mechanical allodynia induced by paclitaxel (4 mg/kg, i.p., on days 1, 3, 5 and 7) and suppressed the paclitaxel-induced increase in macrophage migration in dorsal root ganglion cells. In addition, polaprezinc did not affect the anti-tumor activity of paclitaxel in cultured cell lines or tumor-bearing mice. These results suggest a clinical indication for polaprezinc in the prevention of paclitaxel-induced neuropathy. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  11. Jesridonin in combination with paclitaxel demonstrates synergistic anti-tumor activity in human esophageal carcinoma cells.

    PubMed

    Wang, Cong; Yang, Dongxiao; Jiang, Liping; Wang, Saiqi; Wang, Junwei; Zhou, Kairui; Shi, Xiaoli; Chang, Liming; Liu, Ying; Ke, Yu; Liu, Hongmin

    2017-05-01

    The novel compound jesridonin, has extensive anti-tumor activity. In this study, we aim to investigate the cytotoxic effects of jesridonin in combination with paclitaxel. Our results showed that jesridonin in combination with paclitaxel had synergistic cytotoxic effects on human esophageal carcinoma both in vitro and in vivo. Hoechst 33258 staining and the Annexin-V FITC assay demonstrated that paclitaxel synergized with jesridonin in a stronger induction of apoptosis than treatment with paclitaxel or jesridonin alone. Western blotting results revealed that the synergistic apoptosis-induction effects of paclitaxel and jesridonin were mediated by the mitochondrial pathway. This may provide a novel strategy to overcome drug resistance for esophageal cancer therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. The potential molecular effects of bursal septpeptide II on immune induction and antitumor activity.

    PubMed

    Zhou, Guang Fang; Liu, Qing Tao; Zhou, Bin; Qiu, Ya Feng; Liu, Xiao Dong; Ma, Zhi Yong; Feng, Xiu Li; Cao, Rui Bing; Chen, Pu Yan

    2015-01-01

    The bursa of Fabricius (BF) is the acknowledged central humoral immune organ in birds. Bursal septpeptide II (BSP-II) is an immunomodulatory bioactive peptide isolated from BF. To understand the effects of BSP-II on immune induction, gene expression profiles of hybridoma cells treated with BSP-II were evaluated. Pathway analysis showed that regulated genes were involved in cytokine-cytokine receptor interactions, T cell receptor signaling pathway, and pathway in cancer. It was observed that BSP-II reduced tumor cells proliferation and stimulated p53 expression. These results indicate potential mechanisms underlying the effects of the humoral immune system on immune induction, including antitumor activities. Our study has provided a novel insight into immunotherapeutic strategies for treating human tumors.

  13. 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

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

    PubMed

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

    2011-11-10

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

  15. 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.

  16. 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

  17. 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

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

    PubMed

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

    2013-07-01

    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. To investigate the anti-microorganism, anti-tumor, and immune activities of a novel polysaccharide (TMP-A) isolated from Tricholoma matsutake. 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. 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. 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.

  19. [CCL21-CD40L fusion gene induce augmented antitumor activity in colon cancer].

    PubMed

    Gong, Ting; Zhou, Hong-Li; Ba, Yi

    2013-09-01

    To investigate the anti-tumor activity of CCL21-exCD40L eukaryotic expression vector. CCL21-exCD40L fusion gene were constructed by overlap PCR connecting CCL21 and exCD40L through a flexible linker (Gly3Ser)4, and then was cloned into expression vector pcDNA3.1(+). pcDNA3.1(+)/CCL21 and pcDNA3.1(+)/exCD were constructed as negative control. Wsestern blot was used to identify the fusion protein. CHO cells was transfected with pcDNA3.1(+)/CCL21-exCD, pcDNA3.1(+)/CCL21 and pcDNA3.1(+), respectively. The chemotatic function of the expressed product was detected by Transwell method and its anti-tumor activity was tested with vivo transfection. Gene sequencing and restrictive digestion proved the successful construction of pcDNA3.1(+)/CCL21-exCD40L,and its expression was conformed by western blot. The transfectant supernantes of pcDNA3.1(+)/CCL21-exCD40 group had a significant chmotactic function to DCs, of which the cell numbers passing through the film was 14.95 times of blank control every high power microscope visual field. After tumor orthotoic injection of plasmid carrying fusion gene in Balb/c mouse, the tumor mass reduced remarkablely, and all the mouse in fusion gene group survived after 4 weeks. CCL21-exCD40L fusion protein had a remarkable function to DCs and it can inhibit tumor growth and prolong the mouse survival time, which is more effective than all control group.

  20. Microwave-assisted synthesis, structure and anti-tumor activity of selenized Artemisia sphaerocephala polysaccharide.

    PubMed

    Wang, Junlong; Yang, Xiaoping; Bao, Aijuan; Liu, Xinlong; Zeng, Junyuan; Liu, Xiurong; Yao, Jian; Zhang, Ji; Lei, Ziqiang

    2017-02-01

    In this work, selenylation of Artemisia sphaerocephala polysaccharide (SeASPMW) was studied by using H2SeO3/HNO3/BaCl2 reaction system in microwave field. SeASPMW exhibited the Se content range of 111-264μg/g with high yields (72.1-94.9%). (13)C NMR results indicated that the weak C-6 substitution was occurred. The decrease (from 7.348×10(4)g/mol to 1.736-4.667×10(4)g/mol) in weight average molecular mass (MW) of SeASPMW was observed in size exclusion chromatography combined with multi angle laser light scattering (SEC-MALLS) analysis. SeASPMW exhibited a more rigid solution conformation which might be due to the degradation of polysaccharide chains in acidic reaction reagent. This was also supported by atomic force microscopy (AFM) result that SeASPMW showed short chains and island-like topography. In anti-tumor activity assays, SeASPMW6 exhibited the inhibition rates of 32.381% and 39.776% against human non-small cell lung cancer cell line (H1650) at the concentration of 100 and 200μg/mL, respectively. The relatively weak inhibition effect of SeASPMW was not related to cell apoptosis and cell cycle arrest, suggesting Se content might be a key factor to influence the anti-tumor activities of selenized polysaccharides in vitro. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. 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

  2. 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.

  3. 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.

  4. Memory type 2 helper T cells induce long-lasting antitumor immunity by activating natural killer cells.

    PubMed

    Kitajima, Masayuki; Ito, Toshihiro; Tumes, Damon J; Endo, Yusuke; Onodera, Atsushi; Hashimoto, Kahoko; Motohashi, Shinichiro; Yamashita, Masakatsu; Nishimura, Takashi; Ziegler, Steven F; Nakayama, Toshinori

    2011-07-15

    Functionally polarized helper T cells (Th cells) play crucial roles in the induction of tumor immunity. There is considerable knowledge about the contributions of IFN-producing Th1 cells that supports the role of cytotoxic cluster of differentiation (CD8) T cells and natural killer (NK) cells, but much less is known about how IL-4-producing Th2 cells contribute to tumor immunity. In this study, we investigated the cellular and molecular mechanisms employed by memory Th2 cells in sustaining tumor immunity by using a mouse model system wherein ovalbumin (OVA) is used as a specific tumor antigen. In this model, we found that OVA-specific memory Th2 cells exerted potent and long-lasting antitumor effects against NK-sensitive OVA-expressing tumor cells, wherein antitumor effects were mediated by NK cells. Specifically, NK cell cytotoxic activity and expression of perforin and granzyme B were dramatically enhanced by the activation of memory Th2 cells. Interleukin 4 (IL-4) produced by memory Th2 cells in vivo was critical for the antitumor effects of the NK cells, which IL-4 directly stimulated to induce their perforin- and granzyme-B-dependent cytotoxic activity. Our findings show that memory Th2 cells can induce potent antitumor immunity through IL-4-induced activation of NK cells, suggesting potential applications in cellular therapy for cancer patients. ©2011 AACR.

  5. 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.

  6. 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

  7. 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

  8. 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.

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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

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

    PubMed

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

    2008-07-01

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

  2. 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.

  3. 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.

  4. Crotoxin enhances the antitumor activity of gefinitib (Iressa) in SK-MES-1 human lung squamous carcinoma cells.

    PubMed

    Wang, Jun-Hua; Xie, Yan; Wu, Jun-Chao; Han, Rong; Reid, Paul F; Qin, Zheng-Hong; He, Jing-Kang

    2012-05-01

    Crotoxin (CrTX), a neurotoxin, is isolated from the venom of South American rattlesnakes and has potent antitumor activity. Here, we investigated the antitumor effect of CrTX on the SK-MES-1 human lung squamous cell carcinoma cell line that has acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors. CrTX caused G1 arrest and p-JNK protein upregulation that resulted in apoptosis of SK-MES-1 cells. SP600125, a specific inhibitor of p-JNK, could rescue SK-MES-1 cells from CrTX-induced apoptosis. CrTX and gefinitib (Iressa) both inhibited the viability and proliferation of SK-MES-1 cells in a dose- and time-dependent manner. The combination of CrTX and Iressa significantly enhanced the antitumor activity of Iressa. In vivo studies revealed that CrTX caused increased damage to blood vessels and reduced tumor size when combined with Iressa. The present study showed that the JNK signal transduction pathway mediated the anti-apoptotic effect of CrTX, and furthermore, CrTX could enhance the antitumor effect of tyrosine kinase inhibitors in cells with acquired resistance.

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

    PubMed

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

    2017-09-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2017-05-01

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

  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. 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

  9. Alkyl Caffeates Improve the Antioxidant Activity, Antitumor Property and Oxidation Stability of Edible Oil

    PubMed Central

    Wang, Jun; Gu, Shuang-Shuang; Pang, Na; Wang, Fang-Qin; Pang, Fei; Cui, Hong-Sheng; Wu, Xiang-Yang; Wu, Fu-An

    2014-01-01

    Caffeic acid (CA) is distributed widely in nature and possesses strong antioxidant activity. However, CA has lower solubility in non-polar media, which limits its application in fat-soluble food. To increase the lipophilicity of natural antioxidant CA, a series of alkyl caffeates were synthesized and their antioxidant and antitumor activities were investigated. The antioxidant parameters, including the induction period, acid value and unsaturated fatty acid content, of the alkyl caffeates in edible oil were firstly investigated. The results indicated that alkyl caffeates had a lower DPPH IC50 (14–23 µM) compared to CA, dibutyl hydroxy toluene (BHT) and Vitamin C (24–51 µM), and significantly inhibited four human cancer cells (SW620, SW480, SGC7901 and HepG2) with inhibition ratio of 71.4–78.0% by a MTT assay. With regard to the induction period and acid value assays, methyl and butyl caffeates had higher abilities than BHT to restrain the oxidation process and improve the stability of edible oil. The addition of ethyl caffeate to oil allowed maintenance of a higher unsaturated fatty acid methyl ester content (68.53%) at high temperatures. Overall, the alkyl caffeats with short chain length (n<5) assessed better oxidative stability than those with long chain length. To date, this is the first report to the correlations among the antioxidant activity, anticancer activity and oxidative stability of alkyl caffeates. PMID:24760050

  10. 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). Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  11. 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.

  12. 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

  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. 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

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. Antitumor activity of colloidal silver on MCF-7 human breast cancer cells

    PubMed Central

    2010-01-01

    Background Colloidal silver has been used as an antimicrobial and disinfectant agent. However, there is scarce information on its antitumor potential. The aim of this study was to determine if colloidal silver had cytotoxic effects on MCF-7 breast cancer cells and its mechanism of cell death. Methods MCF-7 breast cancer cells were treated with colloidal silver (ranged from 1.75 to 17.5 ng/mL) for 5 h at 37°C and 5% CO2 atmosphere. Cell Viability was evaluated by trypan blue exclusion method and the mechanism of cell death through detection of mono-oligonucleosomes using an ELISA kit and TUNEL assay. The production of NO, LDH, and Gpx, SOD, CAT, and Total antioxidant activities were evaluated by colorimetric assays. Results Colloidal silver had dose-dependent cytotoxic effect in MCF-7 breast cancer cells through induction of apoptosis, shown an LD50 (3.5 ng/mL) and LD100 (14 ng/mL) (*P < 0.05), significantly decreased LDH (*P < 0.05) and significantly increased SOD (*P < 0.05) activities. However, the NO production, and Gpx, CAT, and Total antioxidant activities were not affected in MCF-7 breast cancer cells. PBMC were not altered by colloidal silver. Conclusions The present results showed that colloidal silver might be a potential alternative agent for human breast cancer therapy. PMID:21080962

  20. 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.

  1. Antitumor activity of colloidal silver on MCF-7 human breast cancer cells.

    PubMed

    Franco-Molina, Moisés A; Mendoza-Gamboa, Edgar; Sierra-Rivera, Crystel A; Gómez-Flores, Ricardo A; Zapata-Benavides, Pablo; Castillo-Tello, Paloma; Alcocer-González, Juan Manuel; Miranda-Hernández, Diana F; Tamez-Guerra, Reyes S; Rodríguez-Padilla, Cristina

    2010-11-16

    Colloidal silver has been used as an antimicrobial and disinfectant agent. However, there is scarce information on its antitumor potential. The aim of this study was to determine if colloidal silver had cytotoxic effects on MCF-7 breast cancer cells and its mechanism of cell death. MCF-7 breast cancer cells were treated with colloidal silver (ranged from 1.75 to 17.5 ng/mL) for 5 h at 37°C and 5% CO2 atmosphere. Cell Viability was evaluated by trypan blue exclusion method and the mechanism of cell death through detection of mono-oligonucleosomes using an ELISA kit and TUNEL assay. The production of NO, LDH, and Gpx, SOD, CAT, and Total antioxidant activities were evaluated by colorimetric assays. Colloidal silver had dose-dependent cytotoxic effect in MCF-7 breast cancer cells through induction of apoptosis, shown an LD50 (3.5 ng/mL) and LD100 (14 ng/mL) (*P < 0.05), significantly decreased LDH (*P < 0.05) and significantly increased SOD (*P < 0.05) activities. However, the NO production, and Gpx, CAT, and Total antioxidant activities were not affected in MCF-7 breast cancer cells. PBMC were not altered by colloidal silver. The present results showed that colloidal silver might be a potential alternative agent for human breast cancer therapy.

  2. 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

  3. 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.

  4. 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.

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

    PubMed

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

    2006-05-05

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

  6. 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.

  7. [The pH dependence of kinetic parameters of Penicillium brevicompactum RNAase].

    PubMed

    Krupianko, V I

    1976-04-01

    The effect of pH on the kinetic parameters (Km and Ki) for extracellular acid Penicillium brevicompactum RNAse (pH max 4.7+/-0.1), non-specific to the chemical nature of nucleic bases, was studied. The pKm--pH dependence curve showed bends within the following intervals of pH: 3.5--4.0 and 5.6--6.0 (upward side concavity) and 6.2--6.8 (downward side concavity). The pKi--pH dependence for adenosine-3'-monophosphate as an inhibitor is identical to the pH dependence on pKm for the substrate. On the other hand, the pKi--pH dependence curves obtained for the base-free inhibitors (ribose-5'-monophosphate, or phosphate (adenosine) show no bends within the pH intervals of 3.0--4.0 and 5.6--7.0 respectively. A possibility is discussed of the presence of a carboxylic (pK 3.58+/-0.1) and two imidazole groups (pK 6.42+/-0.1--a weakly protonated and 5.8+/-+/-0.1--a strongly protonated group) in the RNAse active site and their participation in the formation of the RNAse-nucleotide (RNAse-substrate) complex.

  8. 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.

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

    PubMed

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

    2016-05-13

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

  10. 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.

  11. Antitumor and anticancer stem cell activity of a poly ADP-ribose polymerase inhibitor olaparib in breast cancer cells.

    PubMed

    Shimo, Toshiro; Kurebayashi, Junichi; Kanomata, Naoki; Yamashita, Tetsumasa; Kozuka, Yuji; Moriya, Takuya; Sonoo, Hiroshi

    2014-01-01

    Although the poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitor olaparib is known to have potent antitumor activity in BRCA-related breast cancer cells, a limited number of preclinical and clinical studies have shown antitumor activity of olaparib in non-BRCA-related breast cancer. We investigated antitumor activity of olaparib in breast cancer cell lines derived from patients with nonfamilial sporadic breast cancer. Effects of olaparib alone or in combination with five different chemotherapeutic agents on cell growth, cell cycle progression, apoptosis, and proportion of cancer stem cells using the mammosphere assay and CD44/CD24/ESA cell surface marker assay were investigated in a panel of six sporadic breast cancer cell lines. Extracellular-signal-regulated kinase (ERK) phosphorylation was also investigated to elucidate action mechanisms of olaparib. Olaparib inhibited the growth of two estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell lines and two ER-negative and HER2-negative breast cancer cell lines (50% growth inhibitory concentrations 1.3-3.0 μM) associated with G2/M accumulation and induction of apoptosis. In contrast, two HER2-positive cell lines were resistant to olaparib. Interestingly, olaparib significantly decreased the proportion of putative cancer stem cells in either sensitive or resistant cell lines. In addition, olaparib increased expression of p-ERK. Combined treatments of olaparib with a mitogen-activated protein kinase kinase (MEK) inhibitor U0126 completely suppressed expression of p-ERK. These treatments also inhibited the G2/M accumulation and apoptosis induction by olaparib. Among five chemotherapeutic agents commonly used for breast cancer treatment, only an irinotecan metabolite SN38 showed additive antitumor activity with olaparib. Importantly, the combined treatment enhanced the increase in G2/M accumulation and apoptosis induction as well as a decrease in

  12. 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.

  13. 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

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

    PubMed

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

    2016-01-01

    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.

  15. 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.

  16. 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.

  17. Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors.

    PubMed

    Naing, Aung; Papadopoulos, Kyriakos P; Autio, Karen A; Ott, Patrick A; Patel, Manish R; Wong, Deborah J; Falchook, Gerald S; Pant, Shubham; Whiteside, Melinda; Rasco, Drew R; Mumm, John B; Chan, Ivan H; Bendell, Johanna C; Bauer, Todd M; Colen, Rivka R; Hong, David S; Van Vlasselaer, Peter; Tannir, Nizar M; Oft, Martin; Infante, Jeffrey R

    2016-10-10

    Purpose Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. Results In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 μg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. Conclusion AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune

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

    PubMed

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

    2016-05-02

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

  19. 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.

  20. 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

  1. 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

  2. Dendritic cell-induced activation of adaptive and innate antitumor immunity.

    PubMed

    van den Broeke, Leon T; Daschbach, Emily; Thomas, Elaine K; Andringa, Gerda; Berzofsky, Jay A

    2003-12-01

    While studying Ag-pulsed syngeneic dendritic cell (DC) immunization, we discovered that surprisingly, unpulsed DCs induced protection against tumor lung metastases resulting from i.v. injection of a syngeneic BALB/c colon carcinoma CT26 or a syngeneic C57BL/6 lung carcinoma LL/2. Splenocytes or immature splenic DCs did not protect. The protection was mediated by NK cells, in that it was abrogated by treatment with anti-asialo-GM1 but not anti-CD8, and was induced by CD1(-/-) DCs unable to stimulate NKT cells, but did not occur in beige mice lacking NK cells. Protection correlated with increased NK activity, and increased infiltration of NK but not CD8(+) cells in lungs of tumor-bearing mice. Protection depended on the presence of costimulatory molecules CD80, CD86, and CD40 on the DCs, but surprisingly did not require DCs that could make IL-12 or IL-15. Unexpectedly, protection sensitive to anti-asialo-GM1 and increased NK activity were still present 14 mo after DC injection. As NK cells lack memory, we found by depletion that CD4(+) not CD8(+) T cells were required for induction of the NK antitumor response. The role of DCs and CD4(+) T cells provides a novel mechanism for NK cell induction and innate immunity against cancer that may have potential in preventing clinical metastases.

  3. Structural characteristics of pineapple pulp polysaccharides and their antitumor cell proliferation activities.

    PubMed

    Wang, Ling; Tang, De-Qiang; Kuang, Yu; Lin, Feng-Jiao; Su, Yu

    2015-09-01

    Pineapple has a delicious taste and good health benefits. Bioactive polysaccharides are important components of pineapple that might contribute to its health benefits. Since little structural information on these polysaccharides is currently available, the aim of this study was to investigate their structural characteristics and bioactivities. The polysaccharides of pineapple pulp were fractionated into three fractions (PAPs 1-3) by anion exchange chromatography. Their structural characteristics were first identified, including molecular weights and glycosidic linkages. The monosaccharide compositions were revealed as PAP 1 (Ara, Xyl, Man, Glc and Gal), PAP 2 (Rha, Ara, Xyl, Man, Glc and Gal) and PAP 3 (Rha, Ara, Xyl, Man and Gal). Nuclear magnetic resonance (NMR) spectra suggested that PAP 2 had a backbone of → 4)-α-d-Manp-(1 → 2,4)-α-d-Manp-(1 → with branches attached to O-4 of Manp. The NMR data of α-l-Araf-(1→, →3)-α-l-Araf-(1→, →4)-β-d-Galp-(1 → and → 4)-α-d-GalpAMe-(1 → were assigned. PAPs 1 and 2 showed significant antitumor cell proliferation activities against breast carcinoma cell line and strong antioxidant activities. The above findings indicated that PAPs 1-3 contributed much to the health benefits of pineapple. They could be used as health-beneficial food additives in functional foods. © 2015 Society of Chemical Industry.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. Potentiation of ALA-PDT antitumor activity in mice using topical DMXAA

    NASA Astrophysics Data System (ADS)

    Marrero, Allison; Sunar, Ulas; Sands, Theresa; Oseroff, Allan; Bellnier, David

    2009-06-01

    Photodynamic treatment of subcutaneously implanted Colon 26 tumors in BALB/c mice using the aminolevulinic acid (ALA)-induced photosensitizer protoporphyrin IX (PpIX) was shown to be enhanced by the addition of the vascular disrupting agent 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA; Novartis ASA404). DMXAA increases vascular permeability and decreases blood flow in both murine and human tumors. Sufficiently high parenteral DMXAA doses can lead to tumor collapse and necrosis. We have previously reported marked enhancement of antitumor activity when PDT, using either Photofrin or HPPH, is combined with low-dose intraperitoneal DMXAA. We now describe the first attempt to combine topically-applied DMXAA with PDT. For this, DMXAA was applied two hours before PpIX-activating light delivery. PDT with ALA-PDT alone (ALA 20%; 80 J/cm2 delivered at 75 mW/cm2) caused a 39% decrease in tumor volume compared to unirradiated controls. Addition of topical DMXAA to ALA-PDT resulted in a 74% reduction in tumor volume. Diffuse correlation spectroscopy (DCS), a non-invasive blood flow imaging method, is being used to understand the mechanism of this effect and to aid in the proper design of the therapy. For instance, our most recent DCS data suggests that the 2-hour interval between the DMXAA and light applications may not be optimum. This preliminary study suggests a potential role for topical DMXAA in combination with PDT for dermatologic tumors.

  13. Structure characterization and antitumor activity of a polysaccharide from the alkaline extract of king oyster mushroom.

    PubMed

    Liu, Xinkui; Wang, Lin; Zhang, Chunmei; Wang, Hongmin; Zhang, Xiaohong; Li, Yuexia

    2015-03-15

    A water-soluble polysaccharide, designated as KOMAP, was isolated and purified from the alkaline extract of king oyster mushroom, which was composed of glucose (Glc), mannose (Man) and arabinose (Ara) in a molar ratio of 6.2:2.1:2.0. It had an average molecular weight of 2.1×10(4)Da. GC-MS analysis revealed that KOMAP was a linear structure of the polymer with a backbone composed of β-1,4-linked glucopyranosyl and β-1,3,6-linked mannopyranosyl units, which was terminated with α-1-linked arabinofuranosyl unit at C-6 position of β-1,3,6-linked mannopyranosyl residue along the main chain in the ratio of 3.1:1. The results in the animal experiment showed that 50, 100 and 200mg/mL of KOMAP not only inhibited the tumor growth, but also increased relative thymus and spleen indices, LPS- or ConA-induced lymphocytes proliferation, and serum cytokine IL-2, TNF-α, and IFN-γ levels, as well as the activities of NK cells and CTLs in spleen of Renca tumor-bearing mice. In summary, our data indicate that the KOMAP exerts effective immunoregulatory and anti-tumor activities in vivo. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. 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.

  15. Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca alkaloid.

    PubMed

    Kruczynski, A; Colpaert, F; Tarayre, J P; Mouillard, P; Fahy, J; Hill, B T

    1998-01-01

    Vinflunine, or 20',20'-difluoro-3',4'-dihydrovinorelbine, is a novel Vinca alkaloid obtained by hemisynthesis using superacidic chemistry. The most impressive structural modification of this vinorelbine derivative was the selective introduction of two fluorine atoms at the 20' position, a part of the molecule previously inaccessible by classic chemistry. The antitumor activity of vinflunine was evaluated against a range of transplantable murine and human tumors. Vinflunine exhibited marked activity against murine P388 leukemia grafted i.v. when given i.p. in single or multiple doses according to various schedules or in single i.v. or p.o. doses. Increases in life span achieved with vinflunine, as assessed by T/C ratios, ranged from 200% to 457% and proved markedly superior to those of 129-186% obtained with the other Vinca alkaloids tested. Against s.c.-implanted B16 melanoma, multiple i.p. administration of vinflunine proved active in terms of both survival prolongation and tumor growth inhibition, with optimal T/C values and relative areas under the tumor growth curves (rAUC) being 24% and 36%, respectively. The extent of this activity was superior to that noted for vinorelbine under the same experimental conditions. Growth inhibition of human tumor xenografts LX-1 (lung) and MX-1 (breast) was also observed following four weekly i.p. injections of vinflunine as reflected by optimal T/C values of 23% and 26%, respectively, and significant differences in the rAUCs noted for treated versus control animals. It was also noticeable that vinflunine induced considerably more prolonged inhibitory effects on tumor growth than did vinorelbine. These results demonstrate that vinflunine is well tolerated and is definitively active against a range of experimental animal tumor models. Vinflunine activity has been documented in terms of both survival prolongation and tumor growth inhibition, with definite superiority over vinorelbine being shown in each tumor model evaluated.

  16. Evaluation of phytochemical content, antimicrobial, cytotoxic and antitumor activities of extract from Rumex hastatus D. Don roots.

    PubMed

    Sahreen, Sumaira; Khan, Muhammad Rashid; Khan, Rahmat Ali; Hadda, Taibi Ben

    2015-07-03

    Being a part of Chinese as well as ayurdic herbal system, roots of Rumex hastatus D. Don (RH) is highly medicinal, used to regulated blood pressure. It is also reported that the plant is diuretic, laxative, tonic, used against microbial skin diseases, bilious complaints and jaundice. The present study is conducted to evaluate phytochemical, antimicrobial, antitumor and cytotoxic activities of extract obtained from R. hastatus roots. RH roots were powdered and extracted with methanol to get crude extract. Crude extract was further fractioned on the basis of increasing polarity, with n-hexane (HRR), chloroform (CRR), ethyl acetate (ERR), n-butanol (BRR) and residual aqueous fraction (ARR). Methanol extract and its derived fractions were subjected to phytochemical screening and assayed for antibacterial activities via agar well diffusion method. Antifungal activities were checked through agar tube dilution method whereas potato disc assay was employed for the determination of antitumor activity. On the other hand cytotoxic activities were conducted using brine shrimps procedures. The results obtained from phytochemical analysis indicate the presence of alkaloids, anthraquinones, flavonoids and saponins in all the fractions. Most of the plant fractions showed substantial antimicrobial activities, which is in accordance with the spacious use of tested plant samples in primary healthcare center. Fractions of R. hastatus roots for cytotoxicity were tested as an effective cytotoxic was found as BRR > MRR > CRR > ARR > ERR > HRR. Ranking order of fractions of R. hastatus roots for effective antitumor screening was found as MRR > BRR > ARR > CRR > ERR > HRR. These results showed that R. hastatus appeared as an important source for the discovery of new antimicrobial drugs and antitumor agents; verify its traditional uses and its exploitation as therapeutic agent.

  17. 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

  18. 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. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Shikonin Exerts Antitumor Activity via Proteasome Inhibition and Cell Death Induction in vitro and in vivo

    PubMed Central

    Yang, Huanjie; Zhou, Ping; Huang, Hongbiao; Chen, Di; Ma, Ningfang; Cui, Cindy Qiuzhi; Shen, Shouxing; Dong, Weihua; Zhang, Xiaoyan; Lian, Wen; Wang, Xuejun; Dou, Q. Ping; Liu, Jinbao

    2009-01-01

    Dysregulation of the ubiquitin-proteasome pathway plays an essential role in tumor growth and development. Shikonin, a natural naphthoquinone isolated from the traditional Chinese medicine Zi Cao (gromwell), has been reported to possess tumor cell-killing activity, and results from a clinical study using a shikonin-containing mixture demonstrated its safety and efficacy for the treatment of late-stage lung cancer. In the present study, we reported that shikonin is an inhibitor of tumor proteasome activity in vitro and in vivo. Our computational modeling predicts that the carbonyl carbons C1 and C4 of shikonin potentially interact with the catalytic site of β5 chymotryptic subunit of the proteasome. Indeed, shikonin potently inhibits the chymotrypsin-like activity of purified 20S proteasome (IC50 12.5 μmol/L) and tumor cellular 26S proteasome (IC50 between 2-16 μmol/L). Inhibition of the proteasome by shikonin in murine hepatoma H22, leukemia P388 and human prostate cancer PC-3 cultures resulted in accumulation of ubiquitinated proteins and several proteasome target proapoptotic proteins (IκB-α, Bax and p27), followed by induction of cell death. Shikonin treatment resulted in tumor growth inhibition in both H22 allografts and PC-3 xenografts, associated with suppression of the proteasomal activity and induction of cell death in vivo. Finally, shikonin treatment significantly prolonged the survival period of mice bearing P388 leukemia. Our results indicate that the tumor proteasome is one of the cellular targets of shikonin, and inhibition of the proteasome activity by shikonin contributes to its anti-tumor property. PMID:19165859

  20. Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase

    PubMed Central

    2013-01-01

    Background Urokinase (uPA) and its receptor (uPAR) play an important role in tumour growth and metastasis, and overexpression of these molecules is strongly correlated with poor prognosis in a variety of malignant tumours. Targeting the excessive activation of this system as well as the proliferation of the tumour vascular endothelial cell would be expected to prevent tumour neovasculature and halt tumour development. The amino terminal fragment (ATF) of urokinase has been confirmed effective to inhibit the proliferation, migration and invasiveness of cancer cells via interrupting the interaction of uPA and uPAR. Triptolide (TPL) is a purified diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook F that has shown antitumor activities in various cancer cell types. However, its therapeutic application is limited by its toxicity in normal tissues and complications caused in patients. In this study, we attempted to investigate the synergistic anticancer activity of TPL and ATF in various solid tumour cells. Methods Using in vitro and in vivo experiments, we investigated the combined effect of TPL and ATF at a low dosage on cell proliferation, cell apoptosis, cell cycle distribution, cell migration, signalling pathways, xenograft tumour growth and angiogenesis. Results Our data showed that the sensitivity of a combined therapy using TPL and ATF was higher than that of TPL or ATF alone. Suppression of NF-κB transcriptional activity, activation of caspase-9/caspase-3, cell cycle arrest, and inhibition of uPAR-mediated signalling pathway contributed to the synergistic effects of this combination therapy. Furthermore, using a mouse xenograft model, we demonstrated that the combined treatment completely suppressed tumour growth by inhibiting angiogenesis as compared with ATF or TPL treatment alone. Conclusions Our study suggests that lower concentration of ATF and TPL used in combination may produce a synergistic anticancer efficacy that warrants further

  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. 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

  3. Antitumor activity and immune responses induced by a recombinant carcinoembryonic antigen-vaccinia virus vaccine.

    PubMed

    Kantor, J; Irvine, K; Abrams, S; Kaufman, H; DiPietro, J; Schlom, J

    1992-07-15

    Human carcinoembryonic antigen (CEA) is a 180-kd glycoprotein expressed in human colorectal, gastric, pancreatic, breast, and non-small-cell lung carcinomas. Previous studies have demonstrated enhanced immune responses to other antigens presented with vaccinia virus proteins via a recombinant vaccinia virus construct. In addition, we have developed a recombinant CEA-vaccinia virus construct, designated rV(WR)-CEA, and have demonstrated humoral anti-CEA responses in mice after immunization with that virus. The goals of this study were (a) to construct a recombinant CEA-vaccinia vaccine in a less virulent vaccinia strain that is potentially safe and effective for treatment of patients whose tumors express CEA and (b) to evaluate the ability of the recombinant CEA-vaccinia vaccine to prevent and reverse tumor growth in mice and to elicit cell-mediated and humoral anti-CEA immune responses. Using the New York City strain of vaccinia virus, which is used in smallpox vaccination and is more attenuated for humans than rV(WR), we derived a recombinant CEA-vaccinia construct, designated rV(NYC)-CEA. The ability of this construct to induce antitumor immunity was evaluated in mice receiving subcutaneous injections of murine colon adenocarcinoma cells expressing the human CEA gene. Administration of rV(NYC)-CEA in mice induced strong anti-CEA antibody responses, as well as CEA-specific cell-mediated responses, including delayed-type hypersensitivity, lymphoproliferative, and cytotoxic responses. Vaccination of mice with the rV(NYC)-CEA rendered them resistant to the growth of subsequently transplanted CEA-expressing tumors. Moreover, when mice were vaccinated 7 days after tumor cell injection, tumor growth was either greatly reduced or eliminated. No toxic effects were observed in any of the mice. These studies demonstrate that antitumor activity can be induced with the use of a recombinant CEA-vaccinia virus construct derived from an attenuated vaccinia strain, and they

  4. 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.

  5. 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

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

    PubMed

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

    1998-08-01

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

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. Optimized extraction of polysaccharides from Taxus chinensis var. mairei fruits and its antitumor activity.

    PubMed

    Zhao, Chunjian; Li, Zhao; Li, Chunying; Yang, Lei; Yao, Liping; Fu, Yujie; He, Xin; Shi, Kunming; Lu, Zhicheng

    2015-04-01

    The simultaneous ultrasonic/microwave-assisted extraction (UMAE) method is potentially useful for the extraction of polysaccharides from Taxus chinensis var. mairei fruits (TCFPs). In this study, we used a response surface methodology to identify optimal TCFPs extraction conditions. Optimal parameters were determined as follows: a liquid to raw material ratio of 33 mL/g, an extraction time of 10 min, a microwave power level of 560 W, and a fixed ultrasonic power of 50 W. Under the optimized conditions, TCFPs yields obtained by UMAE were 4.33 ± 0.15%, a 1.79-fold increase compared with conventional heating reflux extraction (HRE). In addition, the extraction time used in UMAE was shorter than that required for HRE: 10 versus 90 min. UMAE is therefore a rapid and efficient method for the extraction of TCFPs. The inhibitory effect of TCFPs on S180 tumor growth in vivo was also studied. The tumor inhibition rate of TCFPs was 76.33%, indicating a tumor-inhibiting effect. Analysis of organ weights demonstrated that TCFPs exhibited no toxicity to liver, kidney, spleen, heart, or lung relative to a positive control group. TCFPs thus show antitumor activity with no organ toxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. 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

  17. 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

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

    PubMed

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

    2015-06-20

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

  19. 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. PMID:28408821

  20. 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

  1. 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.

  2. 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.

  3. Selective Antitumor Activity of Ibrutinib in EGFR-Mutant Non–Small Cell Lung Cancer Cells

    PubMed Central

    Gao, Wen; Wang, Michael; Wang, Li; Lu, Haibo; Wu, Shuhong; Dai, Bingbing; Ou, Zhishuo; Zhang, Liang; Heymach, John V.; Gold, Kathryn A.; Minna, John; Roth, Jack A.; Hofstetter, Wayne L.; Swisher, Stephen G.

    2014-01-01

    Ibrutinib, which irreversibly inhibits Bruton tyrosine kinase, was evaluated for antitumor activity in a panel of non–small cell lung cancer (NSCLC) cell lines and found to selectively inhibit growth of NSCLC cells carrying mutations in the epidermal growth factor receptor (EGFR) gene, including T790M mutant and erlotinib-resistant H1975 cells. Ibrutinib induced dose-dependent inhibition of phosphor-EGFR at both Y1068 and Y1173 sites, suggesting ibrutinib functions as an EGFR inhibitor. Survival was analyzed by Kaplan–Meier estimation and log-rank test. All statistical tests were two-sided. In vivo study showed that ibrutinib statistically significantly suppressed H1975 tumor growth and prolonged survival of the tumor bearing mice (n = 5 per group). The mean survival times for solvent- and erlotinib-treated mice were both 17.8 days (95% confidence interval [CI] = 14.3 to 21.3 days), while the mean survival time for ibrutinib-treated mice was 29.8 days (95% CI = 26.0 to 33.6 days, P = .008). Our results indicate that ibrutinib could be a candidate drug for treatment of EGFR-mutant NSCLC, including erlotinib-resistant tumors. PMID:25214559

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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

  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. 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.

  12. 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.

  13. Codelivery of Doxorubicin and Paclitaxel by Cross-Linked Multilamellar Liposome Enables Synergistic Antitumor Activity

    PubMed Central

    2015-01-01

    Combining chemotherapeutics is a promising method of improving cancer treatment; however, the clinical success of combination therapy is limited by the distinct pharmacokinetics of combined drugs, which leads to nonuniform distribution. In this study, we report a new robust approach to load two drugs with different hydrophilicities into a single cross-linked multilamellar liposomal vesicle (cMLV) to precisely control the drug ratio that reaches the tumor in vivo. The stability of cMLVs improves the loading efficiency and sustained release of doxorubicin (Dox) and paclitaxel (PTX), maximizing the combined therapeutic effect and minimizing the systemic toxicity. Furthermore, we show that the cMLV formulation maintains specific drug ratios in vivo for over 24 h, enabling the ratio-dependent combination synergy seen in vitro to translate to in vivo antitumor activity and giving us control over another parameter important to combination therapy. This combinatorial delivery system may provide a new strategy for synergistic delivery of multiple chemotherapeutics with a ratiometric control over encapsulated drugs to treat cancer and other diseases. PMID:24673622

  14. 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.

  15. High- and low-Molecular Weight oat Beta-Glucan Reveals Antitumor Activity in Human Epithelial Lung Cancer.

    PubMed

    Choromanska, Anna; Kulbacka, Julita; Harasym, Joanna; Oledzki, Remigiusz; Szewczyk, Anna; Saczko, Jolanta

    2017-07-29

    Beta-glucans are widely used in treatment, cosmetics, and the food industry. Glucans play a significant role in activation of the immune and antioxidant system and inhibiting tumor proliferation. In the current study the antitumor activities of new high and low molecular weight beta-glucan derived from oats were investigated in two human lung cancer cell line (A549, H69AR) and normal keratinocytes (HaCaT). The effect of high and low molecular weight beta-glucan from oat was evaluated by cellular viability assessment, lipid peroxidation and manganese superoxide dismutase evaluation and cytoskeleton visualisation. Additionally the level of red blood cells hemolysis was performed. Our results indicate strong anti-tumor properties of new beta-glucan from oat and at the same time no toxicity for normal cells.

  16. 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

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

    PubMed

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

    2010-09-15

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

  18. Anti-tumor activity of paclitaxel through dual-targeting lipoprotein-mimicking nanocarrier.

    PubMed

    Chen, Conghui; Hu, Haiyang; Qiao, Mingxi; Zhao, Xiuli; Wang, Yinjie; Chen, Kang; Chen, Dawei

    2015-05-01

    In the present study, we devised a strategy that paclitaxel (PTX) with lipid and octadecylamine were prepared to lipid nanoparticle (PTX-LNP) with positive charge, folic acid-modified bovine serum albumin (FB)-coated surface of PTX-LNP through electrostatic attraction and generated the lipoprotein-mimicking nanocomplex (FB-PTX-LNP) for dual-targeting therapy. Bovine serum albumin (BSA) was used as the protein model due to its specific targeting to tumor by increased transendothelial gp60-mediated transport and increased intratumoral accumulation as a result of the secreted protein, acidic and rich in cysteine (SPARC)-albumin interaction. The further conjugating folic acid to BSA achieved the dual active targeting. In vitro cytotoxicity tests suggested FB-PTX-LNP and BSA-PTX-LNP exhibited significantly higher cytotoxic activity against MCF-7 and HepG2 cells compared to PTX-LNP. The cellular uptake experiments indicated that FB-coumarin-6-LNP modified with dual-targeting had a faster and greater cellular uptake when compared to BSA-coumarin-6-LNP and coumarin-6-LNP by MCF-7 cells. Thus, both BSA and FA did play roles in in vitro cytotoxicity and cellular uptake. Furthermore, the targeting ability and therapeutic efficacy of FB-PTX-LNP were assessed in vivo. FB-PTX-LNP produced very marked targeting ability and anti-tumor activity in MDA-MB-231 tumor-bearing mice. These results indicate the protein-lipid nanocomplex FB-PTX-LNP is a potential nanocarrier for Paclitaxel dual-targeting to tumor.

  19. Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2.

    PubMed

    Niu, Feng; Zhao, Song; Xu, Chang-Yan; Sha, Hui; Bi, Gui-Bin; Chen, Lin; Ye, Long; Gong, Ping; Nie, Tian-Hong

    2015-10-01

    Osteosarcoma is the most frequent primary malignant bone tumor that occurs in children and adolescents. The present study aimed to identify novel therapeutic strategies for osteosarcoma, by assessing the antitumor activity of the cannabinoid WIN-55,212-2 and its combined effect with adriamycin (ADM) against the MG-63 human osteosarcoma cell line. To evaluate the antiproliferative action of these molecules, a Cell Counting kit-8 (CCK-8) assay was used. The ability of cannabinoid to inhibit the migration, invasion and angiogenic activity of MG-63 cells were assessed by scratch, Transwell® chamber and angiogenesis assays, respectively, in vitro. To examine the alterations in expression of targeted genes, quantitative polymerase chain reaction and western blot analysis were used. The administration of cannabinoid combined with ADM was demonstrated to inhibit the growth of MG-63 cells, resulting in a cell viability of 32.12±3.13%, which was significantly lower (P<0.05) compared with the cell viability following treatment with cannabinoid (70.86±7.55%) and ADM (62.87±5.98%) alone. Greater antimetastasis and antiangiogenic activities were also observed following the coadministration of the two agents compared with individual treatments and controls. In addition, the expression levels of Notch-1, matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in MG-63 cells were downregulated following the treatments with cannabinoid alone or in combination with ADM. In conclusion, the present findings demonstrated that cannabinoid WIN-55,212-2 may significantly potentiate the antiproliferative, antimetastasis and antiangiogenic effects of ADM against MG-63 cells via the downregulation of Notch-1, MMP-2 and VEGF. These findings may offer a novel strategy for the treatment of osteosarcoma.

  20. GITR ligand provided by thrombopoietic cells inhibits NK cell antitumor activity.

    PubMed

    Placke, Theresa; Salih, Helmut R; Kopp, Hans-Georg

    2012-07-01

    Thrombocytopenia inhibits tumor growth and especially metastasis in mice, whereas additional depletion of NK cells reverts this antimetastatic phenotype. It has therefore been speculated that platelets may protect hematogenously disseminating tumor cells from NK-dependent antitumor immunity. Tumor cells do not travel through the blood alone, but are rapidly coated by platelets, and this phenomenon has been proposed to shield disseminating tumor cells from NK-mediated lysis. However, the underlying mechanisms remain largely unclear. In this study, we show that megakaryocytes acquire expression of the TNF family member glucocorticoid-induced TNF-related ligand (GITRL) during differentiation, resulting in GITRL expression by platelets. Upon platelet activation, GITRL is upregulated on the platelet surface in parallel with the α-granular activation marker P-selectin. GITRL is also rapidly mobilized to the platelet surface following interaction with tumor cells, which results in platelet coating. Whereas GITRL, in the fashion of several other TNF family members, is capable of transducing reverse signals, no influence on platelet activation and function was observed upon GITRL triggering. However, platelet coating of tumor cells inhibited NK cell cytotoxicity and IFN-γ production that could partially be restored by blocking GITR on NK cells, thus indicating that platelet-derived GITRL mediates NK-inhibitory forward signaling via GITR. These data identify conferment of GITRL pseudoexpression to tumor cells by platelets as a mechanism by which platelets may alter tumor cell immunogenicity. Our data thus provide further evidence for the involvement of platelets in facilitating evasion of tumor cells from NK cell immune surveillance.

  1. 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.

  2. 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.

  3. Cloning and soluble expression of mature alpha-luffin from Luffa cylindrica and its antitumor activities in vitro.

    PubMed

    Liu, Liling; Wang, Rupeng; He, Wei; He, Fengtian; Huang, Gang

    2010-08-01

    Luffin-a, a single-chain Type I ribosome-inactivating protein, which is known to be the most toxic of the luffin family and apparently possesses antitumor activity, was isolated from Luffa cylindrica seeds. In the present study, mature alpha-luffin was cloned from L. cylindrica and it was found that mature alpha-luffin shared 96% amino acid similarity with luffin-a. The recombinant mature alpha-luffin was successfully expressed in a partly soluble form in Escherichia coli after optimization of expression conditions. The effects of the recombinant protein on bacterial growth and its in vitro protein synthesis inhibition activity were tested. Then, its antitumor activities against different human cancer cell lines were evaluated by CCK-8 assay and flow cytometry. The results indicated that the recombinant alpha-luffin was slightly toxic to E. coli. It could inhibit protein synthesis in the rabbit reticulocyte lysate system. At the same time, it inhibited the growth of the tumor cell lines in a dose- and time-dependent manner. Additionally, recombinant alpha-luffin was able to induce cell death by apoptosis. The cytotoxicity of alpha-luffin towards tumor cells makes it a potential antitumor agent.

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

    PubMed

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

    2014-07-15

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

  5. 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

  6. 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

  7. Vibrational spectroscopic study on pH dependence of some diazines

    NASA Astrophysics Data System (ADS)

    Billes, F.; Gál, M.

    1986-03-01

    The infrared and Raman spectra of several pyrazines and pyridazines were measured in a wide acidity range. Methods of measurements were elaborated for extreme acidity conditions. The approximate assignments of some spectra were determined. The spectra show bands with pH depending frequencies and intensities and give information on the solute—solvent interaction.

  8. Selective anti-tumor activity of the novel fluoropyrimidine polymer F10 towards G48a orthotopic GBM tumors.

    PubMed

    Gmeiner, William H; Lema-Tome, Carla; Gibo, Denise; Jennings-Gee, Jamie; Milligan, Carol; Debinski, Waldemar

    2014-02-01

    F10 is a novel anti-tumor agent with minimal systemic toxicity in vivo and which displays strong cytotoxicity towards glioblastoma (GBM) cells in vitro. Here we investigate the cytotoxicity of F10 towards GBM cells and evaluate the anti-tumor activity of locally-administered F10 towards an orthotopic xenograft model of GBM. The effects of F10 on thymidylate synthase (TS) inhibition and Topoisomerase 1 (Top1) cleavage complex formation were evaluated using TS activity assays and in vivo complex of enzyme bioassays. Cytotoxicity of F10 towards normal brain was evaluated using cortices from embryonic (day 18) mice. F10 displays minimal penetrance of the blood-brain barrier and was delivered by intra-cerebral (i.c.) administration and prospective anti-tumor response towards luciferase-expressing G48a human GBM tumors in nude mice was evaluated using IVIS imaging. Histological examination of tumor and normal brain tissue was used to assess the selectivity of anti-tumor activity. F10 is cytotoxic towards G48a, SNB-19, and U-251 MG GBM cells through dual targeting of TS and Top1. F10 is not toxic to murine primary neuronal cultures. F10 is well-tolerated upon i.c. administration and induces significant regression of G48a tumors that is dose-dependent. Histological analysis from F10-treated mice revealed tumors were essentially completely eradicated in F10-treated mice while vehicle-treated mice displayed substantial infiltration into normal tissue. F10 displays strong efficacy for GBM treatment with minimal toxicity upon i.c. administration establishing F10 as a promising drug-candidate for treating GBM in human patients.

  9. Role of a bacillus Calmette-Guérin fibronectin attachment protein in BCG-induced antitumor activity.

    PubMed

    Zhao, W; Schorey, J S; Bong-Mastek, M; Ritchey, J; Brown, E J; Ratliff, T L

    2000-04-01

    Intravesical Mycobacterium bovis bacillus Calmette-Gu*erin (BCG) is the treatment of choice for superficial bladder cancer. Previous studies showed that attachment of BCG to fibronectin within the bladder was necessary for mediation of the antitumor response. Further studies identified a bacterial receptor, fibronectin attachment protein (FAP), as an important mediator of BCG attachment to fibronectin. In vitro studies showed that a stable BCG/fibronectin interaction was dependent on FAP binding to fibronectin; however, no role for FAP in the attachment of BCG in vivo has been characterized. We now report the cloning of the M. bovis BCG FAP (FAP-B) and demonstrate an important role for FAP in the in vivo attachment of BCG to the bladder wall and in the induction of BCG-mediated antitumor activity. The predicted amino acid sequence for FAP-B shows 61% and 71% homology, respectively, with Mycobacterium avium FAP (FAP-A) and Mycobacterium leprae FAP (FAP-L). Rabbit polyclonal antibodies against Mycobacterium vaccae FAP (FAP-V) reacted with all 3 recombinant FAP proteins on Western blots. Functional studies show FAP-B to bind fibronectin via the highly conserved attachment regions previously identified for FAP-A and FAP-L and also to competitively inhibit attachment of BCG to matrix fibronectin. In vivo studies show FAP to be a necessary protein for the stable attachment of BCG to the bladder wall. Moreover, stable binding of BCG via FAP was shown to be necessary for the expression of BCG-induced antitumor activity. Our results demonstrate a biological role for FAP in the mediation of BCG-induced antitumor activity.

  10. 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

  11. 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

  12. The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma.

    PubMed

    Pignochino, Ymera; Dell'Aglio, Carmine; Inghilleri, Simona; Zorzetto, Michele; Basiricò, Marco; Capozzi, Federica; Canta, Marta; Piloni, Davide; Cemmi, Francesca; Sangiolo, Dario; Gammaitoni, Loretta; Soster, Marco; Marchiò, Serena; Pozzi, Ernesto; Morbini, Patrizia; Luisetti, Maurizio; Aglietta, Massimo; Grignani, Giovanni; Stella, Giulia M

    2015-05-08

    Malignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify 'druggable' pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus. We planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in 'hot spot' regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA). Phosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice. ERM and mTOR pathways are activated in MPM and 'druggable' by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM.

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

    PubMed

    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

    2016-06-01

    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.

  14. Antitumor Activities of Rauwolfia vomitoria Extract and Potentiation of Carboplatin Effects Against Ovarian Cancer☆

    PubMed Central

    Yu, Jun; Ma, Yan; Drisko, Jeanne; Chen, Qi

    2013-01-01

    Background Tumor resistance to platinum-based drugs has been an obstacle to the treatment of ovarian cancer. Extract of the plant Rauwolfia vomitoria has long been used by cancer patients. However, there have not been systematic studies of its anticancer activity. Objective In an effort to enhance the effectiveness of platinum-based drugs, we investigated the anticancer effect of a Rauwolfia vomitoria extract (Rau), both alone and in combination with carboplatin (Cp). Methods In vitro cytotoxicity and colony formation were evaluated in several ovarian cancer cell lines. In vivo effects were evaluated in an intraperitoneal ovarian cancer mouse model. The combination of Rau and Cp was assessed using Chou-Talalay’s constant ratio design and median effect analysis based on the isobologram principle to determine the combination index values. Results Rau decreased cell growth in all 3 tested ovarian cancer cell lines dose dependently and completely inhibited formation of colonies in soft agar. Apoptosis was induced in a time- and dose-dependent manner and was the predominant form of Rau-induced cell death. Synergy of Rau with Cp was detected, with combination index values <1 and dose reduction index values for Cp ranging from 1.7- to 7-fold. Tumor growth in mice was significantly suppressed by 36% or 66% with Rau treatment alone at a low (20 mg/kg) or a high dose (50 mg/kg), respectively, an effect comparable to that of Cp alone. The volume of ascitic fluid and the number of nonblood cells in ascites were also significantly decreased. Combining Rau with Cp remarkably enhanced the effect of Cp and reduced tumor burden by 87% to 90% and ascites volume by 89% to 97%. Conclusions Rau has potent antitumor activity and in combination significantly enhances the effect of Cp against ovarian cancer. PMID:24465036

  15. 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. Prolif