Potentiation of antitumor immunity in tumor-bearing mice by a degraded D-manno-D-glucan (DMG), a new antitumor polysaccharide.

Science.gov (United States)

Nakajima, H; Kita, Y; Hashimoto, S; Tsukada, W; Abe, S; Mizuno, D

1983-12-01

DMG, a degraded D-manno-D-glucan from the culture fluid of Microellobosporia grisea, inhibited the growth of murine syngeneic MM46 mammary carcinoma. Mice in which the tumor had completely regressed by DMG treatment showed tumor-specific antitumor resistance. The antitumor action of DMG was studied by examining the influences of DMG on tumor-specific and non-specific immune responses in tumor-bearing hosts. The tumor-specific delayed hypersensitivity reaction appeared transiently on day 7 after tumor inoculation but had decreased by day 15 in untreated tumor-bearing mice. In contrast, the reaction was retained and augmented in DMG-treated tumor-bearing mice. The tumor-neutralizing activity of spleen cells from DMG-treated tumor-bearing mice, tested by a Winn assay, was tumor-specific and significantly higher than that of untreated tumor-bearing mice. The tumor-neutralizing activity of peritoneal cells and the in vitro cytostatic activity of peritoneal macrophages in response to lymphokine supernatants containing macrophage activation factor were also augmented by DMG treatment. In contrast, the level of antitumor antibody in the serum increased with time, irrespective of DMG administration. Thus, DMG potentiated cellular antitumor effector mechanisms.

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

Directory of Open Access Journals (Sweden)

Subrata Chakraborty

2015-05-01

Full Text Available 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.

An Update on Antitumor Activity of Naturally Occurring Chalcones

Directory of Open Access Journals (Sweden)

En-Hui Zhang

2013-01-01

Full Text Available 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.

Anti-tumor Activity of Toll-Like Receptor 7 Agonists

Directory of Open Access Journals (Sweden)

Huju Chi

2017-05-01

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

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

African Journals Online (AJOL)

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

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

Science.gov (United States)

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.

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

Science.gov (United States)

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

2013-01-01

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

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

African Journals Online (AJOL)

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

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

Directory of Open Access Journals (Sweden)

Song Zhang

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

Antitumor Activity of Monoterpenes Found in Essential Oils

Directory of Open Access Journals (Sweden)

Marianna Vieira Sobral

2014-01-01

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

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

African Journals Online (AJOL)

user

the anti-tumor activity of α-MMC-PEG decreased by about 30% in vitro. This sensitivity increase of 50 ... experiments and were acclimatized in the animal room. They were housed on aspen ..... PEGylation, successful approach to drug delivery.

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

Directory of Open Access Journals (Sweden)

Akihiro Ohashi

Full Text Available 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.

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

African Journals Online (AJOL)

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

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

Science.gov (United States)

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

2017-06-01

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

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

Directory of Open Access Journals (Sweden)

Lu Wang

2014-01-01

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

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

Directory of Open Access Journals (Sweden)

Svetla Angelova

2013-01-01

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

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

Directory of Open Access Journals (Sweden)

Collado Antonia

2006-05-01

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

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

International Nuclear Information System (INIS)

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

2006-01-01

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

Hydrogels based on polysaccharide-calcium phosphate with antibacterial / antitumor activity for 3D printing

Science.gov (United States)

Teterina, A. Yu; Fedotov, A. Yu; Zobkov, Yu V.; Sergeeva, N. S.; Sviridova, I. K.; Kirsanova, V. A.; Karalkin, P. A.; Komlev, V. S.

2018-04-01

The purpose of this study was to develop hydrogels for 3D printing of sodium alginate/gelatin/octacalcium phosphate-based constructs with antibacterial and antitumor activity intended for bone defects replacement in patients with malignant diseases. In this work, we evaluated the drug release kinetic and physico-chemical characteristics of constructs, as well as their specific activity, biocompatibility and osteoplastic properties by means of in vitro and in vivo tests. The principal possibility of creating the biocompatible bone substitutes with antibacterial/antitumor activity and osteoconductive-retaining properties of 3D printing method was demonstrated.

Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition.

Science.gov (United States)

Meng, Fanying; Bhupathi, Deepthi; Sun, Jessica D; Liu, Qian; Ahluwalia, Dharmendra; Wang, Yan; Matteucci, Mark D; Hart, Charles P

2015-05-21

The hypoxia-activated prodrug TH-302 is reduced at its nitroimidazole group and selectively under hypoxic conditions releases the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Here, we have explored the effect of Chk1 inhibition on TH-302-mediated pharmacological activities. We employed in vitro cell viability, DNA damage, cellular signaling assays and the in vivo HT29 human tumor xenograft model to study the effect of Chk1inhibition on TH-302 antitumor activities. TH-302 cytotoxicity is greatly enhanced by Chk1 inhibition in p53-deficient but not in p53-proficient human cancer cell lines. Chk1 inhibitors reduced TH-302-induced cell cycle arrest via blocking TH-302-induced decrease of phosphorylation of histone H3 and increasing Cdc2-Y15 phosphorylation. Employing the single-cell gel electrophoresis (comet) assay, we observed a potentiation of the TH-302 dependent tail moment. TH-302 induced γH2AX and apoptosis were also increased upon the addition of Chk1 inhibitor. Potentiation of TH-302 cytotoxicity by Chk1 inhibitor was only observed in cell lines proficient in, but not deficient in homology-directed DNA repair. We also show that combination treatment led to lowering of Rad51 expression levels as compared to either agent alone. In vivo data demonstrate that Chk1 inhibitor enhances TH-302 anti-tumor activity in p53 mutant HT-29 human tumor xenografts, supporting the hypothesis that these in vitro results can translate to enhanced in vivo efficacy of the combination. TH-302-mediated in vitro and in vivo anti-tumor activities were greatly enhanced by the addition of Chk1 inhibitors. The preclinical data presented in this study support a new approach for the treatment of p53-deficient hypoxic cancers by combining Chk1 inhibitors with the hypoxia-activated prodrug TH-302.

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

Directory of Open Access Journals (Sweden)

Ida Genta

2017-12-01

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

Effects of Different Temperatures on the Chemical Structure and Antitumor Activities of Polysaccharides from Cordyceps militaris

Directory of Open Access Journals (Sweden)

Eliyas Nurmamat

2018-04-01

Full Text Available The effects of different extraction temperatures (4 and 80 °C on the physicochemical properties and antitumor activity of water soluble polysaccharides (CMPs-4 and CMPs-80 from Cordyceps militaris (C. militaris were evaluated in this study. The results of gas chromatography (GC and high-performance gel permeation chromatography (HPGPC showed that a higher extraction temperature could degrade the polysaccharides with 188 kDa, mainly composed of glucose, and increase the dissolution rate of polysaccharides about 308 kDa, mainly consisting of rhamnose and galactose. In addition, the CMPs displayed the same sugar ring and category of glycosidic linkage based on Fourier-transform infrared spectroscopy (FTIR analysis, however, their invisible structural difference occurred in the specific rotation and conformational characteristics according to the results of specific optical rotation measurement and Congo red test. In vitro antitumor experiments indicated that CMPs-4 possessed stronger inhibitory effects on human esophagus cancer Eca-109 cells by inducing cell apoptosis more than CMPs-80 did. These findings demonstrated that the polysaccharides extracted with cold water (4 °C could be applied as a novel alternative chemotherapeutic agent or dietary supplement with its underlying antitumor property.

Experimental study on anti-tumor effect of pcEgr-IFNγ gene-radiotherapy

International Nuclear Information System (INIS)

Wu Congmei; Li Xiuyi; Liu Shuzheng

2001-01-01

Objective: To study the anti-tumor effect of IFN γ gene-radiotherapy to murine melanoma and its immunologic mechanism. Methods: pcEgr-IFNγ plasmids were injected locally into tumor, and 36 hours later, the tumors were given 20 Gy X-ray irradiation. Tumor growth at different time, IFN γ expression 3 days later and immunologic indexes 15 days later were detected. Results: At 3-15 days after pcEgr-IFNγ gene-radiotherapy, the tumor growth rate was lower than that of irradiation alone group. It was also lower than that of gene therapy alone group and control plasmid combined with X-ray irradiation group significantly. Day 3 tumor IFN γ expression was higher than that of plasmid treatment alone group. NK activity, IL-2 and IFN γ secretion activities were higher than those of gene therapy alone and irradiation alone groups significantly. Conclusion: The antitumor effect of IFN γ gene-radiotherapy is better than that of either of them applied solely. Its mechanism might be concerned with the higher expression of IFN γ induced by irradiation in tumors and activation of anti-tumor immunologic functions

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

International Nuclear Information System (INIS)

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

2015-01-01

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

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

Science.gov (United States)

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

2018-01-01

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

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

African Journals Online (AJOL)

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

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

Science.gov (United States)

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

2007-08-01

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

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

Directory of Open Access Journals (Sweden)

Zhu FM

2015-05-01

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

Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand.

Science.gov (United States)

Gourdeau, Henriette; McAlpine, James B; Ranger, Maxime; Simard, Bryan; Berger, Francois; Beaudry, Francis; Farnet, Chris M; Falardeau, Pierre

2008-05-01

ECO-4601 is a structurally novel farnesylated dibenzodiazepinone discovered through DECIPHER technology, Thallion's proprietary drug discovery platform. The compound was shown to have a broad cytotoxic activity in the low micromolar range when tested in the NCI 60 cell line panel. In the work presented here, ECO-4601 was further evaluated against brain tumor cell lines. Preliminary mechanistic studies as well as in vivo antitumor evaluation were performed. Since ECO-4601 has a benzodiazepinone moiety, we first investigated if it binds the central and/or peripheral benzodiazepine receptors. ECO-4601 was tested in radioligand binding assays on benzodiazepine receptors obtained from rat hearts. The ability of ECO-4601 to inhibit the growth of CNS cancers was evaluated on a panel of mouse, rat and human glioma cell lines using a standard MTT assay. Antitumor efficacy studies were performed on gliomas (rat and human), human breast and human prostate mouse tumor xenografts. Antitumor activity and pharmacokinetic analysis of ECO-4601 was evaluated following intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) bolus administrations. ECO-4601 was shown to bind the peripheral but not the central benzodiazepine receptor and inhibited the growth of CNS tumor cell lines. Bolus s.c. and i.p. administration gave rise to low but sustained drug exposure, and resulted in moderate to significant antitumor activity at doses that were well tolerated. In a rat glioma (C6) xenograft model, ECO-4601 produced up to 70% tumor growth inhibition (TGI) while in a human glioma (U-87MG) xenograft, TGI was 34%. Antitumor activity was highly significant in both human hormone-independent breast (MDA-MB-231) and prostate (PC-3) xenografts, resulting in TGI of 72 and 100%, respectively. On the other hand, i.v. dosing was followed by rapid elimination of the drug and was ineffective. Antitumor efficacy of ECO-4601 appears to be associated with the exposure parameter AUC and/or sustained

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

Directory of Open Access Journals (Sweden)

Chong-Sheng Chen

2014-01-01

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

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

Directory of Open Access Journals (Sweden)

Fatmah A.S. Alasmary

2018-02-01

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

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

Science.gov (United States)

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.

Novel T cells with improved in vivo anti-tumor activity generated by RNA electroporation

Directory of Open Access Journals (Sweden)

Xiaojun Liu

2017-05-01

Full Text Available ABSTRACT The generation of T cells with maximal anti-tumor activities will significantly impact the field of T-cell-based adoptive immunotherapy. In this report, we found that OKT3/IL-2-stimulated T cells were phenotypically more heterogeneous, with enhanced anti-tumor activity in vitro and when locally administered in a solid tumor mouse model. To further improve the OKT3/IL-2-based T cell manufacturing procedure, we developed a novel T cell stimulation and expansion method in which peripheral blood mononuclear cells were electroporated with mRNA encoding a chimeric membrane protein consisting of a single-chain variable fragment against CD3 and the intracellular domains of CD28 and 4-1BB (OKT3-28BB. The expanded T cells were phenotypically and functionally similar to T cells expanded by OKT3/IL-2. Moreover, co-electroporation of CD86 and 4-1BBL could further change the phenotype and enhance the in vivo anti-tumor activity. Although T cells expanded by the co-electroporation of OKT3-28BB with CD86 and 4-1BBL showed an increased central memory phenotype, the T cells still maintained tumor lytic activities as potent as those of OKT3/IL-2 or OKT3-28BB-stimulated T cells. In different tumor mouse models, T cells expanded by OKT3-28BB RNA electroporation showed anti-tumor activities superior to those of OKT3/IL-2 T cells. Hence, T cells with both a less differentiated phenotype and potent tumor killing ability can be generated by RNA electroporation, and this T cell manufacturing procedure can be further optimized by simply co-delivering other splices of RNA, thus providing a simple and cost-effective method for generating high-quality T cells for adoptive immunotherapy.

Enhancement of antitumor activity of OK-432 (picibanil) by Triton X-114 phase partitioning.

Science.gov (United States)

Hashimoto, Masahito; Takashige, Katsuhiro; Furuyashiki, Maiko; Yoshidome, Keitaro; Sano, Ryoko; Kawamura, Yutaka; Ijichi, Shinji; Morioka, Hirofumi; Koide, Hiroyuki; Oku, Naoto; Moriya, Yoichiro; Kusumoto, Shoich; Suda, Yasuo

2008-01-01

OK-432 (Picibanil), a Streptococcal immunotherapeutic agent, has been used for immunotherapy of various cancers as a biological response modifier (BRM). However, OK-432 contains multiple components consisting of immunotherapeutic ones and contaminants which may weaken the effects or exert side-effects. In this study, we investigated extraction of contaminants from OK-432 using Triton X-114 (TX-114)-water phase partitioning and examined an antitumor effect of the resulting preparation. OK-432 was subjected to TX-114 partitioning to give residual precipitate designated as OK-TX-ppt. OK-TX-ppt exerted no TLR2-mediated activity, but induced interleukin (IL)-6 in human PBMC. OK-TX-ppt also induced tumor necrosis factor (TNF)-alpha, IL-10, IL-12, and interferon (IFN)-gamma in PBMC. Moreover, IFN-gamma-inducing activity of OK-TX-ppt was significantly higher and IL-10 production was lower than that of OK-432. In tumor-bearing mice model, administration of OK-TX-ppt i.p. extended the survival time of Meth-A-bearing mice compared to OK-432. OK-TX-ppt also increased the levels of IL-12 and IFN-gamma in mouse spleen cells in vitro. These results indicated that TX-114 partitioning removed some contaminants, which attenuates the antitumor effect, from OK-432 and increase the immunotherapeutic effects of OK-432.

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

Directory of Open Access Journals (Sweden)

Soumen Kahali

2010-01-01

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

Study on fluorouracil–chitosan nanoparticle preparation and its antitumor effect

Directory of Open Access Journals (Sweden)

Gaimin Chen

2016-05-01

Full Text Available To successfully prepare fluorouracil–chitosan nanoparticles, and further analyze its anti-tumor activity mechanism, this paper makes a comprehensive study of existing preparation prescription and makes a detailed analysis of fluorouracil–chitosan in vitro release and pharmacodynamic behavior of animals. Two-step synthesis method is adopted to prepare 5-FU–CS–mPEG prodrugs, and infrared, 1H NMR and differential thermal analysis are adopted to analyze characterization synthetic products of prepared drugs. To ensure clinical efficacy of prepared drugs, UV spectrophotometry is adopted for determination of drug loading capacity of prepared drugs, transmission electron microscopy is adopted to observe the appearance, dynamic dialysis method is used to observe in vitro drug release of prepared drugs and fitting of various release models is done. Anti-tumor effect is studied via level of animal pharmacodynamics. After the end of the experiment, tumor inhibition rate, spleen index and thymus index of drugs are calculated. Experimental results show that the prepared drugs are qualified in terms of regular shape, dispersion, drug content, etc. Animal pharmacodynamics experiments have shown that concentration level of drug loading capacity of prepared drugs has a direct impact on anti-tumor rate. The higher the concentration, the higher the anti-tumor rate. Results of pathological tissue sections of mice show that the prepared drugs cause varying degrees of damage to receptor cells, resulting in cell necrosis or apoptosis problem. It can thus be concluded that ion gel method is an effective method to prepare drug-loading nanoparticles, with prepared nanoparticles evenly distributed in regular shape which demonstrate good slow-release characteristics in receptor vitro and vivo. At the same time, after completion of drug preparation, relatively strong anti-tumor activity can be generated for the receptor, so this mode of preparation enjoys broad

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

Science.gov (United States)

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

2015-09-26

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

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

Science.gov (United States)

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.

Antitumor activity of zoledronic acid in primary breast cancer cells determined by the ATP tumor chemosensitivity assay

International Nuclear Information System (INIS)

Fehm, Tanja; Zwirner, Manfred; Wallwiener, Diethelm; Seeger, Harald; Neubauer, Hans

2012-01-01

The NeoAzure study has demonstrated that the use of the bisphosphonate zoledronic acid (Zol) in the neoadjuvant setting increases the rate of complete response in primary breast cancer and therefore indicates direct antitumor activity. The purpose of this study was to compare the antitumor effect of Zol with standard chemotherapy in primary breast cancer cells using ATP-tumor chemosensitivity assay (ATP-TCA). Breast cancer specimens were obtained from patients with breast cancer who underwent primary breast cancer surgery at the Department of Obstetrics and Gynecology, Tübingen, Germany, between 2006 through 2009. Antitumor effects of Zol, TAC (Docetaxel, Adriamycin, Cyclophosphamide) and FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) were tested in 116 fresh human primary breast cancer specimens using ATP-TCA. ATP-TCA results were analyzed with different cut-off levels for the half maximal inhibitory concentration (IC50), for IC90 and for the sensitivity index (IndexSUM). Each single agent or combination was tested at six doubling dilutions from 6.25, 12.5, 25, 50, 100, and 200% of test drug concentrations (TDC) derived from the plasma peak concentrations determined by pharmacokinetic data. The assay was carried out in duplicate wells with positive and negative controls. The median IndexSUM value was lower for Zol than for the combined regimen FEC (36.8%) and TAC (12.9%), respectively, indicating increased antitumor activity of Zol in primary breast cancer cells. The difference regarding Zol and FEC was significant (p < 0.05). The median IC50 value for Zol (8.03% TDC) was significantly lower than the IC50 values for FEC (33.5% TDC) and TAC (19.3% TDC) treatment (p < 0.05). However, the median IC90 value for Zol (152.5% TDC) was significantly higher than the IC90 value obtained with TAC (49.5% TDC; p < 0.05), but similar to the IC90 value for FEC (180.9% TDC). In addition a significant positive correlation was observed for the IndexSum of Zol and the ER status

Cholesterol negatively regulates IL-9-producing CD8+ T cell differentiation and antitumor activity.

Science.gov (United States)

Ma, Xingzhe; Bi, Enguang; Huang, Chunjian; Lu, Yong; Xue, Gang; Guo, Xing; Wang, Aibo; Yang, Maojie; Qian, Jianfei; Dong, Chen; Yi, Qing

2018-05-09

CD8 + T cells can be polarized into IL-9-secreting (Tc9) cells. We previously showed that adoptive therapy using tumor-specific Tc9 cells generated stronger antitumor responses in mouse melanoma than classical Tc1 cells. To understand why Tc9 cells exert stronger antitumor responses, we used gene profiling to compare Tc9 and Tc1 cells. Tc9 cells expressed different levels of cholesterol synthesis and efflux genes and possessed significantly lower cholesterol content than Tc1 cells. Unique to Tc9, but not other CD8 + or CD4 + T cell subsets, manipulating cholesterol content in polarizing Tc9 cells significantly affected IL-9 expression and Tc9 differentiation and antitumor response in vivo. Mechanistic studies showed that IL-9 was indispensable for Tc9 cell persistence and antitumor effects, and cholesterol or its derivatives inhibited IL-9 expression by activating liver X receptors (LXRs), leading to LXR Sumoylation and reduced p65 binding to Il9 promoter. Our study identifies cholesterol as a critical regulator of Tc9 cell differentiation and function. © 2018 Ma et al.

[Effective productions of plant secondary metabolites having antitumor activity by plant cell and tissue cultures].

Science.gov (United States)

Taniguchi, Shoko

2005-06-01

Methods for the effective production of plant secondary metabolites with antitumor activity using plant cell and tissue cultures were developed. The factors in tannin productivity were investigated using culture strains producing different types of hydrolyzable tannins, i.e., gallotannins (mixture of galloylglucoses), ellagi-, and dehydroellagitannins. Production of ellagi- and dehydroellagitannins was affected by the concentrations and ratio of nitrogen sources in the medium. The formation of oligomeric ellagitannins in shoots of Oenothera tetraptera was correlated with the differentiation of tissues. Cultured cells of Eriobotrya japonica producing ursane- and oleanane-type triterpenes with antitumor activities were also established.

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

Science.gov (United States)

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

2016-04-20

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

Induction of mitophagy-mediated antitumor activity with folate-appended methyl-β-cyclodextrin.

Science.gov (United States)

Kameyama, Kazuhisa; Motoyama, Keiichi; Tanaka, Nao; Yamashita, Yuki; Higashi, Taishi; Arima, Hidetoshi

2017-01-01

Mitophagy is the specific autophagic elimination system of mitochondria, which regulates cellular survival via the removal of damaged mitochondria. Recently, we revealed that folate-appended methyl-β-cyclodextrin (FA-M-β-CyD) provides selective antitumor activity in folate receptor-α (FR-α)-expressing cells by the induction of autophagy. In this study, to gain insight into the detailed mechanism of this antitumor activity, we focused on the induction of mitophagy by the treatment of FR-α-expressing tumor cells with FA-M-β-CyD. In contrast to methyl-β-cyclodextrin, FA-M-β-CyD entered KB cells, human epithelial cells from a fatal cervical carcinoma (FR-α (+)) through FR-α-mediated endocytosis. The transmembrane potential of isolated mitochondria after treatment with FA-M-β-CyD was significantly elevated. In addition, FA-M-β-CyD lowered adenosine triphosphate (ATP) production and promoted reactive oxygen species production in KB cells (FR-α (+)). Importantly, FA-M-β-CyD enhanced light chain 3 (LC3) conversion (LC3-I to LC3-II) in KB cells (FR-α (+)) and induced PTEN-induced putative kinase 1 (PINK1) protein expression, which is involved in the induction of mitophagy. Furthermore, FA-M-β-CyD had potent antitumor activity in BALB/c nu/nu mice xenografted with KB cells (FR-α (+)) without any significant side effects. Taken together, these findings demonstrate that the autophagic cell death elicited by FA-M-β-CyD could be associated with mitophagy induced by an impaired mitochondrial function.

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

Science.gov (United States)

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

2010-04-01

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

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

International Nuclear Information System (INIS)

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

2014-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

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

2014-09-01

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

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

Directory of Open Access Journals (Sweden)

Flávia R. S. Lucena

2010-05-01

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

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

Science.gov (United States)

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

2014-11-01

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

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

Energy Technology Data Exchange (ETDEWEB)

Zamola, B; Karminski-Zamola, G; Fuks, Z; Kubovic, M [Zagreb Univ. (Yugoslavia); Wrishcer, M [Institut Rudjer Boskovic, Zagreb (Yugoslavia)

1985-03-01

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

Antitumor and angiostatic activities of the antimicrobial peptide dermaseptin B2.

Science.gov (United States)

van Zoggel, Hanneke; Carpentier, Gilles; Dos Santos, Célia; Hamma-Kourbali, Yamina; Courty, José; Amiche, Mohamed; Delbé, Jean

2012-01-01

Recently, we have found that the skin secretions of the Amazonian tree frog Phyllomedusa bicolor contains molecules with antitumor and angiostatic activities and identified one of them as the antimicrobial peptide dermaseptin (Drs) B2. In the present study we further explored the in vitro and in vivo antitumor activity of this molecule and investigated its mechanism of action. We showed that Drs B2 inhibits the proliferation and colony formation of various human tumor cell types, and the proliferation and capillary formation of endothelial cells in vitro. Furthermore, Drs B2 inhibited tumor growth of the human prostate adenocarcinoma cell line PC3 in a xenograft model in vivo. Research on the mechanism of action of Drs B2 on tumor PC3 cells demonstrated a rapid increasing amount of cytosolic lactate dehydrogenase, no activation of caspase-3, and no changes in mitochondrial membrane potential. Confocal microscopy analysis revealed that Drs B2 can interact with the tumor cell surface, aggregate and penetrate the cells. These data together indicate that Drs B2 does not act by apoptosis but possibly by necrosis. In conclusion, Drs B2 could be considered as an interesting and promising pharmacological and therapeutic leader molecule for the treatment of cancer.

Antitumor and angiostatic activities of the antimicrobial peptide dermaseptin B2.

Directory of Open Access Journals (Sweden)

Hanneke van Zoggel

Full Text Available Recently, we have found that the skin secretions of the Amazonian tree frog Phyllomedusa bicolor contains molecules with antitumor and angiostatic activities and identified one of them as the antimicrobial peptide dermaseptin (Drs B2. In the present study we further explored the in vitro and in vivo antitumor activity of this molecule and investigated its mechanism of action. We showed that Drs B2 inhibits the proliferation and colony formation of various human tumor cell types, and the proliferation and capillary formation of endothelial cells in vitro. Furthermore, Drs B2 inhibited tumor growth of the human prostate adenocarcinoma cell line PC3 in a xenograft model in vivo. Research on the mechanism of action of Drs B2 on tumor PC3 cells demonstrated a rapid increasing amount of cytosolic lactate dehydrogenase, no activation of caspase-3, and no changes in mitochondrial membrane potential. Confocal microscopy analysis revealed that Drs B2 can interact with the tumor cell surface, aggregate and penetrate the cells. These data together indicate that Drs B2 does not act by apoptosis but possibly by necrosis. In conclusion, Drs B2 could be considered as an interesting and promising pharmacological and therapeutic leader molecule for the treatment of cancer.

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

Science.gov (United States)

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

2014-02-19

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

Bovine lactoferrin and lactoferricin exert antitumor activities on human colorectal cancer cells (HT-29) by activating various signaling pathways.

Science.gov (United States)

Jiang, Rulan; Lönnerdal, Bo

2017-02-01

Lactoferrin (Lf) is an iron-binding glycoprotein that is present at high concentrations in milk. Bovine lactoferricin (LfcinB) is a peptide fragment generated by pepsin proteolysis of bovine lactoferrin (bLf). LfcinB consists of amino acid residues 17-41 proximal to the N-terminus of bLf and a disulfide bond between residues 19 and 36, forming a loop. Both bLf and LfcinB have been demonstrated to have antitumor activities. Colorectal cancer is the second most common cause of cancer death in developed countries. We hypothesized that bLf and LfcinB exert antitumor activities on colon cancer cells (HT-29) by triggering various signaling pathways. bLf and LfcinB significantly induced apoptosis in HT-29 cells but not in normal human intestinal epithelial cells, as revealed by the ApoTox-Glo Triplex Assay. The LIVE/DEAD cell viability assay showed that both bLf and LfcinB reduced the viability of HT-29 cells. Transcriptome analysis indicated that bLf, cyclic LfcinB, and linear LfcinB exerted antitumor activities by differentially activating diverse signaling pathways, including p53, apoptosis, and angiopoietin signaling. Immunoblotting results confirmed that both bLf and LfcinBs increased expression of caspase-8, p53, and p21, critical proteins in tumor suppression. These results provide valuable information regarding bLf and LfcinB for potential clinical applications in colon cancer therapy.

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

Directory of Open Access Journals (Sweden)

Ivanka Jerić

2011-11-01

Full Text Available 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.

Anti-Tumor Activity of a Polysaccharide from Blueberry

Directory of Open Access Journals (Sweden)

Xiyun Sun

2015-02-01

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

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

Directory of Open Access Journals (Sweden)

Liu Y

2015-03-01

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

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

African Journals Online (AJOL)

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

Hypoxia-targeting antitumor prodrugs and photosensitizers

International Nuclear Information System (INIS)

Zhang Zhouen; Nishimoto, S.I.

2006-01-01

Tumor hypoxia has been identified as a key subject for tumor therapy, since hypoxic tumor cells show resistance to treatment of tumor tissues by radiotherapy, chemotherapy and phototherapy. For improvement of tumor radiotherapy, we have proposed a series of radiation-activated prodrugs that could selectively release antitumor agent 5-fluorouracil or 5-fluorodeoxyuridine under hypoxic conditions. Recently, we attempted to develop two families of novel hypoxia-targeting antitumor agents, considering that tumor-hypoxic environment is favorable to biological and photochemical reductions. The first family of prodrugs was derived from camptothecin as a potent topoisomerase I inhibitor and several bioreductive motifs. These prodrugs could be activated by NADPH-cytochrome P450 reductase or DT-diaphorase to release free camptothecin, and thereby showed hypoxia-selective cytotoxictiy towards tumor cells. These prodrugs were also applicable to the real-time monitoring of activation and antitumor effect by fluorometry. Furthermore, the camptothecin-bioreductive motif conjugates was confirmed to show an oxygen-independent DAN photocleaving activity, which could overcome a drawback of back electron transfer occurring in the photosensitized one-electron oxidation of DNA. Thus, these camptothecin derivatives could be useful to both chemotherapy and phototherapy for hypoxic tumor cells. The second family of prodrugs harnessed UV light for cancer therapy, incorporating the antitumor agent 5-fluorourcil and the photolabile 2-nitrobenzyl chromophores. The attachment of a tumor-homing cyclic peptide CNGRC was also employed to construct the prototype of tumor-targeting photoactiaved antitumor prodrug. These novel prodrugs released high yield of 5-fluorourcil upon UV irradiation at λ ex =365 nm, while being quite stable in the dark. The photoactivation mechanism was also clarified by means of nanosecond laser flash photolysis. (authors)

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

Directory of Open Access Journals (Sweden)

Ma M

2012-07-01

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’-tetramethylindotricarbocyanine iodide mimicked M-DOC in optical imaging, and accumulated more in tumors in comparison with I-DOC.Conclusion: These results suggest that the lipid-based nanomicelle system was effective in inhibiting tumor growth, with little toxicity. Moreover, we have developed a noninvasive optical imaging method for antitumor drug evaluation, which merits further analysis for potential clinical applications.Keywords: docetaxel, lipid-based micelles, antitumor activity, in vivo optical imaging

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

Science.gov (United States)

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.

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

Science.gov (United States)

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

1997-04-01

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

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

Science.gov (United States)

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

2012-08-01

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

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

Science.gov (United States)

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.

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

Science.gov (United States)

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. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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

Science.gov (United States)

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

Anti-tumor activity of N-hydroxy-7-(2-naphthylthio) heptanomide, a novel histone deacetylase inhibitor

International Nuclear Information System (INIS)

Kim, Dong Hoon; Lee, Jiyong; Kim, Kyung Noo; Kim, Hye Jin; Jeung, Hei Cheul; Chung, Hyun Cheol; Kwon, Ho Jeong

2007-01-01

Histone deacetylase (HDAC), a key enzyme in gene expression and carcinogenesis, is considered an attractive target molecule for cancer therapy. Here, we report a new synthetic small molecule, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), as a HDAC inhibitor with anti-tumor activity both in vitro and in vivo. The compound inhibited HDAC enzyme activity as well as proliferation of human fibrosarcoma cells (HT1080) in vitro. Treatment of cells with HNHA elicited histone hyperacetylation leading to an up-regulation of p21 transcription, cell cycle arrest, and an inhibition of HT1080 cell invasion. Moreover, HNHA effectively inhibited the growth of tumor tissue in a mouse xenograph assay in vivo. Together, these data demonstrate that this novel HDAC inhibitor could be developed as a potential anti-tumor agent targeting HDAC

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

Directory of Open Access Journals (Sweden)

Chuanjin Wang

2016-01-01

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

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

Directory of Open Access Journals (Sweden)

Luciano Polonelli

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

Rhenium–platinum antitumor systems

Directory of Open Access Journals (Sweden)

A. V. Shtemenko

2017-04-01

Full Text Available This review provides an overlook of design (in short, antitumor and other biological activity of quadruple-bonded cluster dirhenium(III compounds and their synergism with cisplatin. In particular, we describe the work of the rhenium-platinum antitumor system (introduction of rhenium and platinum compounds. Among known metal-based anticancer drugs and drug candidates dirhenium(III compounds differ profoundly due to their strong antiradical and antioxidant properties determined by quadruple bond unsaturation. Such advantages of metal complexes as more expressed redox chemical propertie should be exploited for creating more efficient anticancer drugs. Combination of drugs leads to synergistic effects and/or to lowe­ring toxicity of platinides and is very promising in cancer chemotherapy. The review covers the follo­wing items: design of quadruple bonded dirhenium(III clusters, their spectral and antiradical properties (in short; interaction of the dirhenium(III compounds with lipids and formation of liposomes; interaction of the dirhenium(III compounds with erythrocytes and their antihemolytic activity in the models of hemolytic anemia; anticancer activity of dirhenium clusters and work of the rhenium-platinum antitumor system; antianemic and antioxidant properties of the dirhenium(III compounds in the model of tumor growth; interaction of the dirhenium(III compounds with nucleobases and DNA. Some modern trends in the field of bioinorganic and medicinal chemi­stry are also considered regarding their connection to the rhenium-platinum system efficiency: use of combinational therapy and nanomaterials; involvement of some biologically active ligands and redox-activation strategy, etc.

The antitumor activity of a doxorubicin loaded, iRGD-modified sterically-stabilized liposome on B16-F10 melanoma cells: in vitro and in vivo evaluation

Directory of Open Access Journals (Sweden)

Yu KF

2013-07-01

Full Text Available Ke-Fu Yu,1 Wei-Qiang Zhang,1 Li-Min Luo,1 Ping Song,1 Dan Li,1 Ruo Du,1 Wei Ren,1 Dan Huang,1 Wan-Liang Lu,1,2 Xuan Zhang,1 Qiang Zhang1,2 1Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China; 2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China Abstract: Considering the fact that iRGD (tumor-homing peptide demonstrates tumor-targeting and tumor-penetrating activity, and that B16-F10 (murine melanoma cells overexpress both αv integrin receptor and neuropilin-1 (NRP-1, the purpose of this study was to prepare a novel doxorubicin (DOX-loaded, iRGD-modified, sterically-stabilized liposome (SSL (iRGD-SSL-DOX in order to evaluate its antitumor activity on B16-F10 melanoma cells in vitro and in vivo. The iRGD-SSL-DOX was prepared using a thin-film hydration method. The characteristics of iRGD-SSL-DOX were evaluated. The in vitro leakage of DOX from iRGD-SSL-DOX was tested. The in vitro tumor-targeting and tumor-penetrating characteristics of iRGD-modified liposomes on B16-F10 cells were investigated. The in vivo tumor-targeting and tumor-penetrating activities of iRGD-modified liposomes were performed in B16-F10 tumor-bearing nude mice. The antitumor effect of iRGD-SSL-DOX was evaluated in B16-F10 tumor-bearing C57BL/6 mice in vivo. The average particle size of the iRGD-SSL-DOX was found to be 91 nm with a polydispersity index (PDI of 0.16. The entrapment efficiency of iRGD-SSL-DOX was 98.36%. The leakage of DOX from iRGD-SSL-DOX at the 24-hour time point was only 7.5%. The results obtained from the in vitro flow cytometry and confocal microscopy, as well as in vivo biodistribution and confocal immunofluorescence microscopy experiments, indicate that the tumor-targeting and tumor-penetrating activity of the iRGD-modified SSL was higher than that of unmodified SSL. In vivo antitumor activity

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

Directory of Open Access Journals (Sweden)

Cong Wang

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

Phase I trial with BMS-275183, a novel oral taxane with promising antitumor activity

NARCIS (Netherlands)

Broker, LE; de Vos, FYFL; van Groeningen, CJ; Kuenen, BC; Gall, HE; Woo, MH; Voi, M; Gietema, JA; deVries, EGE; Giaccone, G

2006-01-01

Purpose: BMS-275183 is an orally administered C-4 methyl carbonate analogue of paclitaxel. We did a dose-escalating phase I study to investigate its safety, tolerability, pharmacokinetics, and possible antitumor activity. Experimental Design: A cycle consisted of four weekly doses of BMS-275183. The

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

Science.gov (United States)

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

2012-08-01

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

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

Directory of Open Access Journals (Sweden)

Gong Haiyan

2016-07-01

Full Text Available 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.

Induction of mitophagy-mediated antitumor activity with folate-appended methyl-β-cyclodextrin

Directory of Open Access Journals (Sweden)

Kameyama K

2017-04-01

Full Text Available Kazuhisa Kameyama,1,* Keiichi Motoyama,1,* Nao Tanaka,1 Yuki Yamashita,1 Taishi Higashi,1 Hidetoshi Arima1,2,* 1Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, 2Program for Leading Graduate Schools “HIGO (Health Life Science: Interdisciplinary and Glocal Oriented Program,” Kumamoto University, Kumamoto, Japan *These authors contributed equally to this work Abstract: Mitophagy is the specific autophagic elimination system of mitochondria, which regulates cellular survival via the removal of damaged mitochondria. Recently, we revealed that folate-appended methyl-β-cyclodextrin (FA-M-β-CyD provides selective antitumor activity in folate receptor-α (FR-α-expressing cells by the induction of autophagy. In this study, to gain insight into the detailed mechanism of this antitumor activity, we focused on the induction of mitophagy by the treatment of FR-α-expressing tumor cells with FA-M-β-CyD. In contrast to methyl-β-cyclodextrin, FA-M-β-CyD entered KB cells, human epithelial cells from a fatal cervical carcinoma (FR-α (+ through FR-α-mediated endocytosis. The transmembrane potential of isolated mitochondria after treatment with FA-M-β-CyD was significantly elevated. In addition, FA-M-β-CyD lowered adenosine triphosphate (ATP production and promoted reactive oxygen species production in KB cells (FR-α (+. Importantly, FA-M-β-CyD enhanced light chain 3 (LC3 conversion (LC3-I to LC3-II in KB cells (FR-α (+ and induced PTEN-induced putative kinase 1 (PINK1 protein expression, which is involved in the induction of mitophagy. Furthermore, FA-M-β-CyD had potent antitumor activity in BALB/c nu/nu mice xenografted with KB cells (FR-α (+ without any significant side effects. Taken together, these findings demonstrate that the autophagic cell death elicited by FA-M-β-CyD could be associated with mitophagy induced by an impaired mitochondrial function. Keywords: mitophagy, autophagy, folate receptor, methyl

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

Science.gov (United States)

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

2013-01-01

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

Oligodeoxynucleotides Expressing Polyguanosine Motifs Promote Anti-Tumor Activity through the Up-Regulation of IL-2

Science.gov (United States)

Kobayashi, Nobuaki; Hong, Choongman; Klinman, Dennis M.; Shirota, Hidekazu

2012-01-01

The primary goal of cancer immunotherapy is to elicit an immune response capable of eliminating the tumor. One approach towards accomplishing that goal utilizes general (rather than tumor-specific) immunomodulatory agents to boost the number and activity of pre-existing cytotoxic T lymphocytes. We find that the intra-tumoral injection of poly-G ODN has such an effect, boosting anti-tumor immunity and promoting tumor regression. The anti-tumor activity of polyguanosine (poly-G) oligonucleotides (ODN) was mediated through CD8 T cells in a TLR9 independent manner. Mechanistically, poly-G ODN directly induced the phosphorylation of Lck (an essential element of the T cell signaling pathway), thereby enhancing the production of IL-2 and CD8 T cell proliferation. These findings establish poly-G ODN as a novel type of cancer immunotherapy. PMID:23296706

Oral JS-38, a metabolite from Xenorhabdus sp., has both anti-tumor activity and the ability to elevate peripheral neutrophils.

Science.gov (United States)

Liu, Min-Yu; Xiao, Lin; Chen, Geng-Hui; Wang, Yong-Xiang; Xiong, Wei-Xia; Li, Fei; Liu, Ying; Huang, Xiao-Ling; Deng, Yi-Fang; Zhang, Zhen; Sun, Hai-Yan; Liu, Quan-Hai; Yin, Ming

2014-10-01

JS-38 (mitothiolore), a synthetic version of a metabolite isolated from Xenorhabdus sp., was evaluated for its anti-tumor and white blood cell (WBC) elevating activities. These anti-proliferative activities were assessed in vitro using a panel of ten cell lines. The anti-tumor activities were tested in vivo using B16 allograft mouse models and xenograft models of A549 human lung carcinoma and QGY human hepatoma in nude mice. The anti-tumor interactions of JS-38 and cyclophosphamide (CTX) or 5-fluorouracil (5-Fu) were studied in a S180 sarcoma model in ICR mice. Specific stimulatory effects were determined on peripheral neutrophils in normal and CTX- and 5-Fu-induced neutropenic mice. The IC50 values ranged from 0.1 to 2.0 μmol·L(-1). JS-38 (1 μmol·L(-1)) caused an increase in A549 tumor cell apoptosis. Multi-daily gavage of JS-38 (15, 30, and 60 mg·kg(-1)·d(-1)) inhibited in vivo tumor progression without a significant effect on body weight. JS-38 additively enhanced the in vivo anti-tumor effects of CTX or 5-Fu. JS-38 increased peripheral neutrophil counts and neutrophil rates in normal BALB/c mice almost as effectively as granulocyte colony-stimulating factor (G-CSF). In mice with neutropenia induced by CTX or 5-Fu, JS-38 rapidly restored neutrophil counts. These results suggest that JS-38 has anti-tumor activity, and also has the ability to increase peripheral blood neutrophils. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

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

Directory of Open Access Journals (Sweden)

Sergio Arancibia

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

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

Science.gov (United States)

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

2014-01-01

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

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

Science.gov (United States)

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

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

Directory of Open Access Journals (Sweden)

Jun Wang

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

Time-dependent Influence of Procaine Hydrochloride on Cisplatin Antitumor Activity in P388 Tumor Bearing Mice

Czech Academy of Sciences Publication Activity Database

Viale, M.; Vánnozzi, M. O.; Mandys, Václav; Esposito, M.

2001-01-01

Roč. 21, - (2001), s. 485-488 ISSN 0250-7005 Institutional research plan: CEZ:AV0Z5039906 Keywords : cisplatin * procaine * antitumor activity Subject RIV: EA - Cell Biology Impact factor: 1.416, year: 2001

Antitumor effect of degalactosylated gc-globulin on orthotopic grafted lung cancer in mice.

Science.gov (United States)

Hirota, Keiji; Nakagawa, Yoshinori; Takeuchi, Ryota; Uto, Yoshihiro; Hori, Hitoshi; Onizuka, Shinya; Terada, Hiroshi

2013-07-01

Group-specific component (Gc)-globulin-derived macrophage-activating factor (GcMAF) generated by a cascade of catalytic reactions with deglycosidase enzymes exerts antitumor activity. We hypothesized that degalactosyl Gc-globulin (DG3), a precursor of GcMAF, also plays a role in recovery from cancer as well as GcMAF due to progression of deglycosylation by generally resident sialidases and mannosidases. We prepared the subtypes of DG3, such as 1f1f and 1s1s and its 22 homodimers, by using vitamin D3-binding Sepharose CL-6B and examined their antitumor activity in mice bearing Lewis lung carcinoma cells, by counting the number of nodules formed in their lungs. Antitumor activity of DG3 was observed regardless of its subtype, being equivalent to that of GcMAF. The injection route of DG3 affected its antitumor activity, with subcutaneous and intramuscular administration being more favorable than the intraperitoneal or intravenous route. In order to obtain significant antitumor activity, more than 160 ng/kg of DG3 were required. DG3 proved to be promising as an antitumor agent, similarly to GcMAF.

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice

Directory of Open Access Journals (Sweden)

Shoya Shiromizu

2018-04-01

Full Text Available Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Keywords: l-asparaginase, Asparagine, Solid tumor, Chrono-pharmacotherapy

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.

Science.gov (United States)

Shiromizu, Shoya; Kusunose, Naoki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

2018-04-01

Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

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

Directory of Open Access Journals (Sweden)

Shiming Ye

2017-01-01

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

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

Directory of Open Access Journals (Sweden)

Kevine Kamga Silihe

2017-05-01

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

Antitumor and Immunomodulating Activities of Exopolysaccharide Produced by Big Cup Culinary- Medicinal Mushroom Clitocybe maxima (Higher Basidiomycetes) in Liquid Submerged Culture.

Science.gov (United States)

Hu, Shu-Hui; Cheung, Peter Chi Keung; Hung, Raw-Pou; Chen, Yu-Kuei; Wang, Jinn-Chyi; Chang, Sue-Joan

2015-01-01

Water-soluble polysaccharides extracted from mushrooms have been found to have some physiological effects. In this study, exopolysaccharides (EPSs) were extracted by alcohol precipitation from cultivated broth of the mushroom Clitocybe maxima. EPSs with molecular weights of 10(4) and 10(5) Da were obtained by ultrafiltration; they are referred to as EPA and EPB, respectively. The major components of these EPSs were glucose, galactose, mannose, rhamnose, and arabinose. ICR mice with artificially induced metastatic pulmonary tumors were fed a daily diet containing EPA or EPB at doses of 8, 20, or 50 mg/kg. Results showed that the proliferation of pulmonary sarcoma lesions was lower in the groups fed EPS. In addition, the numbers of total T cells, CD4+ cells, CD8+ cells, and macrophages significantly increased in EPS-fed mice compared with the negative control group. The antitumor and immunomodulating effects observed in the EPB-fed groups were higher than those of EPA-fed groups. These results demonstrate the ability of EPSs of C. maxima to inhibit tumor cells while enhancing immune response.

Antitumor activity and systemic effects of PVM/MA-shelled selol nanocapsules in lung adenocarcinoma-bearing mice

International Nuclear Information System (INIS)

De Souza, Ludmilla Regina; Muehlmann, Luis Alexandre; Matos, Lívia Carneiro; Lacava, Zulmira Guerreiro Marques; Báo, Sônia Nair; Azevedo, Ricardo Bentes; Simón-Vázquez, Rosana; González-Fernández, África; De-Paula, Alfredo Maurício Batista; Mosiniewicz-Szablewska, Ewa; Suchocki, Piotr; Morais, Paulo César

2015-01-01

Selol is a semi-synthetic compound containing selenite that is effective against cancerous cells and safer for clinical applications in comparison with other inorganic forms of selenite. Recently, we have developed a formulation of poly(methyl vinyl ether-co-maleic anhydride)-shelled selol nanocapsules (SPN), which reduced the proliferative activity of lung adenocarcinoma cells and presented little deleterious effects on normal cells in in vitro studies. In this study, we report on the antitumor activity and systemic effects induced by this formulation in chemically induced lung adenocarcinoma-bearing mice. The in vivo antitumor activity of the SPN was verified by macroscopic quantification, immunohistochemistry and morphological analyses. Toxicity analyses were performed by evaluations of the kidney, liver, and spleen; analyses of hemogram and plasma levels of alanine aminotransferase, aspartate transaminase, urea, and creatinine; and DNA fragmentation and cell cycle activity of the bone marrow cells. Furthermore, we investigated the potential of the SPN formulation to cause hemolysis, activate the complement system, provoke an inflammatory response and change the conformation of the plasma proteins. Our results showed that the SPN reduced the area of the surface tumor nodules but not the total number of tumor nodules. The biochemical and hematological findings were suggestive of the low systemic toxicity of the SPN formulation. The surface properties of the selol nanocapsules point to characteristics that are consistent with the treatment of the tumors in vivo: low hemolytic activity, weak inflammatory reaction with no activation of the complement system, and mild or absent conformational changes of the plasma proteins. In conclusion, this report suggests that the SPN formulation investigated herein exhibits anti-tumoral effects against lung adenocarcinoma in vivo and is associated with low systemic toxicity and high biocompatibility. (paper)

Scoparone exerts anti-tumor activity against DU145 prostate cancer cells via inhibition of STAT3 activity.

Directory of Open Access Journals (Sweden)

Jeong-Kook Kim

Full Text Available Scoparone, a natural compound isolated from Artemisia capillaris, has been used in Chinese herbal medicine to treat neonatal jaundice. Signal transducer and activator of transcription 3 (STAT3 contributes to the growth and survival of many human tumors. This study was undertaken to investigate the anti-tumor activity of scoparone against DU145 prostate cancer cells and to determine whether its effects are mediated by inhibition of STAT3 activity. Scoparone inhibited proliferation of DU145 cells via cell cycle arrest in G1 phase. Transient transfection assays showed that scoparone repressed both constitutive and IL-6-induced transcriptional activity of STAT3. Western blot and quantitative real-time PCR analyses demonstrated that scoparone suppressed the transcription of STAT3 target genes such as cyclin D1, c-Myc, survivin, Bcl-2, and Socs3. Consistent with this, scoparone decreased phosphorylation and nuclear accumulation of STAT3, but did not reduce phosphorylation of janus kinase 2 (JAK2 or Src, the major upstream kinases responsible for STAT3 activation. Moreover, transcriptional activity of a constitutively active mutant of STAT3 (STAT3C was inhibited by scoparone, but not by AG490, a JAK2 inhibitor. Furthermore, scoparone treatment suppressed anchorage-independent growth in soft agar and tumor growth of DU145 xenografts in nude mice, concomitant with a reduction in STAT3 phosphorylation. Computational modeling suggested that scoparone might bind the SH2 domain of STAT3. Our findings suggest that scoparone elicits an anti-tumor effect against DU145 prostate cancer cells in part through inhibition of STAT3 activity.

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

Energy Technology Data Exchange (ETDEWEB)

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

2012-10-23

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

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

Directory of Open Access Journals (Sweden)

C.B.A. Menezes

2013-01-01

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

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

International Nuclear Information System (INIS)

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

2012-01-01

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

Antitumor Effects of Saffron-Derived Carotenoids in Prostate Cancer Cell Models

Directory of Open Access Journals (Sweden)

Claudio Festuccia

2014-01-01

Full Text Available Crocus sativus L. extracts (saffron are rich in carotenoids. Preclinical studies have shown that dietary intake of carotenoids has antitumor effects suggesting their potential preventive and/or therapeutic roles. We have recently reported that saffron (SE and crocin (CR exhibit anticancer activity by promoting cell cycle arrest in prostate cancer (PCa cells. It has also been demonstrated that crocetin esters are produced after SE gastrointestinal digestion by CR hydrolysis. The aim of the present report was to investigate if SE, crocetin (CCT, and CR affected in vivo tumor growth of two aggressive PCa cell lines (PC3 and 22rv1 which were xenografted in male nude mice treated by oral gavage with SE, CR, and CCT. We demonstrated that the antitumor effects of CCT were higher when compared to CR and SE and treatments reverted the epithelial-mesenchymal transdifferentiation (EMT as attested by the significant reduction of N-cadherin and beta-catenin expression and the increased expression of E-cadherin. Additionally, SE, CR, and CCT inhibited PCa cell invasion and migration through the downmodulation of metalloproteinase and urokinase expression/activity suggesting that these agents may affect metastatic processes. Our findings suggest that CR and CCT may be dietary phytochemicals with potential antitumor effects in biologically aggressive PCa cells.

Monocyte-derived dendritic cells are essential for CD8+ T cell activation and anti-tumor responses after local immunotherapy

Directory of Open Access Journals (Sweden)

Sabine eKuhn

2015-11-01

Full Text Available Tumors harbor several populations of dendritic cells with the ability to prime tumor-specific T cells. However, these T cells mostly fail to differentiate into armed effectors and are unable to control tumor growth. We have previously shown that treatment with immunostimulatory agents at the tumor site can activate anti-tumor immune responses, and is associated with the appearance of a population of monocyte-derived dendritic cells in the tumor and tumor-draining lymph node. Here we use dendritic cell or monocyte depletion and monocyte transfer to show that these monocyte-derived dendritic cells are critical to the activation of anti-tumor immune responses. Treatment with the immunostimulatory agents Monosodium Urate crystals and Mycobacterium smegmatis induced the accumulation of monocytes in the draining lymph node, their upregulation of CD11c and MHCII, and expression of iNOS, TNFα and IL12p40. Blocking monocyte entry into the lymph node and tumor through neutralization of the chemokine CCL2 or inhibition of Colony Stimulating Factor-1 receptor signaling prevented the generation of monocyte-derived dendritic cells, the infiltration of tumor-specific T cells into the tumor, and anti-tumor responses. In a reciprocal fashion, monocytes transferred into mice depleted of CD11c+ cells were sufficient to rescue CD8+ T cell priming in lymph node and delay tumor growth. Thus monocytes exposed to the appropriate conditions become powerful activators of tumor-specific CD8+ T cells and anti-tumor immunity.

Antitumor activity of a novel and orally available inhibitor of serine palmitoyltransferase

International Nuclear Information System (INIS)

Yaguchi, Masahiro; Shibata, Sachio; Satomi, Yoshinori; Hirayama, Megumi; Adachi, Ryutaro; Asano, Yasutomi; Kojima, Takuto; Hirata, Yasuhiro; Mizutani, Akio; Kiba, Atsushi; Sagiya, Yoji

2017-01-01

Metabolic reprogramming is an essential hallmark of neoplasia. Therefore, targeting cancer metabolism, including lipid synthesis, has attracted much interest in recent years. Serine palmitoyltransferase (SPT) plays a key role in the initial and rate-limiting step of de novo sphingolipid biosynthesis, and inhibiting SPT activity prevents the proliferation of certain cancer cells. Here, we identified a novel and orally available SPT inhibitor, compound-2. Compound-2 showed an anti-proliferative effect in several cancer cell models, reducing the levels of the sphingolipids ceramide and sphingomyelin. In the presence of compound-2, exogenously added S1P partially compensated the intracellular sphingolipid levels through the salvage pathway by partially rescuing compound-2-induced cytotoxicity. This suggested that the mechanism underlying the anti-proliferative effect of compound-2 involved the reduction of sphingolipid levels. Indeed, compound-2 promoted multinuclear formation with reduced endogenous sphingomyelin levels specifically in a compound-2-sensitive cell line, indicating that the effect was induced by sphingolipid reduction. Furthermore, compound-2 showed potent antitumor activity without causing significant body weight loss in the PL-21 acute myeloid leukemia mouse xenograft model. Therefore, SPT may be an attractive therapeutic anti-cancer drug target for which compound-2 may be a promising new drug. - Highlights: • We discovered compound-2, a novel and orally available SPT inhibitor. • Compound-2 was cytotoxic against PL-21 acute myeloid leukemia cells. • Compound-2 showed antitumor activity in the PL-21 mouse xenograft model.

3D printed constructs with antibacterial or antitumor activity for surgical treatment of bone defects in cancer patients

Science.gov (United States)

Sergeeva, N. S.; Sviridova, I. K.; Komlev, V. S.; Karalkin, P. A.; Kirsanova, V. A.; Akhmedova, S. A.; Shanskij, Ya. D.; Kuvshinova, E. A.; Fedotov, A. Yu.; Teterina, A. Yu.; Barinov, S. M.

2017-09-01

The concept of functionalization with bioactive molecules and drugs is one of the most advanced areas of modern bone tissue biomaterial science in terms of enhancement of their osteoconductive and therapeutic properties. The purpose of this study was to develop the approaches for 3D printing of sodium alginate /gelatin /octacalcium phosphate-based constructs with antibacterial and antitumor activity intended for bone defects replacement in the patients with malignant diseases. In this work, we evaluated the drug release kinetic and physicochemical characteristics of the constructs, as well as their specific activity, biocompatibility and osteoplastic properties in in vitro and in vivo tests. The experimental results proved the principal possibility of creating the biocompatible bone substitutes with antibacterial/antitumor activity and maintaining osteoconductive properties by means of 3D printing method.

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

Science.gov (United States)

Zhong, Mingqin; Yin, Pinghe; Zhao, Ling

2017-04-01

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

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

International Nuclear Information System (INIS)

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

2011-01-01

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

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

Directory of Open Access Journals (Sweden)

Kyung-A Hwang

2012-04-01

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

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

Science.gov (United States)

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.

Mangiferin exerts antitumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and β-catenin signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Li, Hongzhong; Huang, Jing; Yang, Bing; Xiang, Tingxiu; Yin, Xuedong; Peng, Weiyan; Cheng, Wei [Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Wan, Jingyuan; Luo, Fuling [Department of Pharmacology, Chongqing Medical University, Chongqing (China); Li, Hongyuan [Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Ren, Guosheng, E-mail: rgs726@163.com [Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China)

2013-10-01

Although mangiferin which is a naturally occurring glucosylxanthone has exhibited promising anticancer activities, the detailed molecular mechanism of mangiferin on cancers still remains enigmatic. In this study, the anticancer activity of mangiferin was evaluated in breast cancer cell line-based in vitro and in vivo models. We showed that mangiferin treatment resulted in decreased cell viability and suppression of metastatic potential in breast cancer cells. Further mechanistic investigation revealed that mangiferin induced decreased matrix metalloproteinase (MMP)-7 and -9, and reversal of epithelial–mesenchymal transition (EMT). Moreover, it was demonstrated that mangiferin significantly inhibited the activation of β-catenin pathway. Subsequent experiments showed that inhibiting β-catenin pathway might play a central role in mangiferin-induced anticancer activity through modulation of MMP-7 and -9, and EMT. Consistent with these findings in vitro, the antitumor potential was also verified in mangiferin-treated MDA-MB-231 xenograft mice where significantly decreased tumor volume, weight and proliferation, and increased apoptosis were obtained, with lower expression of MMP-7 and -9, vimentin and active β-catenin, and higher expression of E-cadherin. Taken together, our study suggests that mangiferin might be used as an effective chemopreventive agent against breast cancer. - Highlights: • Mangiferin inhibits growth and metastatic potential in breast cancer cells. • Mangiferin down-regulates MMP-7 and -9 in breast cancer cells. • Mangiferin induces the reversal of EMT in metastatic breast cancer cells. • Mangiferin inhibits the activation of β-catenin pathway in breast cancer cells. • Inhibiting β-catenin is responsible for the antitumor activity of mangiferin.

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

Directory of Open Access Journals (Sweden)

Siqun Jing

2015-01-01

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

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

African Journals Online (AJOL)

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

Enhanced antitumor activity of surface-modified iron oxide nanoparticles and an α-tocopherol derivative in a rat model of mammary gland carcinosarcoma.

Science.gov (United States)

Horák, Daniel; Pustovyy, Vitaliy Igorovych; Babinskyi, Andrii Valeriyovich; Palyvoda, Olga Mikhailovna; Chekhun, Vasyl Fedorovich; Todor, Igor Nikolaevich; Kuzmenko, Oleksandr Ivanovich

2017-01-01

Maghemite (γ-Fe 2 O 3 ) nanoparticles were obtained by coprecipitation of ferrous and ferric salts in an alkaline medium followed by oxidation; the nanoparticles were coated with poly( N,N -dimethylacrylamide) (PDMA) and characterized by transmission electron microscopy, attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering, thermogravimetric and elemental analyses, and magnetic measurements in terms of particle morphology, size, polydispersity, amount of coating, and magnetization, respectively. The effects of α-tocopherol (Toc) and its phenolic (Toc-6-OH) and acetate (Toc-6-Ac) derivatives on Fe 2+ release from γ-Fe 2 O 3 @PDMA, as well as from γ-Fe 2 O 3 and CuFe 2 O 4 nanoparticles (controls), were examined in vitro using 1,10-phenanthroline. The presence of tocopherols enhanced spontaneous Fe 2+ release from nanoparticles, with Toc-6-OH exhibiting more activity than neat Toc. All of the nanoparticles tested were found to initiate blood lipid oxidation in a concentration-dependent manner, as determined by analysis of 2-thiobarbituric acid reactive species. Wistar rats with Walker-256 carcinosarcoma (a model of mammary gland carcinosarcoma) received Toc-6-Ac, magnetic nanoparticles, or their combination per os, and the antitumor activity of each treatment was determined in vivo. γ-Fe 2 O 3 @PDMA nanoparticles exhibited increased antitumor activity compared to both commercial CuFe 2 O 4 particles and the antitumor drug doxorubicin. Moreover, increased antitumor activity was observed after combined administration of γ-Fe 2 O 3 @PDMA nanoparticles and Toc-6-Ac; however, levels of bilirubin, aspartate aminotransferase, and white bloods normalized and did not differ from those of the intact controls. The antitumor activity of the γ-Fe 2 O 3 nanoparticles strongly correlated with Fe 2+ release from the nanoparticles but not with nanoparticle-initiated lipid peroxidation in vitro.

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

Science.gov (United States)

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

2018-04-25

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

Antitumor Activity and Mechanism of a Reverse Transcriptase Inhibitor, Dapivirine, in Glioblastoma

OpenAIRE

Liu, Weiwen; Song, Xian-lu; Zhao, Shan-chao; He, Minyi; Wang, Hai; Chen, Ziyang; Xiang, Wei; Yi, Guozhong; Qi, Songtao; Liu, Yawei

2018-01-01

Ethnopharmacological relevance: Dapivirine is one of reverse transcriptase inhibitors (RTIs). It is the prototype of diarylpyrimidines (DAPY), formerly known as TMC120 or DAPY R147681 (IUPAC name: 4- [[4-(2, 4, 6-trimethylphenyl) amino]-2-pyrimidinyl] amino]-benzonitrile; CAS no.244767-67-7). Aim: The purpose of this study is to investigate the antitumor activity of dapivirine, one of the RTIs, on U87 glioblastoma (GBM) cells in vitro and in vivo. Materials and Methods: U87 GBM cells were cul...

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

Directory of Open Access Journals (Sweden)

Zhi-Yong Wang

2016-01-01

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

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

International Nuclear Information System (INIS)

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

2006-01-01

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

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

International Nuclear Information System (INIS)

Xi, Wei-Hong; Yang, Li-Yun; Cao, Zhong-Yi; Qian, Yong

2015-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

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

2015-02-20

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

Polysaccharies of higher fungi: Biological role, structure and antioxidative activity

NARCIS (Netherlands)

Kozarski, M.S.; Klaus, A.; Niksic, M.; Griensven, van L.J.L.D.; Vrvic, M.M.; Jakovljevic, D.M.

2014-01-01

The fungal polysaccharides attract a lot of attention due to their multiple challenging bio-logical properties, such as: anti-tumor, anti-viral, anticomplementary, anticoagulant, hypo-lipidemic, immunomodulatory and immune-stimulatory activities, which all together make them suitable for application

Hydroxyurea derivatives of irofulven with improved antitumor efficacy.

Science.gov (United States)

Staake, Michael D; Kashinatham, Alisala; McMorris, Trevor C; Estes, Leita A; Kelner, Michael J

2016-04-01

Irofulven is a semi-synthetic derivative of Illudin S, a toxic sesquiterpene isolated from the mushroom Omphalotus illudens. Irofulven has displayed significant antitumor activity in various clinical trials but displayed a limited therapeutic index. A new derivative of irofulven was prepared by reacting hydroxyurea with irofulven under acidic conditions. Acetylation of this new compound with acetic anhydride produced a second derivative. Both of these new derivatives displayed significant antitumor activity in vitro and in vivo comparable to or exceeding that of irofulven. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antitumoral activity of marine organism

International Nuclear Information System (INIS)

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

2010-01-01

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

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

Directory of Open Access Journals (Sweden)

Makanjuola Ogunsina

2013-12-01

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

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

Science.gov (United States)

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

2015-01-01

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

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

Directory of Open Access Journals (Sweden)

Carlos Rogério Figueiredo

2014-10-01

Full Text Available 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.

Chemical Characterization and Antitumor Activities of Polysaccharide Extracted from Ganoderma lucidum

Directory of Open Access Journals (Sweden)

Zengenni Liang

2014-05-01

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

Chemical Characterization and Antitumor Activities of Polysaccharide Extracted from Ganoderma lucidum

Science.gov (United States)

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

Antitumoral activity of marine organism; Actividad antitumoral de los organismos marinos

Energy Technology Data Exchange (ETDEWEB)

Valdes Iglesias, O [Centro de Bioproductos Marinos, La Habana (Cuba); Perez Gil, R; Colom, Y [Instituno Nacional de Oncologia y Radiobiologia (INOR), La Habana (Cuba)

2010-07-01

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

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

Science.gov (United States)

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

2017-02-01

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

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

Science.gov (United States)

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.

Antitumor Activity of Rat Mesenchymal Stem Cells during Direct or Indirect Co-Culturing with C6 Glioma Cells.

Science.gov (United States)

Gabashvili, A N; Baklaushev, V P; Grinenko, N F; Mel'nikov, P A; Cherepanov, S A; Levinsky, A B; Chehonin, V P

2016-02-01

The tumor-suppressive effect of rat mesenchymal stem cells against low-differentiated rat C6 glioma cells during their direct and indirect co-culturing and during culturing of C6 glioma cells in the medium conditioned by mesenchymal stem cells was studied in an in vitro experiment. The most pronounced antitumor activity of mesenchymal stem cells was observed during direct co-culturing with C6 glioma cells. The number of live C6 glioma cells during indirect co-culturing and during culturing in conditioned medium was slightly higher than during direct co-culturing, but significantly differed from the control (C6 glioma cells cultured in medium conditioned by C6 glioma cells). The cytotoxic effect of medium conditioned by mesenchymal stem cells was not related to medium depletion by glioma cells during their growth. The medium conditioned by other "non-stem" cells (rat astrocytes and fibroblasts) produced no tumor-suppressive effect. Rat mesenchymal stem cells, similar to rat C6 glioma cells express connexin 43, the main astroglial gap junction protein. During co-culturing, mesenchymal stem cells and glioma C6 cells formed functionally active gap junctions. Gap junction blockade with connexon inhibitor carbenoxolone attenuated the antitumor effect observed during direct co-culturing of C6 glioma cells and mesenchymal stem cells to the level produced by conditioned medium. Cell-cell signaling mediated by gap junctions can be a mechanism of the tumor-suppressive effect of mesenchymal stem cells against C6 glioma cells. This phenomenon can be used for the development of new methods of cell therapy for high-grade malignant gliomas.

Host-mediated antitumor effect of DMG, a degraded D-manno-D-glucan from Microellobosporia grisea culture fluid.

Science.gov (United States)

Nakajima, H; Hashimoto, S; Nagao, S; Kita, Y; Khono, M; Ogawa, H; Abe, S; Mizuno, D

1984-03-01

DMG, a new polysaccharide with a well-characterized structure, isolated from the culture filtrate of an actinomycetes and then degraded by acid treatment, was tested for antitumor activity on allogeneic and syngeneic tumors in mice. In the allogeneic Ehrlich solid tumor system, DMG showed antitumor activity over a wide dose range, its optimal dose being 10-100 mg/kg. The optimal time of DMG administration was 1-2 weeks after tumor inoculation, but DMG was also effective when given before tumor inoculation. DMG was effective when given ip, sc, it (intratumorally) or iv. DMG also had antitumor effects on syngeneic tumors. It rapidly inhibited the growth of MM46 mammary carcinoma, MH134 hepatoma, and Meth A fibrosarcoma, and also inhibited spontaneous pulmonary metastases of B16-BL6 melanoma. However, it had no direct cytocidal action on tumor cells in vitro. Its antitumor activity was much less in athymic nude mice and in mice immunosuppressed by whole-body X-irradiation than in normal hosts.Thus, DMG was shown to exert antitumor activity via host-mediated mechanisms. Its antitumor activity is discussed in comparison with those of other antitumor polysaccharides.

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

Directory of Open Access Journals (Sweden)

Estelle Daudigeos-Dubus

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

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

Science.gov (United States)

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

2014-04-04

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

Design and Syntheses of Novel Fluoroporphyrin-Anthraquinone Complexes as Antitumor Agents.

Science.gov (United States)

Yang, Gu-Liang; Zhao, Sheng-Fang; Chen, Nian-You; Li, Shiming

2016-01-01

A novel fluoroporphyrin-anthraquinone hybrid with dipeptide link and its metal complexes were synthesized and evaluated for anti-proliferation activity in human cancer cell line HeLa. The preliminary results demonstrated that all the compounds showed moderate to excellent antitumor activities. Among the active compounds, compound 3 which contains fluorinated porphyrin-anthraquinone and zinc ion exhibited the highest potency with IC50 value of 8.83 µM, indicating that it was a promising antitumor candidate.

[Synthesis of a supermolecular nanoparticle γ-hy-PC/Ada-Dox and its antitumor activity].

Science.gov (United States)

Li, Yong-bin; Wang, Kai; Hu, Tian-nan; Wang, Qi-wen; Hu, Qi-da; Zhou, Jun; Hu, Xiu-rong; Tang, Gu-ping

2012-11-01

To synthesize a (2-Hydroxypropyl)-γ-cyclodextrin-polyethylenimine/adamantane-conjugated doxorubicin (γ-hy-PC/Ada-Dox) based supramolecular nanoparticle with host-guest interaction and to identify its physicochemical characterizations and antitumor effect. A novel non-viral gene delivery vector γ-hy-PC/Ada-Dox was synthesized based on host-guest interaction. 1H-NMR, NOESY, UV-Vis, XRD and TGA were used to confirm the structure of the vector. The DNA condensing ability of complexes was investigated by particle size, zeta potential and gel retardation assay. Cytotoxicity of complexes was determined by MTT assay in BEL-7402 and SMMC-7721 cells. Cell wound healing assay was performed in HEK293 and BEL-7404 cells. The transfection efficiency was investigated in HEK293 cells. H/E staining and cell uptake assay was performed in BEL-7402 cells. The structure of γ-hy-PC/Ada-Dox was characterized by 1H-NMR, NOESY, UV-Vis, XRD, TGA. The drug loading was 0.5% and 5.5%. Gel retardation assay showed that γ-hy-PC was able to completely condense DNA at N/P ratio of 2; 0.5% and 5.5% γ-hy-PC/Ada-Dox was able to completely condense DNA at N/P ratio of 3 and 4,respectively. The cytotoxicity of polymers was lower than that of PEI25KDa. The transfection efficiency of γ-hy-PC was higher than that of γ-hy-PC/Ada-Dox at N/P ratio of 30 in HEK293 cells; and the transfection efficiency was decreasing when Ada-Dox loading was increasing. Cell uptake assay showed that γ-hy-PC/Ada-Dox was able to carry drug and FAM-siRNA into cells. The novel vector γ-hy-PC/Ada-Dox has been developed successfully, which has certain transfection efficiency and antitumor activity.

Medicinal Plants and Other Living Organisms with Antitumor Potential against Lung Cancer

Directory of Open Access Journals (Sweden)

Luara de Sousa Monteiro

2014-01-01

Full Text Available Lung cancer is a disease with high morbidity and mortality rates. As a result, it is often associated with a significant amount of suffering and a general decrease in the quality of life. Herbal medicines are recognized as an attractive approach to lung cancer therapy with little side effects and are a major source of new drugs. The aim of this work was to review the medicinal plants and other living organisms with antitumor potential against lung cancer. The assays were conducted with animals and humans, and Lewis lung carcinoma was the most used experimental model. China, Japan, South Korea, and Ethiopia were the countries that most published studies of species with antitumor activity. Of the 38 plants evaluated, 27 demonstrated antitumor activity. In addition, six other living organisms were cited for antitumor activity against lung cancer. Mechanisms of action, combination with chemotherapeutic drugs, and new technologies to increase activity and reduce the toxicity of the treatment are discussed. This review was based on the NAPRALERT databank, Web of Science, and Chemical Abstracts. This work shows that natural products from plants continue to be a rich source of herbal medicines or biologically active compounds against cancer.

The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy.

Science.gov (United States)

Clémenson, Céline; Chargari, Cyrus; Liu, Winchygn; Mondini, Michele; Ferté, Charles; Burbridge, Mike F; Cattan, Valérie; Jacquet-Bescond, Anne; Deutsch, Eric

2017-10-01

Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107-19. ©2017 AACR . ©2017 American Association for Cancer Research.

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

Energy Technology Data Exchange (ETDEWEB)

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

2016-05-15

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

OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models.

Science.gov (United States)

Garton, Andrew J; Crew, Andrew P A; Franklin, Maryland; Cooke, Andrew R; Wynne, Graham M; Castaldo, Linda; Kahler, Jennifer; Winski, Shannon L; Franks, April; Brown, Eric N; Bittner, Mark A; Keily, John F; Briner, Paul; Hidden, Chris; Srebernak, Mary C; Pirrit, Carrie; O'Connor, Matthew; Chan, Anna; Vulevic, Bojana; Henninger, Dwight; Hart, Karen; Sennello, Regina; Li, An-Hu; Zhang, Tao; Richardson, Frank; Emerson, David L; Castelhano, Arlindo L; Arnold, Lee D; Gibson, Neil W

2006-01-15

OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.

Enhancement of anti-tumor activity of hybrid peptide in conjugation with carboxymethyl dextran via disulfide linkers.

Science.gov (United States)

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

2015-05-01

To improve the anti-tumor activity of EGFR2R-lytic hybrid peptide, we prepared peptide-modified dextran conjugates with the disulfide bonds between thiolated carboxymethyl dextran (CMD-Cys) and cysteine-conjugated peptide (EGFR2R-lytic-Cys). In vitro release studies showed that the peptide was released from the CMD-s-s-peptide conjugate in a concentration-dependent manner in the presence of glutathione (GSH, 2μM-2mM). The CMD-s-s-peptide conjugate exhibited a similar cytotoxic activity with free peptide alone against human pancreatic cancer BxPC-3 cells in vitro. Furthermore, it was shown that the CMD-s-s-peptide conjugates were highly accumulated in tumor tissue in a mouse xenograft model using BxPC-3 cells, and the anti-tumor activity of the conjugate was more effective than that of the free peptide. In addition, the plasma concentrations of peptide were moderately increased and the elimination half-life of the peptide was prolonged after intravenous injection of CMD-s-s-peptide conjugates. These results demonstrated that the conjugate based on thiolated CMD polymer would be potentially useful carriers for the sustained release of the hybrid peptide in vivo. Copyright © 2015 Elsevier B.V. All rights reserved.

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

Science.gov (United States)

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

2018-01-11

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

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

Directory of Open Access Journals (Sweden)

De-Hua Yu

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

Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N-Docosahexaenoyl 2′, 2′-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity

Directory of Open Access Journals (Sweden)

Youssef W. Naguib

2016-01-01

Full Text Available In this study, a new compound, 4-(N-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC, was synthesized and characterized. Its antitumor activity was evaluated in cell culture and in mouse models of pancreatic cancer. DHA-dFdC is a poorly soluble, pale yellow waxy solid, with a molecular mass of 573.3 Da and a melting point of about 96°C. The activation energy for the degradation of DHA-dFdC in an aqueous Tween 80–based solution is 12.86 kcal/mol, whereas its stability is significantly higher in the presence of vitamin E. NCI-60 DTP Human Tumor Cell Line Screening revealed that DHA-dFdC has potent and broad-spectrum antitumor activity, especially in leukemia, renal, and central nervous system cancer cell lines. In human and murine pancreatic cancer cell lines, the IC50 value of DHA-dFdC was up to 105-fold lower than that of dFdC. The elimination of DHA-dFdC in mouse plasma appeared to follow a biexponential model, with a terminal phase t1/2 of about 58 minutes. DHA-dFdC significantly extended the survival of genetically engineered mice that spontaneously develop pancreatic ductal adenocarcinoma. In nude mice with subcutaneously implanted human Panc-1 pancreatic tumors, the antitumor activity of DHA-dFdC was significantly stronger than the molar equivalent of dFdC alone, DHA alone, or the physical mixture of them (1:1, molar ratio. DHA-dFdC also significantly inhibited the growth of Panc-1 tumors orthotopically implanted in the pancreas of nude mice, whereas the molar equivalent dose of dFdC alone did not show any significant activity. DHA-dFdC is a promising compound for the potential treatment of cancers in organs such as the pancreas.

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

International Nuclear Information System (INIS)

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

1981-01-01

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

Synthesis and antitumor testing of certain new fused triazolopyrimidine and triazoloquinazoline derivatives

Directory of Open Access Journals (Sweden)

Ghada S. Hassan

2017-02-01

Full Text Available New series of 1,2,4-triazolopyrimidine and 1,2,4-triazoloquinazoline derivatives were designed, synthesized, and evaluated for their antitumor activity. Compounds 6, 11, 26, 29, 41, 44, 48, 49 and 58 were tested as antitumor agents by the use of DNA-binding assay on TLC-plates, colorimetric assay for the degree of DNA-binding (Methyl green-DNA displacement assay, evaluation of antineoplastic activity against Ehrlich Ascites Carcinoma in mice, and finally modulation of apoptosis. 5-Flurouracil, vitamin C and ethidium bromide were used as positive controls in these techniques. Compound 26 proved to be the most active member of these series as antitumor agent with IC50 value of 47 ± 1. Several characteristic features were observed to be essential for activity such as the morpholine group and the phenylazo group, in addition the electron-withdrawing groups favor the activity than the electron-donating ones.

Enhanced antitumor activities of (-)-epigallocatechin-3-O-gallate fatty acid monoester derivatives in vitro and in vivo

International Nuclear Information System (INIS)

Matsumura, Kazuaki; Kaihatsu, Kunihiro; Mori, Shuichi; Cho, Han Hee; Kato, Nobuo; Hyon, Suong Hyu

2008-01-01

(-)-Epigallocatechin-3-O-gallate (EGCG) monoesters modified with butanoyl (EGCG-C4), octanoyl (EGCG-C8), palmitoyl groups (EGCG-C16) were synthesized by a lipase-catalyzed transesterification method and their antitumor activities were investigated in vitro and in vivo. The in vitro antitumor activities of EGCG-monoester derivatives increased in an alkyl chain length-dependent manner. The cytotoxicity of EGCG, EGCG-C4, EGCG-C8 was mainly caused by H 2 O 2 which was generated with their oxidation. On the other hand, EGCG-C16 was more stable than EGCG and it did not generate H 2 O 2 in the cell culture medium. Furthermore, EGCG-C16 inhibited cell proliferation and induced apoptosis in the presence of catalase. EGCG-C16 was found to inhibit the phosphorylation of the epidermal growth factor receptor (EGFR), which is related to various types of tumor growth. EGCG-C16 suppressed tumor growth in vivo in colorectal tumor bearing mice in comparison to an untreated control, vector control (DMSO) and EGCG.

Antitumor activity of newly synthesized oxo and ethylidene derivatives of bile acids and their amides and oxazolines.

Science.gov (United States)

Bjedov, Srđan; Jakimov, Dimitar; Pilipović, Ana; Poša, Mihalj; Sakač, Marija

2017-04-01

Bile acid derivatives with modifications in side chain and modifications on steroid skeleton were synthetized and their antitumor activity against five human cancer cell lines was investigated. Modifications in side chain include amid group, formed in reaction with 2-amino-2-methylpropanol, and 4,4-dimethyloxazoline group, obtained after cyclization of amides. In the steroid skeleton oxo groups were introduced in position 7 (2, 2a, 2b) and 7,12 (3, 3a, 3b). Ethylidene groups were introduced regio- and stereoselectively on C-7, and/or without stereoselectivity on C-3 by Wittig reaction. By combination of these modifications, a series of 19 bile acid derivatives were synthesized. Compounds containing both C-7 ethylidene and C-12 carbonyl groups (6, 6a, 6b) shown very good antitumor activity with IC 50 amide or oxazoline group has positive effect on cytotoxicity. Different molecular descriptors were determined in silico and after principal component analysis was found that molecular descriptor BLTF96 can be used for fast assessment of experimental cytotoxicity of bile acid derivatives. Copyright © 2017 Elsevier Inc. All rights reserved.

Preliminary evaluation of in vitro cytotoxicity and in vivo antitumor activity of Xanthium strumarium in transplantable tumors in mice.

Science.gov (United States)

Aranjani, Jesil Mathew; Manuel, Atulya; Mallikarjuna Rao, Chamallamudi; Udupa, Nayanabhirama; Rao, Josyula Venkata; Joy, Ann Mary; Gandhi, Prajay; Radhakrishnan, Ethiraj Kannat

2013-01-01

In the present study, active fractions of the methanolic extract of Xanthium strumarium (XS) showing potent cytotoxicity were determined using microculture tetrazolium (MTT) and sulforhodamine B (SRB) assays in selected cancer cell lines. The active fractions viz., chloroform soluble fraction of root (CEXSR), hexane soluble fraction of leaf (HEXSL), hexane soluble fraction of fruits (HEXSF) and chloroform soluble fraction of fruits (CEXSF) of XS were tested in transplantable animal tumor models for their antitumor potential. Dalton's ascitic lymphoma (DLA) cells were used to induce solid and liquid (ascites) tumor in mice. The tumor bearing animals were treated with active fractions at two dose levels (100 and 200 mg/kg). The antitumor activities of the active fractions in tumor bearing animals were monitored with parameters such as body weight and increase in life-span as well as biochemical and hematological modalities (in the case of liquid tumor). Tumor incidence and tumor volume were the parameters monitored in the case of the solid tumor model. The results were analyzed by one-way ANOVA followed by Tukey's post hoc test. The extracts were found to increase the life-span of tumor bearing animals and restore the altered hematological and biochemical parameters significantly.

Oil-in-water biocompatible microemulsion as a carrier for the antitumor drug compound methyl dihydrojasmonate

Directory of Open Access Journals (Sweden)

Silva GB

2015-01-01

Full Text Available Gisela Bevilacqua Rolfsen Ferreira da Silva,1 Maria Virginia Scarpa,1 Iracilda Zepone Carlos,2 Marcela Bassi Quilles,2 Raphael Carlos Comeli Lia,3 Eryvaldo Socrates Tabosa do Egito,4 Anselmo Gomes de Oliveira1 1Departamento de Fármacos e Medicamentos, 2Departamento de Análises Clínicas, UNESP–Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas, PPG em Nanotecnologia Farmacêutica, Rodovia Araraquara-Jaú Km 01, Araraquara, SP, Brazil; 3Instituto de Patologia Cirúrgica e Citopatologia (IPC, Araraquara, SP, Brazil; 4UFRN–Universidade Federal do Rio Grande do Norte, Programa de Pós-graduação em Ciências da Saúde, Natal, RN, Brazil Abstract: Methyl dihydrojasmonate (MJ has been studied because of its application as an antitumor drug compound. However, as MJ is a poorly water-soluble compound, a suitable oil-in-water microemulsion (ME has been studied in order to provide its solubilization in an aqueous media and to allow its administration by the parenteral route. The ME used in this work was characterized on the pseudo-ternary phase diagram by dynamic light scattering and rheological measurements. Regardless of the drug presence, the droplet size was directly dependent on the oil/surfactant (O/S ratio. Furthermore, the drug incorporation into the ME significantly increased the ME diameter, mainly at low O/S ratios. The rheological evaluation of the systems showed that in the absence of drug a Newtonian behavior was observed. On the other hand, in the presence of MJ the ME systems revealed pseudoplastic behavior, independently of the O/S ratio. The in vivo studies demonstrated that not only was the effect on the tumor inhibition inversely dependent on the MJ-loaded ME administered dose, but also it was slightly higher than the doxorubicin alone, which was used as the positive control. Additionally, a small antiangiogenic effect for MJ-loaded ME was found at doses in which it possesses antitumor activity. MJ revealed to

Antitumor efficacy of a novel CLA-PTX microemulsion against brain tumors: in vitro and in vivo findings.

Science.gov (United States)

Li, Dan; Yang, Ke; Li, Jie-Si; Ke, Xi-Yu; Duan, Yu; Du, Ruo; Song, Ping; Yu, Ke-Fu; Ren, Wei; Huang, Dan; Li, Xing-Huo; Hu, Xin; Zhang, Xuan; Zhang, Qiang

2012-01-01

Considering the observations that linoleic acid conjugated with paclitaxel (CLA-PTX) possesses antitumor activity against brain tumors, is able to cross the blood-brain barrier, but has poor water solubility, the purpose of this study was to prepare a novel CLA-PTX microemulsion and evaluate its activity against brain tumors in vitro and in vivo. The in vitro cytotoxicity of a CLA-PTX microemulsion was investigated in C6 glioma cells. The in vivo antitumor activity of the CLA-PTX microemulsion was evaluated in tumor-bearing nude mice and rats. The pharmacokinetics of the CLA-PTX microemulsion were investigated in rats, and its safety was also evaluated in mice. The average droplet size of the CLA-PTX microemulsion was approximately 176.3 ± 0.8 nm and the polydispersity index was 0.294 ± 0.024. In vitro cytotoxicity results showed that the IC(50) of the CLA-PTX microemulsion was 1.61 ± 0.83 μM for a C6 glioma cell line, which was similar to that of free paclitaxel and CLA-PTX solution (P > 0.05). The antitumor activity of the CLA-PTX microemulsion against brain tumors was confirmed in our in vivo C6 glioma tumor-bearing nude mice as well as in a rat model. In contrast, Taxol(®) had almost no significant antitumor effect in C6 glioma tumor-bearing rats, but could markedly inhibit growth of C6 tumors in C6 glioma tumor-bearing nude mice. The pharmacokinetic results indicated that CLA-PTX in solution has a much longer circulation time and produces higher drug plasma concentrations compared with the CLA-PTX microemulsion. The results of the acute toxicity study showed that the LD(50) of CLA-PTX solution was 103.9 mg/kg. In contrast, the CLA-PTX microemulsion was well tolerated in mice when administered at doses up to 200 mg/kg. CLA-PTX microemulsion is a novel formulation with significant antitumor efficacy in the treatment of brain tumors, and is safer than CLA-PTX solution.

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

Science.gov (United States)

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

2015-06-01

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

EVALUATION OF ANTIBACTERIAL, ANTITUMOR, ANTIOXIDANT ACTIVITIES AND PHENOLIC CONSTITUENTS OF FIELD-GROWN AND IN VITRO-GROWN LYSIMACHIA VULGARIS L.

Science.gov (United States)

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

2017-01-01

Lysimachia vulgaris L. (Yellow loosestrife) is a medicinal plant in the family Myrsinaceae. It has been used in the treatment of fever, ulcer, diarrhea and wounds in folk medicine. It has also analgesic, expectorant, astringent and anti-inflammatory activities. Two different sources of the plant (field-grown and in vitro -grown) were used to evaluate the biological activities (antibacterial, antitumor and antioxidant) of L. vulgaris. In vitro-grown plant materials were collected from L. vulgaris plants that were previously regenerated in our laboratory. Plant materials were extracted with water, ethanol and acetone. For antibacterial test, disc diffusion method and 10 different pathogenic bacteria were used. Antioxidant activity was indicated by using DPPH method. The total phenol amount by using Folin-Ciocaltaeu method and the total flavonoid amount by using aluminum chloride (AlCl 3 ) colorimetric method were determined. Generally, yellow loosestrife extracts demonstrated antibacterial activity against Gram-positive bacteria (Staphylococcus aureus, S. epidermidis and Streptococcus pyogenes) . Strong antitumor activity of yellow loosestrife was observed via potato disc diffusion bioassay. Nine different phenolics were also determined and compared by using High-Performance Liquid Chromatography (HPLC). Future investigations should be focused on fractionation of the extracts to identify active components for biological activity.

Optimization of Ultrasonic-Assisted Enzymatic Extraction Conditions for Improving Total Phenolic Content, Antioxidant and Antitumor Activities In Vitro from Trapa quadrispinosa Roxb. Residues.

Science.gov (United States)

Li, Feng; Mao, Yi-Dan; Wang, Yi-Fan; Raza, Aun; Qiu, Li-Peng; Xu, Xiu-Quan

2017-03-06

Stems are the important residues of Trapa quadrispinosa Roxb., which are abundant in phenolic compounds. Ultrasonic-assisted enzymatic extraction (UAEE) is confirmed as a novel extraction technology with main advantages of enhancing extraction yield and physiological activities of the extracts from various plants. In this study, UAEE was applied to obtain the highest yield of phenolic content, strongest antioxidant, and antitumor activities and to optimize the extraction conditions using response surface methodology (RSM). The extracts from the stems of T. quadrispinosa were characterized by determination of their antioxidant activities through 2,2-azinobis(3-ethylbenzthiazoline)-6-sulfonic acid (ABTS), 1,1-Diphenyl-2-picrylhydrazxyl (DPPH) radical scavenging, total antioxidant capacity (TAC), ferric reducing antioxidant capacity (FRAC) methods and of their antitumor activity by MTT method. The selected key independent variables were cellulase concentration ( X ₁: 1.5%-2.5%), extraction time ( X ₂: 20-30 min) and extraction temperature ( X ₃: 40-60 °C). The optimal extraction conditions for total phenolic content (TPC) value of the extracts were determined as 1.74% cellulase concentration, 25.5 min ultrasonic extraction time and 49.0 °C ultrasonic temperature. Under these conditions, the highest TPC value of 53.6 ± 2.2 mg Gallic acid equivalent (GAE)/g dry weight (DW) was obtained, which agreed well with the predicted value (52.596 mg GAE/g·DW. Furthermore, the extracts obtained from UAEE presented highest antioxidant activities through ABTS, DPPH, TAC and FRAC methods were of 1.54 ± 0.09 mmol Trolox equivalent (TE)/g·DW; 1.45 ± 0.07 mmol·TE/g·DW; 45.2 ± 2.2 mg·GAE/g·DW; 50.4 ± 2.6 μmol FeSO₄ equivalent/g·DW and lowest IC 50 values of 160.4 ± 11.6 μg/mL, 126.1 ± 10.8 μg/mL, and 178.3 ± 13.1 μg/mL against Hela, HepG-2 and U251 tumor cells, respectively. The results indicated that the UAEE was an efficient alternative to improve

Evaluation of the antitumor effects of vitamin K2 (menaquinone-7) nanoemulsions modified with sialic acid-cholesterol conjugate.

Science.gov (United States)

Shi, Jia; Zhou, Songlei; Kang, Le; Ling, Hu; Chen, Jiepeng; Duan, Lili; Song, Yanzhi; Deng, Yihui

2018-02-01

Numerous studies have recently shown that vitamin K 2 (VK 2 ) has antitumor effects in a variety of tumor cells, but there are few reports demonstrating antitumor effects of VK 2 in vivo. The antitumor effects of VK 2 in nanoemulsions are currently not known. Therefore, we sought to characterize the antitumor potential of VK 2 nanoemulsions in S180 tumor cells in the present study. Furthermore, a ligand conjugate sialic acid-cholesterol, with enhanced affinity towards the membrane receptors overexpressed in tumors, was anchored on the surface of the nanoemulsions to increase VK 2 distribution to the tumor tissue. VK 2 was encapsulated in oil-in-water nanoemulsions, and the physical and chemical stability of the nanoemulsions were characterized during storage at 25 °C. At 25 °C, all nanoemulsions remained physically and chemically stable with little change in particle size. An in vivo study using syngeneic mice with subcutaneously established S180 tumors demonstrated that intravenous or intragastric administration of VK 2 nanoemulsions significantly suppressed the tumor growth. The VK 2 nanoemulsions modified with sialic acid-cholesterol conjugate showed higher tumor growth suppression than the VK 2 nanoemulsions, while neither of them exhibited signs of drug toxicity. In summary, VK 2 exerted effective antitumor effects in vivo, and VK 2 nanoemulsions modified with sialic acid-cholesterol conjugate enhanced the antitumor activity, suggesting that these VK 2 may be promising agents for the prevention or treatment of tumor in patients.

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

Science.gov (United States)

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

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

International Nuclear Information System (INIS)

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

2000-01-01

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

Neurofibromin 1 Impairs Natural Killer T-Cell-Dependent Antitumor Immunity against a T-Cell Lymphoma

Directory of Open Access Journals (Sweden)

Jianyun Liu

2018-01-01

Full Text Available Neurofibromin 1 (NF1 is a tumor suppressor gene encoding a Ras GTPase that negatively regulates Ras signaling pathways. Mutations in NF1 are linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. In terms of antitumor immunity, CD1d-dependent natural killer T (NKT cells play an important role in the innate antitumor immune response. Generally, Type-I NKT cells protect (and Type-II NKT cells impair host antitumor immunity. We have previously shown that CD1d-mediated antigen presentation to NKT cells is regulated by cell signaling pathways. To study whether a haploinsufficiency in NF1 would affect CD1d-dependent activation of NKT cells, we analyzed the NKT-cell population as well as the functional expression of CD1d in Nf1+/− mice. Nf1+/− mice were found to have similar levels of NKT cells as wildtype (WT littermates. Interestingly, however, reduced CD1d expression was observed in Nf1+/− mice compared with their WT littermates. When inoculated with a T-cell lymphoma in vivo, Nf1+/− mice survived longer than their WT littermates. Furthermore, blocking CD1d in vivo significantly enhanced antitumor activity in WT, but not in Nf1+/− mice. In contrast, a deficiency in Type-I NKT cells increased antitumor activity in Nf1+/− mice, but not in WT littermates. Therefore, these data suggest that normal NF1 expression impairs CD1d-mediated NKT-cell activation and antitumor activity against a T-cell lymphoma.

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

Science.gov (United States)

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.

Antitumor effects and mechanisms of Ganoderma extracts and spores oil.

Science.gov (United States)

Chen, Chun; Li, Peng; Li, Ye; Yao, Guan; Xu, Jian-Hua

2016-11-01

Ganoderma lucidum is a popular herbal medicine used in China to promote health. Modern studies have disclosed that the active ingredients of Ganoderma can exhibit several effects, including antitumor effects and immunomodulation. The present study evaluated the antitumor effects of self-prepared Ganoderma extracts and spores oil, and investigated the possible underlying mechanisms by observing the effects of the extracts and oil on topoisomerases and the cell cycle. The results showed that Ganoderma extracts and spores oil presented dose-dependent inhibitory effects on tumor cells. The half maximal inhibitory concentration (IC 50 ) values of Ganoderma extracts on HL60, K562 and SGC-7901 cells for 24 h were 0.44, 0.39 and 0.90 mg/ml, respectively; for Ganoderma spores oil, the IC 50 values were 1.13, 2.27 and 6.29 mg/ml, respectively. In the in vivo study, the inhibitory rates of Ganoderma extracts (4 g/kg/d, intragastrically) on S180 and H22 cells were 39.1 and 44.6%, respectively, and for Ganoderma spores oil (1.2 g/kg/d, intragastrically) the inhibitory rates were 30.9 and 44.9%, respectively. Ganoderma extracts and spores oil inhibited the activities of topoisomerase I and II. Ganoderma spores oil was shown block the cell cycle at the transition between the G1 and S phases and induce a marked decrease in cyclin D1 levels in K562 cells, with no significant change in cyclin E level. These results suggest that the Ganoderma extracts and spores oil possessed antitumor effects in the in vitro and in vivo studies. The antitumor mechanisms of the extracts and spores oil were associated with inhibitory effects on topoisomerase I and II activities, and for Ganoderma spores oil, the antitumor effects may also be associated with decreased cyclin D1 levels, thus inducing G1 arrest in the cell cycle.

How does ionizing irradiation contribute to the induction of anti-tumor immunity?

Directory of Open Access Journals (Sweden)

Yvonne eRubner

2012-07-01

Full Text Available Radiotherapy (RT with ionizing irradiation is commonly used to locally attack tumors. It induces a stop of cancer cell proliferation and finally leads to tumor cell death. During the last years it has become more and more evident that besides a timely and locally restricted radiation-induced immune suppression, a specific immune activation against the tumor and its metastases is achievable by rendering the tumor cells visible for immune attack. The immune system is involved in tumor control and we here outline how RT induces anti-inflammation when applied in low doses and contributes in higher doses to the induction of anti-tumor immunity. We especially focus on how local irradiation induces abscopal effects. The latter are partly mediated by a systemic activation of the immune system against the individual tumor cells. Dendritic cells are the key players in the initiation and regulation of adaptive anti-tumor immune responses. They have to take up tumor antigens and consecutively present tumor peptides in the presence of appropriate co-stimulation. We review how combinations of RT with further immune stimulators such as AnnexinA5 and hyperthermia foster the dendritic cell-mediated induction of anti-tumor immune responses and present reasonable combination schemes of standard tumor therapies with immune therapies. It can be concluded that RT leads to targeted killing of the tumor cells and additionally induces non-targeted systemic immune effects. Multimodal tumor treatments should therefore tend to induce immunogenic tumor cell death forms within a tumor microenvironment that stimulates immune cells.

How Does Ionizing Irradiation Contribute to the Induction of Anti-Tumor Immunity?

International Nuclear Information System (INIS)

Rubner, Yvonne; Wunderlich, Roland; Rühle, Paul-Friedrich; Kulzer, Lorenz; Werthmöller, Nina; Frey, Benjamin; Weiss, Eva-Maria; Keilholz, Ludwig; Fietkau, Rainer; Gaipl, Udo S.

2012-01-01

Radiotherapy (RT) with ionizing irradiation is commonly used to locally attack tumors. It induces a stop of cancer cell proliferation and finally leads to tumor cell death. During the last years it has become more and more evident that besides a timely and locally restricted radiation-induced immune suppression, a specific immune activation against the tumor and its metastases is achievable by rendering the tumor cells visible for immune attack. The immune system is involved in tumor control and we here outline how RT induces anti-inflammation when applied in low doses and contributes in higher doses to the induction of anti-tumor immunity. We especially focus on how local irradiation induces abscopal effects. The latter are partly mediated by a systemic activation of the immune system against the individual tumor cells. Dendritic cells are the key players in the initiation and regulation of adaptive anti-tumor immune responses. They have to take up tumor antigens and consecutively present tumor peptides in the presence of appropriate co-stimulation. We review how combinations of RT with further immune stimulators such as AnnexinA5 and hyperthermia foster the dendritic cell-mediated induction of anti-tumor immune responses and present reasonable combination schemes of standard tumor therapies with immune therapies. It can be concluded that RT leads to targeted killing of the tumor cells and additionally induces non-targeted systemic immune effects. Multimodal tumor treatments should therefore tend to induce immunogenic tumor cell death forms within a tumor microenvironment that stimulates immune cells.

DNA strand scission by the novel antitumor antibiotic leinamycin

International Nuclear Information System (INIS)

Hara, Mitsunobu; Saitoh, Yutaka; Nakano, Hirofumi

1990-01-01

Leinamycin is a recently discovered antitumor antibiotic with an unusual 1,3-dioxo-1,2-dithiolane structure. It preferentially inhibits the incorporation of [ 3 H]thymidine into the acid-insoluble fraction of Bacillus subtilis. In vitro, leinamycin causes single-strand cleavage of supercoiled double-helical pBR322 DNA in the presence of thiol cofactors. Scavengers of oxygen radical did not suppress the DNA-cleaving activity. Thiol-activated leinamycin binds calf thymus DNA at 4 degree C and thermal treatment of the leinamycin-DNA adduct released a chemically modified leinamycin from the complex. The lack of cytotoxicity and DNA-cleaving activity for S-deoxyleinamycin indicates that the 1,3-dioxo-1,2-dithiolane moiety is essential for the activity of leinamycin. Thus, the primary cellular target of leinamycin appears to be DNA. It binds DNA and causes single-strand break at low concentrations, which may account for the potent antitumor activity

Effects of Androgen Ablation on Anti-Tumor Immunity

National Research Council Canada - National Science Library

Kast, Martin

2004-01-01

.... This AA induced autoimmune-like response exerts limited anti-tumor activity in a murine prostate cancer model, but could be synergistic with CTLA-4 blockade that promotes the development of autoreactive T cell...

Antitumor effects and mechanisms of Ganoderma extracts and spores oil

OpenAIRE

Chen, Chun; Li, Peng; Li, Ye; Yao, Guan; Xu, Jian-Hua

2016-01-01

Ganoderma lucidum is a popular herbal medicine used in China to promote health. Modern studies have disclosed that the active ingredients of Ganoderma can exhibit several effects, including antitumor effects and immunomodulation. The present study evaluated the antitumor effects of self-prepared Ganoderma extracts and spores oil, and investigated the possible underlying mechanisms by observing the effects of the extracts and oil on topoisomerases and the cell cycle. The results showed that Ga...

New cysteamine (2-chloroethyl)nitrosoureas. Synthesis and preliminary antitumor results.

Science.gov (United States)

Madelmont, J C; Godeneche, D; Parry, D; Duprat, J; Chabard, J L; Plagne, R; Mathe, G; Meyniel, G

1985-09-01

Three chemical pathways were used for the synthesis of four new N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]- and N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N- or N'-nitrosoureas. These compounds are plasma metabolites of CNCC, a promising antineoplastic (2-chloroethyl)nitrosourea. Preliminary antitumor evaluation was performed against L1210 leukemia implanted intraperitoneally in mice. Among these compounds, two of them exhibited a greater antitumor activity compared to that of the parent mixture.

Enhanced antitumor effects of novel intracellular delivery of an active form of menaquinone-4, menahydroquinone-4, into hepatocellular carcinoma.

Science.gov (United States)

Setoguchi, Shuichi; Watase, Daisuke; Matsunaga, Kazuhisa; Matsubara, Misa; Kubo, Yohei; Kusuda, Mariko; Nagata-Akaho, Nami; Enjoji, Munechika; Nakashima, Manabu; Takeshita, Morishige; Karube, Yoshiharu; Takata, Jiro

2015-02-01

Reduced cellular uptake of menaquinone-4 (MK-4), a vitamin K2 homolog, in human hepatocellular carcinoma (HCC) limits its usefulness as a safe long-term antitumor agent for recurrent HCC and produces des-γ-carboxy prothrombin (DCP). We hypothesized that effective delivery of menahydroquinone-4 (MKH), the active form of MK-4 for γ-glutamyl carboxylation, into HCC cells is critical for regulating HCC growth, and may enable it to be applied as a safe antitumor agent. In this study, we verified this hypothesis using menahydroquinone-4 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG), a prodrug of MKH, and demonstrated its effectiveness. Intracellular delivery of MKH and subsequent growth inhibition of PLC/PRF/5 and Hep3B (DCP-positive) and SK-Hep-1 (DCP-negative) cells after MKH-DMG administration were determined and compared with MK-4. The activity of MKH-DMG against tumor progression in the liver alongside DCP formation was determined in a spleen-liver metastasis mouse model. MKH-DMG exhibited greater intracellular delivery of MKH in vitro (AUC0-72 hour of MKH) and increased growth-inhibitory activity against both DCP-positive and DCP-negative HCC cell lines. The phenomena of MKH delivery into cells in parallel with simultaneous growth inhibition suggested that MKH is the active form for growth inhibition of HCC cells. Cell-cycle arrest was determined to be involved in the growth inhibition mechanisms of MKH-DMG. Furthermore, MKH-DMG showed significant inhibition of tumor progression in the liver, and a substantial decrease in plasma DCP levels in the spleen-liver metastasis mouse model. Our results suggest that MKH-DMG is a promising new candidate antitumor agent for safe long-term treatment of HCC. ©2014 American Association for Cancer Research.

Evaluation of cytotoxic and antitumoral properties of Tessaria absinthioides (Hook & Arn DC, "pájaro bobo", aqueous extract

Directory of Open Access Journals (Sweden)

Fabio A. Persia

2017-08-01

Full Text Available Higher plants have provided various natural derived drugs used currently in western medicine. Tessaria absinthioides (Hook. & Arn. DC, Asteraceae, is a native plant from South-America with reported ethnopharmacological and culinary uses. Despite recent scientific reports about plants properties, there is not a well conducted research about its anticancer and potential toxic effects. The current work demonstrates the plant aqueous extract composition; the in vitro induced cytotoxicity, and explores, in vivo, its oral toxicity and antitumoral effects. Composition of aqueous extract was determined by phytochemical reactions. Cytotoxicity was tested in tumoral (Hela, Gli-37, HCT-116 and MCF-7 and non-tumoral (HBL-100 cells, using MTT assay. Oral toxicity and the antitumor activity against colorectal carcinoma were studied in rodents. The chemical analysis revealed the presence of flavonoids, carbohydrates, sterols, terpenes and tannins. Cytotoxicity towards tumoral cells was observed (CV50: 3.0 to 14.8 ug/ml; while in non-tumoral cells, extracts evidenced a selective reduced toxicity (CV50: 29.5 ug/ml. Oral administration of the extract does not induce acute nor dose-repeated toxicity at doses up to 2000 mg/kg and 1000 mg/kg/day, respectively. The antitumoral effect was confirmed by a significant increase in a median survival from 24 weeks (non-treated to 30 weeks (T. absinthioides treated. The present data indicate that T. absinthioides extract exhibits cytotoxicity against cancer cell lines, with no-toxic effects and significant antitumoral effects in colorectal cancer when is orally administrated. In conclusion, T. absinthioides possesses selective cytotoxicity and antitumoral activities, making its plant derivatives products promising for cancer research and treatment.

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

Science.gov (United States)

Beltrán-Rocha, Julio Cesar

2018-01-01

Cancer cases result in 13% of all deaths worldwide. Unwanted side effects in patients under conventional treatments have led to the search for beneficial alternative therapies. Microalgae synthesize compounds with known in vitro and in vivo biological activity against different tumor cell lines. Therefore, native microalgae from the State of Nuevo Leon, Mexico may become a potential source of antitumor agents. The aim of the present study was to evaluate the in vitro cytotoxic effect of Nuevo Leon regional Chlorella sorokiniana (Chlorellales: Chlorellaceae) and Scenedesmus sp. (Chlorococcales: Scenedesmaceae). Native microalgae crude organic extracts cytotoxicity against murine L5178Y-R lymphoma cell line and normal lymphocyte proliferation were evaluated using the MTT reduction colorimetric assay. Cell death pathway was analyzed by acridine orange and ethidium bromide staining, DNA degradation in 2% agarose gel electrophoresis and caspases activity. Results indicated significant (p Scenedesmus sp. methanol extracts, respectively, at 500 µg/mL, by the mechanism of apoptosis. This study contributes to Mexican microalgae biodiversity knowledge and their potential as antitumor agent sources. PMID:29441241

The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG.

Science.gov (United States)

Lv, Chao; Zeng, Hua-Wu; Wang, Jin-Xin; Yuan, Xing; Zhang, Chuang; Fang, Ting; Yang, Pei-Ming; Wu, Tong; Zhou, Yu-Dong; Nagle, Dale G; Zhang, Wei-Dong

2018-02-07

Tanshinone IIA (Tan IIA), the primary bioactive compound derived from the traditional Chinese medicine (TCM) Salvia miltiorrhiza Bunge, has been reported to possess antitumor activity. However, its antitumor mechanisms are not fully understood. To resolve the potential antitumor mechanism(s) of Tan IIA, its gene expression profiles from our database was analyzed by connectivity map (CMAP) and the CMAP-based mechanistic predictions were confirmed/validated in further studies. Specifically, Tan IIA inhibited total protein kinase C (PKC) activity and selectively suppressed the expression of cytosolic and plasma membrane PKC isoforms ζ and ε. The Ras/MAPK pathway that is closely regulated by the PKC signaling is also inhibited by Tan IIA. While Tan IIA did not inhibit heat shock protein 90 (Hsp90), it synergistically enhanced the antitumor efficacy of the Hsp90 inhibitors 17-AAG and ganetespib in human breast cancer MCF-7 cells. In addition, Tan IIA significantly inhibited PI3K/Akt/mTOR signaling, and induced both cell cycle arrest and autophagy. Collectively, these studies provide new insights into the molecular mechanisms responsible for antitumor activity of Tan IIA.

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

Science.gov (United States)

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. Published by Elsevier Inc.

Development of a new high-affinity human antibody with antitumor activity against solid and blood malignancies.

Science.gov (United States)

Sioud, Mouldy; Westby, Phuong; Vasovic, Vlada; Fløisand, Yngvar; Peng, Qian

2018-04-16

mAbs have emerged as a promising strategy for the treatment of cancer. However, in several malignancies, no effective antitumor mAbs are yet available. Identifying therapeutic mAbs that recognize common tumor antigens could render the treatment widely applicable. Here, a human single-chain variable fragment (scFv) antibody library was sequentially affinity selected against a panel of human cancer cell lines and an antibody fragment (named MS5) that bound to solid and blood cancer cells was identified. The MS5 scFv was fused to the human IgG1 Fc domain to generate an antibody (MS5-Fc fusion) that induced antibody-dependent cellular cytotoxicity and phagocytosis of cancer cells by macrophages. In addition, the MS5-Fc antibody bound to primary leukemia cells and induced antibody-dependent cellular cytotoxicity. In the majority of analyzed cancer cells, the MS5-Fc antibody induced cell surface redistribution of the receptor complexes, but not internalization, thus maximizing the accessibility of the IgG1 Fc domain to immune effector cells. In vitro stability studies showed that the MS5-Fc antibody was stable after 6 d of incubation in human serum, retaining ∼60% of its initial intact form. After intravenous injections, the antibody localized into tumor tissues and inhibited the growth of 3 different human tumor xenografts (breast, lymphoma, and leukemia). These antitumor effects were associated with tumor infiltration by macrophages and NK cells. In the Ramos B-cell lymphoma xenograft model, the MS5-Fc antibody exhibited a comparable antitumor effect as rituximab, a chimeric anti-CD20 IgG1 mAb. These results indicate that human antibodies with pan-cancer abilities can be generated from phage display libraries, and that the engineered MS5-Fc antibody could be an attractive agent for further clinical investigation.-Sioud, M., Westby, P., Vasovic, V., Fløisand, Y., Peng, Q. Development of a new high-affinity human antibody with antitumor activity against solid and

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

Directory of Open Access Journals (Sweden)

Kuniaki Tsutsumi

2016-06-01

Full Text Available 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.

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

Directory of Open Access Journals (Sweden)

N. A. Navolokin

2016-01-01

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

Inhibition of Hypoxia Inducible Factor Alpha and Astrocyte-Elevated Gene-1 Mediates Cryptotanshinone Exerted Antitumor Activity in Hypoxic PC-3 Cells

Directory of Open Access Journals (Sweden)

Hyo-Jeong Lee

2012-01-01

Full Text Available Although cryptotanshinone (CT was known to exert antitumor activity in several cancers, its molecular mechanism under hypoxia still remains unclear. Here, the roles of AEG-1 and HIF-1α in CT-induced antitumor activity were investigated in hypoxic PC-3 cells. CT exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation and AEG-1 expression in hypoxic PC-3 cells. Also, AEG-1 was overexpressed in prostate cancer cells. Interestingly, HIF-1α siRNA transfection enhanced the cleavages of caspase-9,3, and PAPR and decreased expression of Bcl-2 and AEG1 induced by CT in hypoxic PC-3 cells. Of note, DMOG enhanced the stability of AEG-1 and HIF-1α during hypoxia. Additionally, CT significantly reduced cellular level of VEGF in PC-3 cells and disturbed tube formation of HUVECs. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1α to VEGF promoter. Furthermore, CT at 10 mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67, CD34, VEGF, carbonic anhydrase IX, and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1α, AEG1, and VEGF as a potent chemotherapeutic agent.

Antitumor activity of novel chimeric peptides derived from cyclinD/CDK4 and the protein transduction domain 4.

Science.gov (United States)

Wang, Haili; Chen, Xi; Chen, Yanping; Sun, Lei; Li, Guodong; Zhai, Mingxia; Zhai, Wenjie; Kang, Qiaozhen; Gao, Yanfeng; Qi, Yuanming

2013-02-01

CyclinD1/CDK4 and cyclinD3/CDK4 complexes are key regulators of the cell progression and therefore constitute promising targets for the design of anticancer agents. In the present study, the key peptide motifs were selected from these two complexes. Chimeric peptides with these peptides conjugated to the protein transduction domain 4 (PTD4) were designed and synthesized. The chimeric peptides, PTD4-D1, PTD4-D3, PTD4-K4 exhibited significant anti-proliferation effects on cancer cell lines. These peptides could compete with the cyclinD/CDK4 complex and induce the G1/S phase arrest and apoptosis of cancer cells. In the tumor challenge experiment, these peptides showed potent antitumor effects with no significant side effects. Our results suggested that these peptides could be served as novel leading compounds with potent antitumor activity.

Anti-tumor bioactivities of curcumin on mice loaded with gastric carcinoma.

Science.gov (United States)

Wang, Xiao-Ping; Wang, Qiao-Xia; Lin, Huan-Ping; Chang, Na

2017-09-20

Curcumin, a derivative from the dried rhizome of curcuma longa, has been proven to possess anti-tumor effects. However, the detailed molecular mechanisms have not been fully elucidated. In this study, we aimed to explore the anti-tumor mechanisms of curcumin in treating gastric cancer. BALB/C mice grafted with a mouse gastric adenocarcinoma cell line (MFC) were used as the experimental model. Mice received different doses of curcumin after grafting. Tumor size was measured and tumor weight was determined after tumor inoculation. TUNEL assay and flow cytometric analysis were applied to evaluate the apoptosis of the cancer cells. Serum cytokines IFN-γ, TNF-α, granzyme B and perforin were detected by ELISA assay. The anti-tumor effect was determined using cytotoxic T-lymphocyte (CTL) assays and in vivo tumor prevention tests. The expression of DEC1, HIF-1α, STAT3 and VEGF in tumor tissues was examined by immunostaining and analyzed using an Image J analysis system. Compared with controls, tumor growth (size and weight) was significantly inhibited by curcumin treatment (P curcumin treatment group. Splenocyte cells from mice treated with curcumin exhibited higher cytolytic effects on MFC cancer cells than those from mice treated with saline (P curcumin treatment. Our results indicate that curcumin inhibits the proliferation of gastric carcinoma by inducing the apoptosis of tumor cells, activating immune cells to secrete a large amount of cytokines, and down-regulating the DEC1, HIF-1α, VEGF and STAT3 signal transduction pathways.

Enhanced antitumor efficacy of doxorubicin-encapsulated halloysite nanotubes

Directory of Open Access Journals (Sweden)

Li K

2017-12-01

Full Text Available Kai Li,1,* Yongxing Zhang,2,* Mengting Chen,1 Yangyang Hu,1 Weiliang Jiang,1 Li Zhou,1 Sisi Li,1 Min Xu,1 Qinghua Zhao,2 Rong Wan1 1Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Orthopaedics, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: To improve the antitumor efficacy of doxorubicin (DOX and provide novel clinical treatment of gastric cancer, halloysite nanotubes (HNTs loaded with DOX were encapsulated by soybean phospholipid (LIP and the formed HNTs/DOX/LIP was systematically characterized via different techniques. The in vitro anticancer activity of HNTs/DOX/LIP was examined using an MTT assay. The antitumor efficacy and biocompatibility were monitored by measuring the tumor volume and assessing the blood routine and serum biochemistry using an ectopic implantation cancer model. The results show that when the concentration of HNTs was 3 mg/mL and the concentration of DOX was 1 mg/mL the optimal DOX loading efficiency was as high as 22.01%±0.43%. In vitro drug release behavior study demonstrated that HNTs/DOX/LIP shows a pH-responsive release property with fast drug release under acidic conditions (pH =5.4. MTT assays and in vivo experimental results revealed that HNTs/DOX/LIP exhibits a significantly higher inhibitory efficacy on the growth of mouse gastric cancer cells than free DOX at the same drug concentration. In addition, the life span of tumor-bearing mice in the HNTs/DOX/LIP-treated group was obviously prolonged compared with the control groups. Moreover, HNTs/DOX/LIP possessed excellent hemocompatibility as shown in the blood and histology studies. These findings indicated that the formed HNTs/DOX/LIP possesses higher antitumor efficacy and may be used as a targeted

Indicine-N-oxide: the antitumor principle of Heliotropium indicum.

Science.gov (United States)

Kugelman, M; Liu, W C; Axelrod, M; McBride, T J; Rao, K V

1976-01-01

Extracts of Heliotropium indicum Linn. (Boraginaceae) showed significant activity in several experimental tumor systems. The active principle is isolated and shown to be the N-oxide of the alkaloid, indicine, previously isolated from this plant. Supporting structural data and anti-tumor data are provided.

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

Directory of Open Access Journals (Sweden)

Zhang Kang-Jian

2012-02-01

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

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

Science.gov (United States)

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

2014-09-15

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

Antitumor Properties of Modified Detonation Nanodiamonds and Sorbed Doxorubicin on the Model of Ehrlich Ascites Carcinoma.

Science.gov (United States)

Medvedeva, N N; Zhukov, E L; Inzhevatkin, E V; Bezzabotnov, V E

2016-01-01

We studied antitumor properties of modified detonation nanodiamonds loaded with doxorubicin on in vivo model of Ehrlich ascites carcinoma. The type of tumor development and morphological characteristics of the liver, kidneys, and spleen were evaluated in experimental animals. Modified nanodiamonds injected intraperitoneally produced no antitumor effect on Ehrlich carcinoma. However, doxorubicin did not lose antitumor activity after sorption on modified nanodiamonds.

Antitumor Activity of Ethanolic Extract of Dendrobium formosum in T-Cell Lymphoma: An In Vitro and In Vivo Study

Directory of Open Access Journals (Sweden)

Ritika Prasad

2014-01-01

Full Text Available Dendrobium, a genus of orchid, was found to possess useful therapeutic activities like anticancer, hypoglycaemic, antimicrobial, immunomodulatory, hepatoprotective, antioxidant, and neuroprotective activities. The study was aimed to evaluate the anticancer property of the ethanolic extract of Dendrobium formosum on Dalton’s lymphoma. In vitro cytotoxicity was determined by MTT assay, apoptosis was determined by fluorescence microscopy, and cell cycle progression was analysed using flow cytometry; in vivo antitumor activity was performed in Dalton’s lymphoma bearing mice. The IC50 value of ethanolic extract was obtained at 350 μg/mL in Dalton’s lymphoma cells. Fluorescence microscopy analysis showed significant increase in apoptotic cell death in dose- and time-dependent manner which was further confirmed through the resulting DNA fragmentation. Further, flow cytometry analysis showed that the ethanolic extract arrests the cells in G2/M phase of the cell cycle. The in vivo anticancer activity study illustrates significant increase in the survival time of Dalton’s lymphoma bearing mice on treatment with ethanolic extract when compared to control. These results substantiate the antitumor properties of ethanolic extract of Dendrobium formosum and suggest an alternative in treatment of cancer. Further studies are required regarding the isolation and characterization of bioactive components along with the analysis of molecular mechanism involved.

Antitumor Activity of Ethanolic Extract of Dendrobium formosum in T-Cell Lymphoma: An In Vitro and In Vivo Study

Science.gov (United States)

Prasad, Ritika; Koch, Biplob

2014-01-01

Dendrobium, a genus of orchid, was found to possess useful therapeutic activities like anticancer, hypoglycaemic, antimicrobial, immunomodulatory, hepatoprotective, antioxidant, and neuroprotective activities. The study was aimed to evaluate the anticancer property of the ethanolic extract of Dendrobium formosum on Dalton's lymphoma. In vitro cytotoxicity was determined by MTT assay, apoptosis was determined by fluorescence microscopy, and cell cycle progression was analysed using flow cytometry; in vivo antitumor activity was performed in Dalton's lymphoma bearing mice. The IC50 value of ethanolic extract was obtained at 350 μg/mL in Dalton's lymphoma cells. Fluorescence microscopy analysis showed significant increase in apoptotic cell death in dose- and time-dependent manner which was further confirmed through the resulting DNA fragmentation. Further, flow cytometry analysis showed that the ethanolic extract arrests the cells in G2/M phase of the cell cycle. The in vivo anticancer activity study illustrates significant increase in the survival time of Dalton's lymphoma bearing mice on treatment with ethanolic extract when compared to control. These results substantiate the antitumor properties of ethanolic extract of Dendrobium formosum and suggest an alternative in treatment of cancer. Further studies are required regarding the isolation and characterization of bioactive components along with the analysis of molecular mechanism involved. PMID:24959588

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

Science.gov (United States)

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 G 0 /G 1 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. Copyright © 2016 Elsevier B.V. All rights reserved.

Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models.

Science.gov (United States)

Higgins, Brian; Kolinsky, Kenneth; Smith, Melissa; Beck, Gordon; Rashed, Mohammad; Adames, Violeta; Linn, Michael; Wheeldon, Eric; Gand, Laurent; Birnboeck, Herbert; Hoffmann, Gerhard

2004-06-01

Our objective was the preclinical assessment of the pharmacokinetics, monotherapy and combined antitumor activity of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib in athymic nude mice bearing non-small cell lung cancer (NSCLC) xenograft models. Immunohistochemistry determined the HER1/EGFR status of the NSCLC tumor models. Pharmacokinetic studies assessed plasma drug concentrations of erlotinib in tumor- and non-tumor-bearing athymic nude mice. These were followed by maximum tolerated dose (MTD) studies for erlotinib and each chemotherapy. Erlotinib was then assessed alone and in combination with these chemotherapies in the NSCLC xenograft models. Complete necropsies were performed on most of the animals in each study to further assess antitumor or toxic effects. Erlotinib monotherapy dose-dependently inhibited tumor growth in the H460a tumor model, correlating with circulating levels of drug. There was antitumor activity at the MTD with each agent tested in both the H460a and A549 tumor models (erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition). When each compound was given at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 25% of the MTD to determine efficacy. In both NSCLC models, doses of gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD were well tolerated. For the slow growing A549 tumor, there was significant tumor growth inhibition in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100 and 98%, respectively), with partial regressions. For the faster growing H460a tumor, there was significant but less remarkable tumor growth inhibition in these same combinations (86 and 53% respectively). These results show that in NSCLC xenograft tumors with similar

TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding.

Science.gov (United States)

Petrova, Penka S; Viller, Natasja Nielsen; Wong, Mark; Pang, Xinli; Lin, Gloria H Y; Dodge, Karen; Chai, Vien; Chen, Hui; Lee, Vivian; House, Violetta; Vigo, Noel T; Jin, Debbie; Mutukura, Tapfuma; Charbonneau, Marilyse; Truong, Tran; Viau, Stephane; Johnson, Lisa D; Linderoth, Emma; Sievers, Eric L; Maleki Vareki, Saman; Figueredo, Rene; Pampillo, Macarena; Koropatnick, James; Trudel, Suzanne; Mbong, Nathan; Jin, Liqing; Wang, Jean C Y; Uger, Robert A

2017-02-15

Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein α (SIRPα) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPαFc) is a fully human recombinant fusion protein that blocks the CD47-SIRPα axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication. Experimental Design: The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPαFc constructs with different Fc tails. Results: TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo , TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcγ receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies. Conclusions: These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications. Clin Cancer Res; 23(4); 1068-79. ©2016 AACR . ©2016 American Association for Cancer Research.

Chemically crosslinked nanogels of PEGylated poly ethyleneimine (L-histidine substituted) synthesized via metal ion coordinated self-assembly for delivery of methotrexate: Cytocompatibility, cellular delivery and antitumor activity in resistant cells

Energy Technology Data Exchange (ETDEWEB)

Abolmaali, Samira Sadat, E-mail: s.abolmaali@gmail.com [Pharmaceutical Nanotechnology Department, Shiraz University of Medical Sciences, Shiraz 71345 (Iran, Islamic Republic of); Tamaddon, Ali Mohammad, E-mail: amtamadon@gmail.com [Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz 71345 (Iran, Islamic Republic of); Mohammadi, Samaneh, E-mail: samaneh.mohammadi1986@gmail.com [Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz 71345 (Iran, Islamic Republic of); Amoozgar, Zohreh, E-mail: zohreh_amoozgar@dfci.harvard.edu [Department of Cancer Immunology and Aids, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115 (United States); Dinarvand, Rasoul, E-mail: dinarvand@tums.ac.ir [Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14174 (Iran, Islamic Republic of)

2016-05-01

Self-assembled nanogels were engineered by forming Zn{sup 2+}-coordinated micellar templates of PEGylated poly ethyleneimine (PEG-g-PEI), chemical crosslinking and subsequent removal of the metal ion. Creation of stable micellar templates is a crucial step for preparing the nanogels. To this aim, imidazole moieties were introduced to the polymer by Fmoc-L-histidine using carbodiimide chemistry. It was hypothesized the nanogels loaded with methotrexate (MTX), a chemotherapeutic agent, circumvent impaired carrier activity in HepG2 cells (MTX-resistant hepatocellular carcinoma). So, the nanogels were post-loaded with MTX and characterized by {sup 1}H-NMR, FTIR, dynamic light scattering-zeta potential, atomic force microscopy, and drug release experiments. Cellular uptake and the antitumor activity of MTX-loaded nanogels were investigated by flow cytometry and MTT assay. Discrete, spherical and uniform nanogels, with sizes about 77–83 nm and a relatively high drug loading (54 ± 4% w/w), showed a low polydispersity and neutral surface charges. The MTX-loaded nanogels, unlike empty nanogels, lowered viability of HepG2 cells; the nanogels demonstrated cell-cycle arrest and apoptosis comparably higher than MTX as free drug that was shown to be through i) cellular uptake of the nanogels by clathrin-mediated transport and ii) endosomolytic activity of the nanogels in HepG2 cells. These findings indicate the potential antitumor application of this preparation, which has to be investigated in-vivo. - Highlights: • Nanogel synthesis through chemical crosslinking of the transition metal ion coordinated polymer self-assembly • An enhanced cytocompatibility if compared to unmodified polymer • A noticeable endocytic cellular internalization and endosomolytic activity • A specific antitumor cytotoxicity, cell cycle arrest and apoptosis in resistant tumor cells.

Antitumor effects and mechanisms of Ganoderma extracts and spores oil

Science.gov (United States)

Chen, Chun; Li, Peng; Li, Ye; Yao, Guan; Xu, Jian-Hua

2016-01-01

Ganoderma lucidum is a popular herbal medicine used in China to promote health. Modern studies have disclosed that the active ingredients of Ganoderma can exhibit several effects, including antitumor effects and immunomodulation. The present study evaluated the antitumor effects of self-prepared Ganoderma extracts and spores oil, and investigated the possible underlying mechanisms by observing the effects of the extracts and oil on topoisomerases and the cell cycle. The results showed that Ganoderma extracts and spores oil presented dose-dependent inhibitory effects on tumor cells. The half maximal inhibitory concentration (IC50) values of Ganoderma extracts on HL60, K562 and SGC-7901 cells for 24 h were 0.44, 0.39 and 0.90 mg/ml, respectively; for Ganoderma spores oil, the IC50 values were 1.13, 2.27 and 6.29 mg/ml, respectively. In the in vivo study, the inhibitory rates of Ganoderma extracts (4 g/kg/d, intragastrically) on S180 and H22 cells were 39.1 and 44.6%, respectively, and for Ganoderma spores oil (1.2 g/kg/d, intragastrically) the inhibitory rates were 30.9 and 44.9%, respectively. Ganoderma extracts and spores oil inhibited the activities of topoisomerase I and II. Ganoderma spores oil was shown block the cell cycle at the transition between the G1 and S phases and induce a marked decrease in cyclin D1 levels in K562 cells, with no significant change in cyclin E level. These results suggest that the Ganoderma extracts and spores oil possessed antitumor effects in the in vitro and in vivo studies. The antitumor mechanisms of the extracts and spores oil were associated with inhibitory effects on topoisomerase I and II activities, and for Ganoderma spores oil, the antitumor effects may also be associated with decreased cyclin D1 levels, thus inducing G1 arrest in the cell cycle. PMID:27900038

1.2.2.Synthesis, crystal structure and in vitro anti-tumor activity of dibutyltin complex of 2,4-dichloro-5-fluorobenzoic acid

Directory of Open Access Journals (Sweden)

Ming Li, Liqin Wang, Zhenlei Zhang, Yue Xin, Laijin Tian*

2014-04-01

Full Text Available The dibutyltin complex of 2,4-dichloro-5- fluorobenzoic acid, [(2,4-Cl2 -5-FC6 H2 C(OOSnBu2 2 O]2 (Bu = CH2 CH2 CH2 CH3 (1 , has been synthesized and characterized by elemental analysis, FT-IR, 119 Sn NMR spectroscopy, and Xray single crystal diffraction. Compound 1 is a centrosymmetric dimmer with two distinct types of carboxylate moieties and tin atoms with distorted trigonal bipyramidal geometries. The in vitro  anti-tumor activity of 1 against two human tumor cell lines was found to be higher than that for cis-platin [cis diaminedichloroplatinum( II] used clinically. Supporting information : FT-IR, 119 Sn NMR, X-Ray, Proliferation inhibitory rate, Cif file.

Unique antitumor property of the Mg-Ca-Sr alloys with addition of Zn

Science.gov (United States)

Wu, Yuanhao; He, Guanping; Zhang, Yu; Liu, Yang; Li, Mei; Wang, Xiaolan; Li, Nan; Li, Kang; Zheng, Guan; Zheng, Yufeng; Yin, Qingshui

2016-02-01

In clinical practice, tumor recurrence and metastasis after orthopedic prosthesis implantation is an intensely troublesome matter. Therefore, to develop implant materials with antitumor property is extremely necessary and meaningful. Magnesium (Mg) alloys possess superb biocompatibility, mechanical property and biodegradability in orthopedic applications. However, whether they possess antitumor property had seldom been reported. In recent years, it showed that zinc (Zn) not only promote the osteogenic activity but also exhibit good antitumor property. In our present study, Zn was selected as an alloying element for the Mg-1Ca-0.5Sr alloy to develop a multifunctional material with antitumor property. We investigated the influence of the Mg-1Ca-0.5Sr-xZn (x = 0, 2, 4, 6 wt%) alloys extracts on the proliferation rate, cell apoptosis, migration and invasion of the U2OS cell line. Our results show that Zn containing Mg alloys extracts inhibit the cell proliferation by alteration the cell cycle and inducing cell apoptosis via the activation of the mitochondria pathway. The cell migration and invasion property were also suppressed by the activation of MAPK (mitogen-activated protein kinase) pathway. Our work suggests that the Mg-1Ca-0.5Sr-6Zn alloy is expected to be a promising orthopedic implant in osteosarcoma limb-salvage surgery for avoiding tumor recurrence and metastasis.

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

Directory of Open Access Journals (Sweden)

Pastorino Fabio

2010-06-01

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

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

Directory of Open Access Journals (Sweden)

Pavel Štarha

2014-07-01

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

Screening for Genes Coding for Putative Antitumor Compounds, Antimicrobial and Enzymatic Activities from Haloalkalitolerant and Haloalkaliphilic Bacteria Strains of Algerian Sahara Soils

Directory of Open Access Journals (Sweden)

Okba Selama

2014-01-01

Full Text Available Extreme environments may often contain unusual bacterial groups whose physiology is distinct from those of normal environments. To satisfy the need for new bioactive pharmaceuticals compounds and enzymes, we report here the isolation of novel bacteria from an extreme environment. Thirteen selected haloalkalitolerant and haloalkaliphilic bacteria were isolated from Algerian Sahara Desert soils. These isolates were screened for the presence of genes coding for putative antitumor compounds using PCR based methods. Enzymatic, antibacterial, and antifungal activities were determined by using cultural dependant methods. Several of these isolates are typical of desert and alkaline saline soils, but, in addition, we report for the first time the presence of a potential new member of the genus Nocardia with particular activity against the yeast Saccharomyces cerevisiae. In addition to their haloalkali character, the presence of genes coding for putative antitumor compounds, combined with the antimicrobial activity against a broad range of indicator strains and their enzymatic potential, makes them suitable for biotechnology applications.

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

Science.gov (United States)

Reyna-Martinez, Raul; Gomez-Flores, Ricardo; López-Chuken, Ulrico; Quintanilla-Licea, Ramiro; Caballero-Hernandez, Diana; Rodríguez-Padilla, Cristina; Beltrán-Rocha, Julio Cesar; Tamez-Guerra, Patricia

2018-01-01

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

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

Directory of Open Access Journals (Sweden)

Raul Reyna-Martinez

2018-02-01

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

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

Science.gov (United States)

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

2010-01-01

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

Tumor-altered dendritic cell function: implications for anti-tumor immunity

Directory of Open Access Journals (Sweden)

Kristian Michael Hargadon

2013-07-01

Full Text Available Dendritic cells are key regulators of both innate and adaptive immunity, and the array of immunoregulatory functions exhibited by these cells is dictated by their differentiation, maturation, and activation status. Although a major role for these cells in the induction of immunity to pathogens has long been appreciated, data accumulated over the last several years has demonstrated that DC are also critical regulators of anti-tumor immune responses. However, despite the potential for stimulation of robust anti-tumor immunity by DC, tumor-altered DC function has been observed in many cancer patients and tumor-bearing animals and is often associated with tumor immune escape. Such dysfunction has significant implications for both the induction of natural anti-tumor immune responses as well as the efficacy of immunotherapeutic strategies that target endogenous DC in situ or that employ exogenous DC as part of anti-cancer immunization maneuvers. In this review, the major types of tumor-altered DC function will be described, with emphasis on recent insights into the mechanistic bases for the inhibition of DC differentiation from hematopoietic precursors, the altered programming of DC precursors to differentiate into myeloid-derived suppressor cells or tumor-associated macrophages, the suppression of DC maturation and activation, and the induction of immunoregulatory DC by tumors, tumor-derived factors, and tumor-associated cells within the milieu of the tumor microenvironment. The impact of these tumor-altered cells on the quality of the overall anti-tumor immune response will also be discussed. Finally, this review will also highlight questions concerning tumor-altered DC function that remain unanswered, and it will address factors that have limited advances in the study of this phenomenon in order to focus future research efforts in the field on identifying strategies for interfering with tumor-associated DC dysfunction and improving DC-mediated anti-tumor

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

Directory of Open Access Journals (Sweden)

Yan Zhang

2017-12-01

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

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

Directory of Open Access Journals (Sweden)

Daniel V Correia

Full Text Available BACKGROUND: The unique responsiveness of Vgamma9Vdelta2 T-cells, the major gammadelta subset of human peripheral blood, to non-peptidic prenyl pyrophosphate antigens constitutes the basis of current gammadelta T-cell-based cancer immunotherapy strategies. However, the molecular mechanisms responsible for phosphoantigen-mediated activation of human gammadelta T-cells remain unclear. In particular, previous reports have described a very slow kinetics of activation of T-cell receptor (TCR-associated signal transduction pathways by isopentenyl pyrophosphate and bromohydrin pyrophosphate, seemingly incompatible with direct binding of these antigens to the Vgamma9Vdelta2 TCR. Here we have studied the most potent natural phosphoantigen yet identified, (E-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP, produced by Eubacteria and Protozoa, and examined its gammadelta T-cell activation and anti-tumor properties. METHODOLOGY/PRINCIPAL FINDINGS: We have performed a comparative study between HMB-PP and the anti-CD3epsilon monoclonal antibody OKT3, used as a reference inducer of bona fide TCR signaling, and followed multiple cellular and molecular gammadelta T-cell activation events. We show that HMB-PP activates MEK/Erk and PI-3K/Akt pathways as rapidly as OKT3, and induces an almost identical transcriptional profile in Vgamma9(+ T-cells. Moreover, MEK/Erk and PI-3K/Akt activities are indispensable for the cellular effects of HMB-PP, including gammadelta T-cell activation, proliferation and anti-tumor cytotoxicity, which are also abolished upon antibody blockade of the Vgamma9(+ TCR Surprisingly, HMB-PP treatment does not induce down-modulation of surface TCR levels, and thereby sustains gammadelta T-cell activation upon re-stimulation. This ultimately translates in potent human gammadelta T-cell anti-tumor function both in vitro and in vivo upon transplantation of human leukemia cells into lymphopenic mice, CONCLUSIONS/SIGNIFICANCE: The development of

Enhancement of antitumor activity of gammaretrovirus carrying IL-12 gene through genetic modification of envelope targeting HER2 receptor: a promising strategy for bladder cancer therapy.

Science.gov (United States)

Tsai, Y-S; Shiau, A-L; Chen, Y-F; Tsai, H-T; Tzai, T-S; Wu, C-L

2010-01-01

The objective of this study was to develop an HER2-targeted, envelope-modified Moloney murine leukemia virus (MoMLV)-based gammaretroviral vector carrying interleukin (IL)-12 gene for bladder cancer therapy. It displayed a chimeric envelope protein containing a single-chain variable fragment (scFv) antibody to the HER2 receptor and carried the mouse IL-12 gene. The fragment of anti-erbB2scFv was constructed into the proline-rich region of the viral envelope of the packaging vector lacking a transmembrane subunit of the carboxyl terminal region of surface subunit. As compared with envelope-unmodified gammaretroviruses, envelope-modified ones had extended viral tropism to human HER2-expressing bladder cancer cell lines, induced apoptosis, and affected cell cycle progression despite lower viral titers. Moreover, animal studies showed that envelope-modified gammaretroviruses carrying IL-12 gene exerted higher antitumor activity in terms of retarding tumor growth and prolonging the survival of tumor-bearing mice than unmodified ones, which were associated with enhanced tumor cell apoptosis as well as increased intratumoral levels of IL-12, interferon-gamma, IL-1beta, and tumor necrosis factor-alpha proteins. Therefore, the antitumor activity of gammaretroviruses carrying the IL-12 gene was enhanced through genetic modification of the envelope targeting HER2 receptor, which may be a promising strategy for bladder cancer therapy.

Synthesis, antitumor and antimicrobial activity of novel 1-substituted phenyl-3-[3-alkylamino(methyl)-2-thioxo-1,3,4-oxadiazole-5-yl] beta-carboline derivatives

Energy Technology Data Exchange (ETDEWEB)

Savariz, Franciele C.; Formagio, Anelise S. N.; Barbosa, Valeria A.; Sarragiotto, Maria Helena [Universidade Estadual de Maringa (UEM), PR (Brazil). Dept. de Quimica; Foglio, Mary Ann; Carvalho, Joao E. de; Duarte, Marta C.T. [Universidade Estadual de Campinas (UNICAMP), SP (Brazil). Centro Pluridisciplinar de Pesquisas Quimicas, Biologicas e Agricolas; Dias Filho, Benedito P. [Universidade Estadual de Maringa (UEM), PR (Brazil). Dept. de Analises Clinicas

2010-07-01

With the purpose of activity enhancement of 1-substituted phenyl-3-(2-thioxo-1,3,4-oxadiazole-5-yl) beta-carbolines 1a-c, reported as potential antitumor agents in our previous study, herein we report the synthesis and antitumor activity evaluation of several novel Mannich bases 2-7(a-c), by the introduction of different alkylamino(methyl) groups in the 1,3,4-oxadiazole unity of 1a-c. The antimicrobial activities of 1a-c and of 2-7(a-c) were also evaluated. Additionally, an in silico study of the ADME properties of novel synthesized beta-carboline derivatives 2-7(a-c) was performed by evaluation of their Lipinski's parameters and topological polar surface area (TPSA) and percentage of absorption (% ABS) data. (author)

Preparation, characterization and antitumor activity evaluation of apigenin nanoparticles by the liquid antisolvent precipitation technique.

Science.gov (United States)

Wu, Weiwei; Zu, Yuangang; Wang, Li; Wang, Lingling; Wang, Huimei; Li, Yuanyuan; Wu, Mingfang; Zhao, Xiuhua; Fu, Yujie

2017-11-01

The present work aimed to apply the liquid antisolvent precipitation (LAP) method for preparing the apigenin nanoparticles and thereby improving the solubility and bioavailability of apigenin. The different experimental parameters on particle size were optimized through central composite design (CCD) using the Design-Expert ® software. Under the optimum conditions, the particle size of the apigenin nanosuspension was about 159.2 nm. In order to get apigenin nanoparticles, the freeze-drying method was selected and the mannitol was used as a cryoprotectant. Then the solid state properties of the apigenin nanoparticles were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermo gravimetric (TG), and X-ray diffraction (XRD). The results obtained displayed that the apigenin nanoparticles exhibited near-spherical shape and could be transformed into an amorphous form. In addition, the dissolving test, the bioavailability in rats, and the antitumor activity were also studied. The experimental results showed that the solubility of the apigenin nanoparticles were about 29.61 times and 64.81 times of raw apigenin in artificial gastric juice and in artificial intestinal juice, respectively, and the apigenin nanoparticles showed higher dissolution rates compared to raw apigenin, and was about 6.08 times and 6.14 times than that of raw apigenin in artificial gastric juice and in artificial intestinal juice. The oral bioavailability of apigenin nanoparticles was about 4.96 times higher than that of the raw apigenin, but the apigenin nanoparticles had no toxic effect on the organs of rats. In addition, the apigenin nanoparticles had a higher inhibition to HepG2 cells by lower IC50 than that of raw apigenin.

Foxo1 and Foxp1 play opposing roles in regulating the differentiation and antitumor activity of TH9 cells programmed by IL-7

Science.gov (United States)

Bi, Enguang; Ma, Xingzhe; Lu, Yong; Yang, Maojie; Wang, Qiang; Xue, Gang; Qian, Jianfei; Wang, Siqing; Yi, Qing

2018-01-01

Tumor-specific CD4+ T helper 9 (TH9) cells, so-called because of their production of the cytokine interleukin-9 (IL-9), are a powerful effector T cell subset for cancer immunotherapy. We found that pretreatment of naïve CD4+ T cells with IL-7 further enhanced their differentiation into TH9 cells and augmented their antitumor activity. IL-7 markedly increased the abundance of the histone acetyltransferase p300 by activating the STAT5 and PI3K-AKT-mTOR signaling pathways and promoting the acetylation of histones at the Il9 promoter. As a result, the transcriptional regulator Foxo1 was dephosphorylated and translocated to the nucleus, bound to the Il9 promoter, and induced the production of IL-9 protein. In contrast, Foxp1, which bound to the Il9 promoter in naïve CD4+ T cells and inhibited Il9 expression, was outcompeted for binding to the Il9 promoter by Foxo1 and translocated to the cytoplasm. Furthermore, forced expression of Foxo1 or a deficiency in Foxp1 in CD4+ T cells markedly increased the production of IL-9, whereas a deficiency in Foxo1 inhibited the ability of IL-7 to enhance the differentiation and antitumor activity of TH9 cells. Thus, we identified the roles of Foxo1 as a positive regulator and Foxp1 as a negative regulator of TH9 cell differentiation and antitumor activity, which may provide potential targets for cancer immunotherapy. PMID:29018172

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

International Nuclear Information System (INIS)

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

2015-01-01

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

Antibacterial, antioxidant and antitumor properties of Moroccan medicinal plants: A review

Directory of Open Access Journals (Sweden)

Abdelhakim Bouyahya

2017-01-01

Full Text Available Aromatic and medicinal plants have been traditionally used since antiquity to fight against illnesses. Recently, several researches have focused on the pharmacological properties and various bioactivities of natural products are extracted from medicinal plants, including the properties of antibacterial, antitumor and antioxidant activities. The products of medicinal plants are the secondary metabolites belonging to different compound classes such as essential oils, polyphenols, flavonoids and other phytochemical classes. In Morocco, medicinal plants are the major source of bioactive compounds and the majority of them are used in phytotherapy. The biological potential of various Moroccan medicinal plants attracts a lot of interest in the literature. They include antibacterial, antioxidant and antitumor investigations. In this context, this work aims at discussing antibacterial, antitumor and antioxidant properties of Moroccan medicinal plants.

Modification of carcinogenic and antitumor radiation effects (biomedical aspects)

International Nuclear Information System (INIS)

Vilenchik, M.M.

1985-01-01

In the book the data on modification of carcinogenic radiation effects by physiologicaly active compounds (caffeine, hormones, promoters and others) as well as on potentiation of antitumor radiation effects by means of hyperthermia are systematized. It is shown that as a basis of synergetic (superadditive) carcinogenic or antitumor radiation effects combined with other factor can be the inhibiting effects of the latter on the reparation process of radiation-induced DNA injuries. The results of experimental investigations and the data on quantitative analysis can be used as a theoretical basis for improvement of the ways and means of the prophylaxis of tumor diseases as well as for increasing the efficiency of radiotherapy

Antitumor Immunity Is Controlled by Tetraspanin Proteins

Directory of Open Access Journals (Sweden)

Fleur Schaper

2018-05-01

Full Text Available Antitumor immunity is shaped by the different types of immune cells that are present in the tumor microenvironment (TME. In particular, environmental signals (for instance, soluble factors or cell–cell contact transmitted through the plasma membrane determine whether immune cells are activated or inhibited. Tetraspanin proteins are emerging as central building blocks of the plasma membrane by their capacity to cluster immune receptors, enzymes, and signaling molecules into the tetraspanin web. Whereas some tetraspanins (CD81, CD151, CD9 are widely and broadly expressed, others (CD53, CD37, Tssc6 have an expression pattern restricted to hematopoietic cells. Studies using genetic mouse models have identified important immunological functions of these tetraspanins on different leukocyte subsets, and as such, may be involved in the immune response against tumors. While multiple studies have been performed with regards to deciphering the function of tetraspanins on cancer cells, the effect of tetraspanins on immune cells in the antitumor response remains understudied. In this review, we will focus on tetraspanins expressed by immune cells and discuss their potential role in antitumor immunity. New insights in tetraspanin function in the TME and possible prognostic and therapeutic roles of tetraspanins will be discussed.

Synthesis, structure, antitumor activity of novel pharmaceutical co-crystals based on bispyridyl-substituted α, β-unsaturated ketones with gallic acid

Science.gov (United States)

Liu, Lian-Dong; Liu, Shu-Lian; Liu, Zhi-Xian; Hou, Gui-Ge

2016-05-01

Three novel pharmaceutical co-crystals, (A)·(gallic acid) (1), (B)·(gallic acid) (2), and (C)·(gallic acid) (3) were generated based on 2,6-bis((pyridin-4-yl)methylene)cyclohexanone (A), N-methyl-3,5-bis((pyridin-3-yl)methylene)-4-piperidone (B), N-methyl-3,5-bis((pyridin-4-yl)methylene)-4-piperidone (C) with gallic acid, respectively. They are characterized by elemental analysis, FTIR spectroscopy, 1H NMR and single-crystal X-ray diffraction. Structural analysis reveals that two pharmaceutical ingredients link each other into H-bonding-driven 3D network in 1, 2, or 2D plane in 3. In addition, their antitumor activities against human neoplastic cell lines A549, SGC-7901, MCF-7, OVCA-433, HePG2 and cytotoxicity for HUVEC cell lines by CCK-8 method were evaluated primarily. Compared with gallic acid and free A, B and C, their antitumor activities have improved distinctly, while cytotoxicities have reduced markedly, especially for co-crystal 1. This is mainly because of the synergistic effect between pharmaceutical ingredients A, B, and C and gallic acid.

Synthesis and Antitumor Activity of Triazole-Containing Sorafenib Analogs

Directory of Open Access Journals (Sweden)

Wenjing Ye

2017-10-01

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

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

Directory of Open Access Journals (Sweden)

Hongzhuan Xuan

2014-01-01

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

Studies on anti-tumor effect of electromagnetic waves

International Nuclear Information System (INIS)

Kadota, Ikuhito; Wakabayashi, Toshio; Ogoshi, Kyoji; Kamijo, Akemi

1995-01-01

Hyperthermia have treated cancer with thermal effect of electromagnetic waves for biological systems, but the expected effect is not shown. Also non-thermal effect of electromagnetic waves is out of consideration. If irradiation conditions of electromagnetic waves with non-thermal anti-tumor effect are obtained, we can expect newly spread in cancer therapy. We had in vivo experiments that electromagnetic waves were irradiated to mice. In some irradiation conditions, the non-thermal anti-tumor effect of electromagnetic waves showed. In order to specify the irradiation conditions, we had in vitro experiments. We found that activity ratio of tumor cells which was measured by MTT method depended on irradiation time and power of electromagnetic waves. These results are useful for the cancer therapy. (author)

CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo.

Science.gov (United States)

Buggy, Joseph J; Cao, Z Alexander; Bass, Kathryn E; Verner, Erik; Balasubramanian, Sriram; Liu, Liang; Schultz, Brian E; Young, Peter R; Dalrymple, Stacie A

2006-05-01

CRA-024781 is a novel, broad spectrum hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor activity in vitro and in vivo preclinically and is under evaluation in phase I clinical trials for cancer. CRA-024781 inhibited pure recombinant HDAC1 with a K(i) of 0.007 mumol/L, and also inhibited the other HDAC isozymes HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-024781 resulted in the accumulation of acetylated histone and acetylated tubulin, resulting in an inhibition of tumor cell growth and the induction of apoptosis. CRA-024781 parenterally administered to mice harboring HCT116 or DLD-1 colon tumor xenografts resulted in a statistically significant reduction in tumor growth at doses that were well tolerated as measured by body weight. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells, and an alteration in the expression of many genes in the tumors, including several involved in apoptosis and cell growth. These results reveal CRA-024781 to be a novel HDAC inhibitor with potent antitumor activity.

Anti-tumor effect of a recombinant plasmid expressing human interleukin-12: an initial research

International Nuclear Information System (INIS)

Zheng Chuansheng; Xia Xiangwen; Feng Gansheng; Li Xin; Liang Huimin; Liang Bin

2010-01-01

Objective: To study the anti-tumor effect of a recombinant plasmid expressing human interleukin-12 (pEGFP-CI I L- 12) in vivo and in vitro. Methods: We transduct the recombinant gene (pEGFP-CI I L-12) to liver cancer cell HepG 2 in vitro, and detect reproductive activity of the cell using MTT and the activity of expressing vascular endothelial growth factor(VEGF) using semiquantitative PCR. And then, we deliver the gene to rabbit liver tumor tissue intraarterial and combine with chemoembolization to observe the anti- tumor effect to VX 2 tumor in vivo. Results: There are no statistical difference compared With control group in activity of reproductive and expressing VEGF in vitro. In vivo, tumor growth rate significantly reduce in gene therapy combined with chemoembolization group. Conclusion: Recombinant gene (pEGFP-Cl I L-12) exhibit significant anti-tumor effect in vivo but not in vitro, perhaps the anti-tumor effect is associated with an indirect pathway instead of a direct pathway. (authors)

Anti-angiogenesis and anti-tumor activity of recombinant anginex

International Nuclear Information System (INIS)

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

2006-01-01

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

Experimental study of anti-tumor activity of direct current

International Nuclear Information System (INIS)

Ito, Hisao; Hashimoto, Shozo

1989-01-01

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

[Experimental study of the relationships between activation of erythropoiesis and hematotoxicity of some antitumoral agents (author's transl)].

Science.gov (United States)

Pannacciulli, I; Bogliolo, G; Massa, G; Ronco, D; Fresco, G; Saviane, A; Dolcino, G; Celle, G

1975-01-01

The changes in the blood toxicity of some antitumoral chemotherapeutic agents in the presence of erythropoiesis activation by bleeding are evaluated. The general toxicity seems to be unaffected but the damage to erythropoiesis proved, in absolute terms, to be more severe in the bled animals. The recovery of hematopoiesis was slower after some drug than others. These results are discussed in the light of present knowledge of hematopoietic kinetics and of the relationships between antiblastic drugs and staminal hematopoietic compartments.

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

Directory of Open Access Journals (Sweden)

Yunyun Geng

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

Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer.

Science.gov (United States)

Yoshioka, Takahiro; Shien, Kazuhiko; Namba, Kei; Torigoe, Hidejiro; Sato, Hiroki; Tomida, Shuta; Yamamoto, Hiromasa; Asano, Hiroaki; Soh, Junichi; Tsukuda, Kazunori; Nagasaka, Takeshi; Fujiwara, Toshiyoshi; Toyooka, Shinichi

2018-04-01

Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti-human epidermal growth factor receptor 2 (HER2) drugs have been developed, trastuzumab is still the only anti-HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2-positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan-HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER2-amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene that inhibits the activation of insulin-like growth factor-1 receptor (IGF-1R), were less sensitive to pan-HER inhibitors. A combination therapy consisting of pan-HER inhibitors and an IGF-1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2-amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF-1R-targeting therapy can overcome drug insensitiveness in HER2-amplified gastric cancer. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Reprogramming Antitumor Immune Responses with microRNAs

Science.gov (United States)

2013-10-01

disease, including cancer etiology (4) and the generation and inhibition of antitumor immune responses (5–9). Biologically active miRNAs bind to MREs...breast, colorectal, lung, pancreatic , and thyroid carcinomas and in liquid tumors including lymphomas and some acute myeloid leukemias (9, 35). The...immunity [9], underscoring the potential of targeting this major microenvironmental compartment. Accumulating evidence suggests that chronic

A Chemoinformatics Approach to the Discovery of Lead-Like Molecules from Marine and Microbial Sources En Route to Antitumor and Antibiotic Drugs

Science.gov (United States)

Pereira, Florbela; Latino, Diogo A. R. S.; Gaudêncio, Susana P.

2014-01-01

The comprehensive information of small molecules and their biological activities in the PubChem database allows chemoinformatic researchers to access and make use of large-scale biological activity data to improve the precision of drug profiling. A Quantitative Structure–Activity Relationship approach, for classification, was used for the prediction of active/inactive compounds relatively to overall biological activity, antitumor and antibiotic activities using a data set of 1804 compounds from PubChem. Using the best classification models for antibiotic and antitumor activities a data set of marine and microbial natural products from the AntiMarin database were screened—57 and 16 new lead compounds for antibiotic and antitumor drug design were proposed, respectively. All compounds proposed by our approach are classified as non-antibiotic and non-antitumor compounds in the AntiMarin database. Recently several of the lead-like compounds proposed by us were reported as being active in the literature. PMID:24473174

SYNTHESIS AND ANTITUMOR ACTIVITY OF COPPER, NICKEL AND COBALT COORDINATION COMPOUNDS WITH 1-(2-HYDROXYPHENYLETHANONE N(4-ALLYL-3-THIOSEMICARBAZONE

Directory of Open Access Journals (Sweden)

Vasilii GRAUR

2015-12-01

Full Text Available The paper presents the synthesis of the ligand 1-(2-hydroxyphenylethanone N(4-allyl-3-thiosemicarbazone (H2L and six coordination compounds of copper, nickel and cobalt with this ligand. The structure of thiosemicarbazone H2L was studied using 1H and 13С NMR spectroscopy. The synthesized coordination compounds were studied using elemental analysis, gravimetric analysis of water content, molar conductivity, and magnetochemistry. For H2L the antitumor activity towards human leukemia HL-60 cells and cervical cancer HeLa cells was determined. It was established that the substitution of hydrogen atom with methyl group in the azomethinic fragment leads to the growth of antitumor activity.SINTEZA ŞI ACTIVITATEA ANTITUMORALĂ A COMPUŞILOR COMPLECŞI AI CUPRULUI, NICHELULUI ŞI COBALTULUI CU N(4-ALIL-3-TIOSEMICARBAZONA 1-(2-HIDROXIFENILETANONEILucrarea conţine descrierea sintezei N(4-alil-3-tiosemicarbazonei 1-(2-hidroxifeniletanonei (H2L şi a şase compuşi coordinativi ai cuprului, nichelului şi cobaltului cu acest ligand. Structura tiosemicarbazonei H2L a fost stabilită în baza datelor spectroscopiei RMN 1H şi 13C. Compuşi coordinativi au fost studiaţi cu ajutorul analizei elementale, analizei gravimetrice a conţinutului de apă, conductivitaţii molare şi magnetochimiei. Pentru H2L a fost determinată activitatea antitumorală faţă de celulele leucemiei umane HL-60 şi ale cancerului cervical HeLa. S-a stabilit că înlocuirea atomului de hidrogen cu o grupare metil în fragmentul azomethinic conduce la creşterea activitaţii antitumorale.

TCR-Engineered, Customized, Antitumor T Cells for Cancer Immunotherapy: Advantages and Limitations

Directory of Open Access Journals (Sweden)

Arvind Chhabra

2011-01-01

Full Text Available The clinical outcome of the traditional adoptive cancer immunotherapy approaches involving the administration of donor-derived immune effectors, expanded ex vivo, has not met expectations. This could be attributed, in part, to the lack of sufficient high-avidity antitumor T-cell precursors in most cancer patients, poor immunogenicity of cancer cells, and the technological limitations to generate a sufficiently large number of tumor antigen-specific T cells. In addition, the host immune regulatory mechanisms and immune homeostasis mechanisms, such as activation-induced cell death (AICD, could further limit the clinical efficacy of the adoptively administered antitumor T cells. Since generation of a sufficiently large number of potent antitumor immune effectors for adoptive administration is critical for the clinical success of this approach, recent advances towards generating customized donor-specific antitumor-effector T cells by engrafting human peripheral blood-derived T cells with a tumor-associated antigen-specific transgenic T-cell receptor (TCR are quite interesting. This manuscript provides a brief overview of the TCR engineering-based cancer immunotherapy approach, its advantages, and the current limitations.

TCR-engineered, customized, antitumor T cells for cancer immunotherapy: advantages and limitations.

Science.gov (United States)

Chhabra, Arvind

2011-01-05

The clinical outcome of the traditional adoptive cancer immunotherapy approaches involving the administration of donor-derived immune effectors, expanded ex vivo, has not met expectations. This could be attributed, in part, to the lack of sufficient high-avidity antitumor T-cell precursors in most cancer patients, poor immunogenicity of cancer cells, and the technological limitations to generate a sufficiently large number of tumor antigen-specific T cells. In addition, the host immune regulatory mechanisms and immune homeostasis mechanisms, such as activation-induced cell death (AICD), could further limit the clinical efficacy of the adoptively administered antitumor T cells. Since generation of a sufficiently large number of potent antitumor immune effectors for adoptive administration is critical for the clinical success of this approach, recent advances towards generating customized donor-specific antitumor-effector T cells by engrafting human peripheral blood-derived T cells with a tumor-associated antigen-specific transgenic T-cell receptor (TCR) are quite interesting. This manuscript provides a brief overview of the TCR engineering-based cancer immunotherapy approach, its advantages, and the current limitations.

Antioxidative and antitumor properties of in vitro-cultivated broccoli (Brassica oleracea var. italica).

Science.gov (United States)

Cakar, Jasmina; Parić, Adisa; Maksimović, Milka; Bajrović, Kasim

2012-02-01

Broccoli [Brassica oleracea L. var. italica Plenck. (Brassicaceae)] contains substantial quantities of bioactive compounds, which are good free radical scavengers and thus might have strong antitumor properties. Enhancing production of plant secondary metabolites could be obtained with phytohormones that have significant effects on the metabolism of secondary metabolites. In that manner, in vitro culture presents good model for manipulation with plant tissues in order to affect secondary metabolite production and thus enhance bioactive properties of plants. Estimation of the antioxidative and antitumor properties of broccoli cultivated in different in vitro conditions. In vitro germinated and cultivated broccoli seedlings, as well as spontaneously developed calli, were subjected to Soxhlet extraction. Antioxidative activity of the herbal extracts was determined using 1,1-diphenyl-2-picrylhydrazyl (DPPH(•)) radical method. Antitumor properties of the extracts were determined using crown-gall tumor inhibition (potato disc) assay. Three, 10, 20, and 30 days old broccoli seedlings, cultivated in vitro on three different Murashige-Skoog media, two types of callus, and seedlings from sterile filter paper were used for extraction. In total, 15 aqueous extracts were tested for antioxidative and antitumor potential. Three day-old seedlings showed the highest antioxidative activity. Eleven out of 15 aqueous extracts demonstrated above 50% of crown-gall tumor inhibition in comparison with the control. Tumor inhibition was in association with types and concentrations of phytohormones presented in growing media. It is demonstrated that phytohormones in plant-growing media could affect the bioactive properties of broccoli either through increasing or decreasing their antioxidative and antitumor potential.

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

Directory of Open Access Journals (Sweden)

Taigang Liang

2013-04-01

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

Antitumor and radiation protection effects of β-1,3-D-glucan extracted from yeast (saccharomyces cerevisiae)

International Nuclear Information System (INIS)

Yoshimura, Akinobu; Hasegawa, Takeo; Monzen, Hajime; Takahashi, Tohru

2003-01-01

Various natural extracts are manufactured and on sale as health food products, which are raising popular consciousness of being fit, because they are considered effective or suppressible for cancer. In the current experiment, we measured the immunological activity, antitumor effects, and radioprotective effects of β-1,3-D-glucan (Macroglucan) extracted from bread yeast. Macroglucan of 0, 200, 400, and 800 mg/kg were administered intraperitoneally to C3H/HeJ mice, respectively. The antitumor effects of Macroglucan were examined by measuring natural killer (NK) and lymphokine activated killer (LAK) cell activity and tumor volume. Change in weight, survival, and microscopic manifestation of the intestine were evaluated in the C3H/HeJ mice received total body irradiation to measure radioprotective effect of Macroglucan. According to measurements of cellular cytotoxicity, levels of NK and LAK cell activity were significantly higher in the group administered Macroglucan than in the control group. Macroglucan's role in immunological activity was suggested by the observed suppression of tumor growth in the Macroglucan-administered group. That group also experienced suppression of weight loss after irradiation in the experiment for radioprotection, and a consequent increase in the survival rate compared with the control group. Protective effects appeared in photomicrographs of the intestinal cells. These results confirmed Macroglucan's radioprotective effects. These effects may be related to the suppression of infection accompanying immunological activation due to Macroglucan administration, antioxidant activity, and radical scavenging capacity. (author)

Multifunctional antitumor magnetite/chitosan-l-glutamic acid (core/shell) nanocomposites

International Nuclear Information System (INIS)

Santos, Daniela P.; Ruiz, M. Adolfina; Gallardo, Visitación; Zanoni, Maria Valnice B.; Arias, José L.

2011-01-01

The development of anticancer drug delivery systems based on biodegradable nanoparticles has been intended to maximize the localization of chemotherapy agents within tumor interstitium, along with negligible drug distribution into healthy tissues. Interestingly, passive and active drug targeting strategies to cancer have led to improved nanomedicines with great tumor specificity and efficient chemotherapy effect. One of the most promising areas in the formulation of such nanoplatforms is the engineering of magnetically responsive nanoparticles. In this way, we have followed a chemical modification method for the synthesis of magnetite/chitosan-l-glutamic acid (core/shell) nanostructures. These magnetic nanocomposites (average size ≈340 nm) exhibited multifunctional properties based on its capability to load the antitumor drug doxorubicin (along with an adequate sustained release) and its potential for hyperthermia applications. Compared to drug surface adsorption, doxorubicin entrapment into the nanocomposites matrix yielded a higher drug loading and a slower drug release profile. Heating characteristics of the magnetic nanocomposites were investigated in a high-frequency alternating magnetic gradient: a stable maximum temperature of 46 °C was successfully achieved within 40 min. To our knowledge, this is the first time that such kind of stimuli-sensitive nanoformulation with very important properties (i.e., magnetic targeting capabilities, hyperthermia, high drug loading, and little burst drug release) has been formulated for combined antitumor therapy against cancer.

Multifunctional antitumor magnetite/chitosan- l-glutamic acid (core/shell) nanocomposites

Science.gov (United States)

Santos, Daniela P.; Ruiz, M. Adolfina; Gallardo, Visitación; Zanoni, Maria Valnice B.; Arias, José L.

2011-09-01

The development of anticancer drug delivery systems based on biodegradable nanoparticles has been intended to maximize the localization of chemotherapy agents within tumor interstitium, along with negligible drug distribution into healthy tissues. Interestingly, passive and active drug targeting strategies to cancer have led to improved nanomedicines with great tumor specificity and efficient chemotherapy effect. One of the most promising areas in the formulation of such nanoplatforms is the engineering of magnetically responsive nanoparticles. In this way, we have followed a chemical modification method for the synthesis of magnetite/chitosan- l-glutamic acid (core/shell) nanostructures. These magnetic nanocomposites (average size ≈340 nm) exhibited multifunctional properties based on its capability to load the antitumor drug doxorubicin (along with an adequate sustained release) and its potential for hyperthermia applications. Compared to drug surface adsorption, doxorubicin entrapment into the nanocomposites matrix yielded a higher drug loading and a slower drug release profile. Heating characteristics of the magnetic nanocomposites were investigated in a high-frequency alternating magnetic gradient: a stable maximum temperature of 46 °C was successfully achieved within 40 min. To our knowledge, this is the first time that such kind of stimuli-sensitive nanoformulation with very important properties (i.e., magnetic targeting capabilities, hyperthermia, high drug loading, and little burst drug release) has been formulated for combined antitumor therapy against cancer.

Adenovirus-mediated interleukin-12 gene transfer combined with cytosine deaminase followed by 5-fluorocytosine treatment exerts potent antitumor activity in Renca tumor-bearing mice

International Nuclear Information System (INIS)

Hwang, Kyung-Sun; Cho, Won-Kyung; Yoo, Jinsang; Yun, Hwan-Jung; Kim, Samyong; Im, Dong-Soo

2005-01-01

Therapeutic gene transfer affords a clinically feasible and safe approach to cancer treatment but a more effective modality is needed to improve clinical outcomes. Combined transfer of therapeutic genes with different modes of actions may be a means to this end. Interleukin-12 (IL-12), a heterodimeric immunoregulatory cytokine composed of covalently linked p35 and p40 subunits, has antitumor activity in animal models. The enzyme/prodrug strategy using cytosine deaminase (CD) and 5-fluorocytosine (5-FC) has been used for cancer gene therapy. We have evaluated the antitumor effect of combining IL-12 with CD gene transfer in mice bearing renal cell carcinoma (Renca) tumors. Adenoviral vectors were constructed encoding one or both subunits of murine IL-12 (Ad.p35, Ad.p40 and Ad.IL-12) or cytosine deaminase (Ad.CD). The functionality of the IL-12 or CD gene products expressed from these vectors was validated by splenic interferon (IFN)-γ production or viability assays in cultured cells. Ad.p35 plus Ad.p40, or Ad.IL-12, with or without Ad.CD, were administered (single-dose) intratumorally to Renca tumor-bearing mice. The animals injected with Ad.CD also received 5-FC intraperitoneally. The antitumor effects were then evaluated by measuring tumor regression, mean animal survival time, splenic natural killer (NK) cell activity and IFN-γ production. The inhibition of tumor growth in mice treated with Ad.p35 plus Ad.p40 and Ad.CD, followed by injection of 5-FC, was significantly greater than that in mice treated with Ad.CD/5-FC, a mixture of Ad.p35 plus Ad.p40, or Ad.GFP (control). The combined gene transfer increased splenic NK cell activity and IFN-γ production by splenocytes. Ad.CD/5-FC treatment significantly increased the antitumor effect of Ad.IL-12 in terms of tumor growth inhibition and mean animal survival time. The results suggest that adenovirus-mediated IL-12 gene transfer combined with Ad.CD followed by 5-FC treatment may be useful for treating cancers

Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18

Directory of Open Access Journals (Sweden)

Biliang Hu

2017-09-01

Full Text Available The effects of transgenically encoded human and mouse IL-18 on T cell proliferation and its application in boosting chimeric antigen receptor (CAR T cells are presented. Robust enhancement of proliferation of IL-18-secreting human T cells occurred in a xenograft model, and this was dependent on TCR and IL-18R signaling. IL-18 augmented IFN-γ secretion and proliferation of T cells activated by the endogenous TCR. TCR-deficient, human IL-18-expressing CD19 CAR T cells exhibited enhanced proliferation and antitumor activity in the xenograft model. Antigen-propelled activation of cytokine helper ensemble (APACHE CAR T cells displayed inducible expression of IL-18 and enhanced antitumor immunity. In an intact mouse tumor model, CD19-IL-18 CAR T cells induced deeper B cell aplasia, significantly enhanced CAR T cell proliferation, and effectively augmented antitumor effects in mice with B16F10 melanoma. These findings point to a strategy to develop universal CAR T cells for patients with solid tumors.

Zoledronic acid enhances antitumor efficacy of liposomal doxorubicin.

Science.gov (United States)

Hattori, Yoshiyuki; Shibuya, Kazuhiko; Kojima, Kaori; Miatmoko, Andang; Kawano, Kumi; Ozaki, Kei-Ichi; Yonemochi, Etsuo

2015-07-01

Previously, we found that the injection of zoledronic acid (ZOL) into mice bearing tumor induced changes of the vascular structure in the tumor. In this study, we examined whether ZOL treatment could decrease interstitial fluid pressure (IFP) via change of tumor vasculature, and enhance the antitumor efficacy of liposomal doxorubicin (Doxil®). When ZOL solution was injected at 40 µg/mouse per day for three consecutive days into mice bearing murine Lewis lung carcinoma LLC tumor, depletion of macrophages in tumor tissue and decreased density of tumor vasculature were observed. Furthermore, ZOL treatments induced inflammatory cytokines such as interleukin (IL)-10 and -12, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-α in serum of LLC tumor-bearing mice, but not in normal mice, indicating that ZOL treatments might induce an inflammatory response in tumor tissue. Furthermore, ZOL treatments increased antitumor activity by Doxil in mice bearing a subcutaneous LLC tumor, although they did not significantly increase the tumor accumulation of doxorubicin (DXR). These results suggest that ZOL treatments might increase the therapeutic efficacy of Doxil via improvement of DXR distribution in a tumor by changing the tumor vasculature. ZOL treatment can be an alternative approach to increase the antitumor effect of liposomal drugs.

Expression of microRNA-15b and the glycosyltransferase GCNT3 correlates with antitumor efficacy of Rosemary diterpenes in colon and pancreatic cancer.

Directory of Open Access Journals (Sweden)

Margarita González-Vallinas

Full Text Available Colorectal and pancreatic cancers remain important contributors to cancer mortality burden and, therefore, new therapeutic approaches are urgently needed. Rosemary (Rosmarinus officinalis L. extracts and its components have been reported as natural potent antiproliferative agents against cancer cells. However, to potentially apply rosemary as a complementary approach for cancer therapy, additional information regarding the most effective composition, its antitumor effect in vivo and its main molecular mediators is still needed. In this work, five carnosic acid-rich supercritical rosemary extracts with different chemical compositions have been assayed for their antitumor activity both in vivo (in nude mice and in vitro against colon and pancreatic cancer cells. We found that the antitumor effect of carnosic acid together with carnosol was higher than the sum of their effects separately, which supports the use of the rosemary extract as a whole. In addition, gene and microRNA expression analyses have been performed to ascertain its antitumor mechanism, revealing that up-regulation of the metabolic-related gene GCNT3 and down-regulation of its potential epigenetic modulator miR-15b correlate with the antitumor effect of rosemary. Moreover, plasmatic miR-15b down-regulation was detected after in vivo treatment with rosemary. Our results support the use of carnosic acid-rich rosemary extract as a complementary approach in colon and pancreatic cancer and indicate that GCNT3 expression may be involved in its antitumor mechanism and that miR-15b might be used as a non-invasive biomarker to monitor rosemary anticancer effect.

Doxil Synergizes with Cancer Immunotherapies to Enhance Antitumor Responses in Syngeneic Mouse Models

Directory of Open Access Journals (Sweden)

Jonathan Rios-Doria

2015-08-01

Full Text Available Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti–PD-L1, PD-1, and CTLA-4 mAbs and TNF receptor agonists (OX40 and GITR ligand fusion proteins in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti–PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system. Using established tumors and maximally efficacious doses of Doxil and cancer immunotherapies in either CT26 or MCA205 tumor models, combination groups produced strong synergistic antitumor effects, a larger percentage of complete responders, and increased survival. In vivo pharmacodynamic studies showed that Doxil treatment decreased the percentage of tumor-infiltrating regulatory T cells and, in combination with anti–PD-L1, increased the percentage of tumor-infiltrating CD8+ T cells. In the tumor, Doxil administration increased CD80 expression on mature dendritic cells. CD80 expression was also increased on both monocytic and granulocytic myeloid cells, suggesting that Doxil may induce these tumor-infiltrating cells to elicit a costimulatory phenotype capable of activating an antitumor T-cell response. These results uncover a novel role for Doxil in immunomodulation and support the use of Doxil in combination with checkpoint blockade or TNFR agonists to increase response rates and antitumor activity.

The in vitro antitumor activity of vitamins C and K3 against ovarian carcinoma.

Science.gov (United States)

von Gruenigen, Vivian E; Jamison, James M; Gilloteaux, Jacques; Lorimer, Heather E; Summers, Marcia; Pollard, Robert R; Gwin, Carley A; Summers, Jack L

2003-01-01

The objective was to evaluate the cytotoxic effect and mechanism of action of vitamins C (VC) and K3 (VK3) on ovarian carcinoma. Cytotoxicity assays were performed on ovarian cancer cell lines with VC, VK3 or a VC/VK3 combination. FIC index was employed to evaluate synergism. Flow cytometry was accomplished at 90% cytotoxic doses. Light, transmission electron microscopy and DNA isolation were performed. Antitumor activity was exhibited by both VC, VK3 and VC/VK3. VC/VK3 demonstrated synergistic activity. VC/VK3 may induce a G1 block in the cell cycle. Combined vitamin treatment resulted in cells that maintain apparently intact nuclei while extruding pieces of organelle-free cytoplasm. Degradation of chromosomal DNA was observed. Cell death (autoschizis) displayed characteristics of both apoptosis and necrosis. The cytotoxic effects observed may enable vitamins C and K3 to play an adjuvant role in the treatment of ovarian cancer.

A new class of nitrosoureas. 4. Synthesis and antitumor activity of disaccharide derivatives of 3,3-disubstituted 1-(2-chloroethyl)-1-nitrosoureas.

Science.gov (United States)

Tsujihara, K; Ozeki, M; Morikawa, T; Kawamori, M; Akaike, Y; Arai, Y

1982-04-01

A series of 33 N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of N-substituted glycosylamines has been prepared and tested for antitumor activities. The compounds were obtained by reaction of glycosylamines with isocyanate, followed by nitrosation with N2O4. Structure-activity relationships of these trisubstituted nitrosoureas were investigated by varying the N-substituents and disaccharide groups and by comparing them with the corresponding disubstituted analogues. A large number of the nitrosoureas bearing a maltosyl group exhibited strong antitumor activities against leukemia L1210 and Ehrlich ascites carcinoma, and 60-day survivors against leukemia L1210 were found at the optimal dose for these derivatives. In contrast, the lactosyl and the melibiosyl derivatives were almost inactive. The most interesting compound in this series, the 3-isobutyl-3-maltosyl derivative (37), was tested against leukemia L1210 by single and multiple treatment. Its therapeutic ratio (96.3) obtained by multiple treatment is 3 times larger than that (31.5) obtained by single treatment, suggesting a possible clinical utility of 37 by multiple treatment. The favorable effect of a maltosyl moiety in this class of compounds is discussed.

Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect.

Science.gov (United States)

Lugini, Luana; Federici, Cristina; Borghi, Martina; Azzarito, Tommaso; Marino, Maria Lucia; Cesolini, Albino; Spugnini, Enrico Pierluigi; Fais, Stefano

2016-08-01

Tumor acidity represents a major cause of chemoresistance. Proton pump inhibitors (PPIs) can neutralize tumor acidity, sensitizing cancer cells to chemotherapy. To compare the anti-tumor efficacy of different PPIs in vitro and in vivo. In vitro experiments PPIs anti-tumor efficacy in terms of cell proliferation and cell death/apoptosis/necrosis evaluation were performed. In vivo PPIs efficacy experiments were carried out using melanoma xenograft model in SCID mice. Lansoprazole showed higher anti-tumor effect when compared to the other PPIs. The lansoprazole effect lasted even upon drug removal from the cell culture medium and it was independent from the lipophilicity of the PPIs formulation. These PPIs have shown different anti-tumoral efficacy, and the most effective at low dose was lansoprazole. The possibility to contrast tumor acidity by off-label using PPIs opens a new field of oncology investigation.

Water-soluble derivatives of 25-OCH3-PPD and their anti-proliferative activities.

Science.gov (United States)

Zhou, Wu-Xi; Sun, Yuan-Yuan; Yuan, Wei-Hui; Zhao, Yu-Qing

2017-05-01

(20R)-25-Methoxyl-dammarane-3β,12β,20-triol (25-OCH 3 -PPD, AD-1) is a dammarane-type sapogenin showing anti-tumor potential. In the search for new anti-tumor agents with higher potency than our previously identified compound 25-OCH 3 -PPD, 11 novel sulfamic acid and diacid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 25-OCH 3 -PPD, compounds 1, 4, and 5 exhibited higher cytotoxic activity on almost all cell lines, together with lower toxicity in the normal cell. In particular, compound 1 exhibited the best anti-tumor activity in the in vitro assays. The water solubility of 25-OCH 3 -PPD and its derivatives was tested and the results showed that the solubility of 25-OCH 3 -PPD sulfamic acid and diacid derivatives were better than that of 25-OCH 3 -PPD in water, which may provide valuable data for the research and development of new anti-tumor agents. Copyright © 2017 Elsevier Inc. All rights reserved.

Structure, chain conformation and antitumor activity of a novel polysaccharide from Lentinus edodes.

Science.gov (United States)

Yu, Zhang; Ming, Gu; Kaiping, Wang; Zhixiang, Chen; Liquan, Dai; Jingyu, Liu; Fang, Zeng

2010-12-01

A water-soluble polysaccharide LT1 was isolated from the basidiocarps of Lentinus edodes by hot water extraction and ethanol precipitations, further purified by gel chromatography. The Mw of LT1 was estimated to be 642 kDa by using HPGPC. Chemical and spectroscopic studies illustrated that LT1 has a backbone chain composed of 1 → 4-linked and 1 → 3-linked glucopyranosyl residues and has branches of single glucosyl stubs at C-6 of β-(1 → 4)-linked glucopyranosyl. AFM and Congo-red test revealed that LT1 existed as triple helix chain in 0.10 M NaOH solution or distilled water. Our studies showed that LT1 presented significant antitumor bioactivities on Sarcoma180 solid tumor cell implanted in BALB/c mice, which implies that LT1 could be potentially applied as a natural antitumor drug. Copyright © 2010 Elsevier B.V. All rights reserved.

Induction of antitumor immunity through xenoplacental immunization

Directory of Open Access Journals (Sweden)

Agadjanyan Michael G

2006-05-01

Full Text Available Abstract Historically cancer vaccines have yielded suboptimal clinical results. We have developed a novel strategy for eliciting antitumor immunity based upon homology between neoplastic tissue and the developing placenta. Placenta formation shares several key processes with neoplasia, namely: angiogenesis, activation of matrix metalloproteases, and active suppression of immune function. Immune responses against xenoantigens are well known to break self-tolerance. Utilizing xenogeneic placental protein extracts as a vaccine, we have successfully induced anti-tumor immunity against B16 melanoma in C57/BL6 mice, whereas control xenogeneic extracts and B16 tumor extracts where ineffective, or actually promoted tumor growth, respectively. Furthermore, dendritic cells were able to prime tumor immunity when pulsed with the placental xenoantigens. While vaccination-induced tumor regression was abolished in mice depleted of CD4 T cells, both CD4 and CD8 cells were needed to adoptively transfer immunity to naïve mice. Supporting the role of CD8 cells in controlling tumor growth are findings that only freshly isolated CD8 cells from immunized mice were capable of inducing tumor cell caspases-3 activation ex vivo. These data suggest feasibility of using xenogeneic placental preparations as a multivalent vaccine potently targeting not just tumor antigens, but processes that are essential for tumor maintenance of malignant potential.

Secretion of Rhoptry and Dense Granule Effector Proteins by Nonreplicating Toxoplasma gondii Uracil Auxotrophs Controls the Development of Antitumor Immunity.

Directory of Open Access Journals (Sweden)

Barbara A Fox

2016-07-01

Full Text Available Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP and dense granule (GRA proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α+ dendritic cells, the IL-12/interferon-gamma (IFN-γ TH1 axis, as well as CD4+ and CD8+ T cells. Deletion of parasitophorous vacuole membrane (PVM associated proteins ROP5, ROP17, ROP18, ROP35 or ROP38, intravacuolar network associated dense granule proteins GRA2 or GRA12, and GRA24 which traffics past the PVM to the host cell nucleus severely abrogated the antitumor response. In contrast, deletion of other secreted effector molecules such as GRA15, GRA16, or ROP16 that manipulate host cell signaling and transcriptional pathways, or deletion of PVM associated ROP21 or GRA3 molecules did not affect the antitumor activity. Association of ROP18 with the PVM was found to be essential for the development of the antitumor responses. Surprisingly, the ROP18 kinase activity required for resistance to IFN-γ activated host innate immunity related GTPases and virulence was not essential for the antitumor response. These data show that PVM functions of parasite secreted effector molecules, including ROP18, manipulate host cell responses through ROP18 kinase virulence independent mechanisms to activate potent antitumor responses. Our results demonstrate that PVM associated rhoptry effector proteins secreted prior to host cell invasion and dense granule effector proteins localized to the intravacuolar network and host nucleus that are secreted after host cell invasion coordinately

Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo.

Science.gov (United States)

Chakrabarti, Mrinmay; Ray, Swapan K

2016-03-01

Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo.

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer.

Science.gov (United States)

Telli, M L; Stover, D G; Loi, S; Aparicio, S; Carey, L A; Domchek, S M; Newman, L; Sledge, G W; Winer, E P

2018-05-07

Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

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

Science.gov (United States)

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

2016-01-01

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

Antitumor effects of traditional Chinese medicine targeting the cellular apoptotic pathway

Directory of Open Access Journals (Sweden)

Xu HL

2015-05-01

Full Text Available Huanli Xu,1 Xin Zhao,2 Xiaohui Liu,1 Pingxiang Xu,1 Keming Zhang,2 Xiukun Lin11Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, 2Department of Hepatobiliary Surgery, 302 Hospital of Chinese People’s Liberation Army, Beijing, People’s Republic of ChinaAbstract: Defects in apoptosis are common phenomena in many types of cancer and are also a critical step in tumorigenesis. Targeting the apoptotic pathway has been considered an intriguing strategy for cancer therapy. Traditional Chinese medicine (TCM has been used in the People’s Republic of China for thousands of years, and many of the medicines have been confirmed to be effective in the treatment of a number of tumors. With increasing cancer rates worldwide, the antitumor effects of TCMs have attracted more and more attention globally. Many of the TCMs have been shown to have antitumor activity through multiple targets, and apoptosis pathway-related targets have been extensively studied and defined to be promising. This review focuses on several antitumor TCMs, especially those with clinical efficacy, based on their effects on the apoptotic signaling pathway. The problems with and prospects of development of TCMs as anticancer agents are also presented.Keywords: traditional Chinese medicine, antitumor effects, apoptotic pathway

Nanovectorized radiotherapy: a new strategy to induce anti-tumor immunity

International Nuclear Information System (INIS)

Vanpouille-Box, Claire; Hindré, François

2012-01-01

Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radiotherapy. However, clinically apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nanodevices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immunostimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome.

Nanovectorized radiotherapy, a new strategy to induce anti-tumor immunity

Directory of Open Access Journals (Sweden)

Claire eVanpouille-Box

2012-10-01

Full Text Available Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radio-therapy. However, clinically-apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nano-devices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immuno-stimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome.

Potent antitumor bifunctional DNA alkylating agents, synthesis and biological activities of 3a-aza-cyclopenta[a]indenes.

Science.gov (United States)

Kakadiya, Rajesh; Dong, Huajin; Lee, Pei-Chih; Kapuriya, Naval; Zhang, Xiuguo; Chou, Ting-Chao; Lee, Te-Chang; Kapuriya, Kalpana; Shah, Anamik; Su, Tsann-Long

2009-08-01

A series of bifunctional DNA interstrand cross-linking agents, bis(hydroxymethyl)- and bis(carbamates)-8H-3a-azacyclopenta[a]indene-1-yl derivatives were synthesized for antitumor evaluation. The preliminary antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro and antitumor therapeutic efficacy against human tumor xenografts in vivo. Furthermore, these derivatives have little or no cross-resistance to either Taxol or Vinblastine. Remarkably, complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft by 13a,b and 14g,h and significant suppression against prostate adenocarcinoma PC3 xenograft by 13b were achieved at the maximum tolerable dose with relatively low toxicity. In addition, these agents induce DNA interstrand cross-linking and substantial G2/M phase arrest in human non-small lung carcinoma H1299 cells. The current studies suggested that these agents are promising candidates for preclinical studies.

Systematic screening of bryophytes for antitumor agents

OpenAIRE

Spjut, Richard W.; Kingston, David G. I.; Cassady, John M.

1992-01-01

References are made to cytotoxic and/or antitumor compounds that have been isolated - ansamitocin P-3 from Claopodium crispifolium (Hook.) Ren. & Card. and Anomodon attenuatus Hueb., or an associated actinomycete, and ohioensins and pallidisetums from Polytrichum spp. Several hundred collections, which have been obtained from temperate regions of North America during 1990 and 1991, are currently being screened in new bioassays; active sesquiterpene lactones have been recently isolated from sp...

Regulatory T cells as suppressors of anti-tumor immunity: Role of metabolism.

Science.gov (United States)

De Rosa, Veronica; Di Rella, Francesca; Di Giacomo, Antonio; Matarese, Giuseppe

2017-06-01

Novel concepts in immunometabolism support the hypothesis that glucose consumption is also used to modulate anti-tumor immune responses, favoring growth and expansion of specific cellular subsets defined in the past as suppressor T cells and currently reborn as regulatory T (Treg) cells. During the 1920s, Otto Warburg and colleagues observed that tumors consumed high amounts of glucose compared to normal tissues, even in the presence of oxygen and completely functioning mitochondria. However, the role of the Warburg Effect is still not completely understood, particularly in the context of an ongoing anti-tumor immune response. Current experimental evidence suggests that tumor-derived metabolic restrictions can drive T cell hyporesponsiveness and immune tolerance. For example, several glycolytic enzymes, deregulated in cancer, contribute to tumor progression independently from their canonical metabolic activity. Indeed, they can control apoptosis, gene expression and activation of specific intracellular pathways, thus suggesting a direct link between metabolic switches and pro-tumorigenic transcriptional programs. Focus of this review is to define the specific metabolic pathways controlling Treg cell immunobiology in the context of anti-tumor immunity and tumor progression. Copyright © 2017 Elsevier Ltd. All rights reserved.

Anti-tumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo: direct correlation between reduction of established metastases and cytolytic activity of lymphokine-activated killer cells

International Nuclear Information System (INIS)

Mule, J.J.; Yang, J.; Shu, S.; Rosenberg, S.A.

1986-01-01

Our previous studies demonstrated that the incubation of human peripheral blood lymphocytes or murine splenocytes in recombinant interleukin 2 (RIL 2) resulted in the generation of lymphokine-activated killer (LAK) cells capable of lysing a broad spectrum of fresh tumors in short-term chromium-release assays. Moreover, injections of LAK cells plus RIL 2 were highly effective in eliminating established 3 day metastases in the lung and liver. We have examined several parameters to define whether or not the cytolytic activity of LAK cells as measured in vitro correlated directly with the in vivo anti-tumor efficacy of adoptively transferred LAK cells. LAK cells plus RIL 2 could mediate marked reductions of established pulmonary metastases in mice rendered T cell deficient by adult thymectomy and lethal, total body irradiation followed by reconstitution with T cell-depleted bone marrow and spleen cells. Thus there was no requirement for additional T lymphocytes of host origin for successful therapy with adoptively transferred LAK cells plus RIL 2. Fresh splenocytes depleted of T cells by anti-Thy-1.2 monoclonal antibody plus complement generated LAK cells that were as highly lytic to fresh tumor in vitro and were as effective in reducing established pulmonary metastases as those generated from untreated or complement-treated splenocytes. Thus, the precursor to LAK cells with anti-tumor activity in vitro and in vivo did not express the Thy-1 antigenic marker. In contrast, treatment of LAK effector cells (those generated from a 3-day incubation of fresh, normal splenocytes in RIL 2) with anti-Thy-1.2 antibody plus complement reduced or abolished their in vitro cytolytic activity

Anti-tumor activity of self-charged (Eu,Ca):WO3 and Eu:CaWO4 nanoparticles

International Nuclear Information System (INIS)

Lin, Cao; Cong, Wang; De'An, Pan; Jiexin, Cao; Ping, Che; Volinsky, Alex A.

2012-01-01

Non-stoichiometric (Eu,Ca):WO 3 and Eu:CaWO 4 nanoparticles with anti-tumor activity are synthesized in a sol-gel method by adding excessive Eu 3+ and Ca 2+ ions to tungsten oxide crystal structure. Colorimetric assay shows that 10 nm (Eu,Ca):WO 3 and Eu:CaWO 4 nanoparticles can effectively inhibit growth of mammary cancer cells without any harm to normal cells. Nanoparticles are characterized by X-ray diffraction, high resolution transmission electron microscopy and fluorescence optical spectrometry. Nanomaterials, insoluble in synthesized water, have complicated self-charging surfaces that trap mammary cancer cells. Surface self-charging effect is suggested as the inhibition mechanism. (author)

RhoB mediates antitumor synergy of combined ixabepilone and sunitinib in human ovarian serous cancer.

Science.gov (United States)

Vishnu, Prakash; Colon-Otero, Gerardo; Kennedy, Gregory T; Marlow, Laura A; Kennedy, William P; Wu, Kevin J; Santoso, Joseph T; Copland, John A

2012-03-01

The aim was to evaluate antitumor activity of the combination of ixabepilone and sunitinib in pre-clinical models of chemotherapy naïve and refractory epithelial ovarian tumors, and to investigate the mechanism of synergy of such drug combination. HOVTAX2 cell line was derived from a metastatic serous papillary epithelial ovarian tumor (EOC) and a paclitaxel-resistant derivative was established. Dose response curves for ixabepilone and sunitinib were generated and synergy was determined using combination indexes. The molecular mechanism of antitumor synergy was examined using shRNA silencing. The combination of ixabepilone and sunitinib demonstrated robust antitumor synergy in naïve and paclitaxel-resistant HOVTAX2 cell lines due to increased apoptosis. The GTPase, RhoB, was synergistically upregulated in cells treated with ixabepilone and sunitinib. Using shRNA, RhoB was demonstrated to mediate antitumor synergy. These results were validated in two other EOC cell lines. Ixabepilone plus sunitinib demonstrated antitumor synergy via RhoB in naïve and paclitaxel-resistant cells resulting in apoptosis. This study demonstrates a novel mechanism of action leading to antitumor synergy and provides 'proof-of-principle' for combining molecular targeted agents with cytotoxic chemotherapy to improve antitumor efficacy. RhoB could be envisioned as an early biomarker of response to therapy in a planned Phase II clinical trial to assess the efficacy of ixabepilone combined with a receptor tyrosine kinase inhibitor such as sunitinib. To the best of our knowledge, this is the first demonstration of antitumor synergy between these two classes of drugs in EOC and the pivotal role of RhoB in this synergy. Copyright © 2011 Elsevier Inc. All rights reserved.

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

Science.gov (United States)

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

2018-04-01

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

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

Science.gov (United States)

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

2018-11-01

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

Antitumor and Immunomodulatory Effects of Polysaccharides from Broken-Spore of Ganoderma lucidum

Directory of Open Access Journals (Sweden)

Peng-Yun eWang

2012-07-01

Full Text Available The antitumor activity of Gl-BSP, a polysaccharide isolated from boiling water extract of the broken-spores of Ganoderma lucidum (Leyss ex Fr Karst. and its possible mechanism were investigated in vivo and in vitro. It was showed that Gl-BSP (50, 100, 200 mg/kg exhibited antitumor effect against Sarcoma 180 (S180 in BALB/c mice. The Gl-BSP was not cytotoxicity in S180 cells and PG cells (human lung carcinoma cell in vitro. However, Gl-BSP-treated serum potently inhibited S180 cells and PG cells proliferation in vitro. Moreover, Gl-BSP could promote the splenic lymphocyte proliferation induced by Con A or LPS, enhance nature killer cell (NK cell cytotoxic activity, augment the percentage of neutral red (NR phagocytosis by macrophages, and increase the percentage of the CD4+ or CD8+ subset in S180-bearing BALB/c mice. The level of IFN-γ, TNF-α and NO of serum apparently was increased by Gl-BSP. Gl-BSP also showed immunomodulatory activities in tumor-bearing mice. Furthermore，It was proved that neutralization with anti-TNF-α and/or anti-IFN-γ significantly diminished growth inhibition induced by Gl-BSP –treated serum in S180 or PG cells. Blocking effect was noted in the combination of anti-TNF-α and anti-IFN-γ. These observations suggest that the antitumor activity of Gl-BSP may mainly relate to the activation of the immune response of the host organism by the stimulation of NK cells, T cells, and macrophages.

Effect of immunomodifier on radiation-induced antitumor immunity following local irradiation to tumor, 2

International Nuclear Information System (INIS)

Mukae, Shiro; Norimura, Toshiyuki; Tsuchiya, Takehiko

1988-01-01

This study was carried out to clarify whether or not the antitumor cell-mediated immunity of host is more effectively induced by the combined use of mouse interferon-α/β (MuIFN-α/β) with local irradiation than by simple local irradiation to tumor. C3H/He female mice, MM46 tumor cells and mouse interferon-α/β (MuIFN-α/β) were used in the experiment. Antitumor activity in mice was evaluated by the inhibition of tumor growth and mean survival days after treatment. Spleen cell killing activity to MM46 tumor cells was measured to evaluate the antitumor activity in vitro. In the case of single use of MuIFN-α/β, tumor growth was more rapid than in the non-treated group (control) in vivo. The mean survival days were also reduced. There was no siginificant difference in tumor growth inhibition between combined therapy using X-irradiation and MuIFN-α/β, and single therapy by local irradiation. However, in the case of administration of MuIFN-α/β after irradiation, the mean survival days was significantly increased compared with the group receiving X-ray irradiation only. (author)

Antioxidants impair anti-tumoral effects of Vorinostat, but not anti-neoplastic effects of Vorinostat and caspase-8 downregulation.

Science.gov (United States)

Bergadà, Laura; Yeramian, Andree; Sorolla, Annabel; Matias-Guiu, Xavier; Dolcet, Xavier

2014-01-01

We have recently demonstrated that histone deacetylase inhibitor, Vorinostat, applied as a single therapy or in combination with caspase-8 downregulation exhibits high anti-tumoral activity on endometrial carcinoma cell lines. In the present study, we have assessed the signalling processes underlying anti-tumoral effects of Vorinostat. Increasing evidence suggests that reactive oxygen species are responsible for histone deacetylase inhibitor-induced cell killing. We have found that Vorinostat induces formation of reactive oxygen species and DNA damage. To investigate the role of oxidative stress as anti-neoplastic mechanism, we have evaluated the effects of different antioxidants (Bha, Nac and Tiron) on endometrial carcinoma cell line Ishikawa treated with Vorinostat. We show that Bha, Nac and Tiron markedly inhibited the cytotoxic effects of Vorinostat, increasing cell viability in vitro. We found that all three antioxidants did not inhibited accumulation of acetyl Histone H4, so that antioxidants did not inhibit Vorinostat activity. Finally, we have evaluated the effects of antioxidants on anti-tumoral activity of Vorinostat as monotherapy or in combination with caspase-8 downregulation in vivo. Interestingly, antioxidants blocked the reduction of tumour growth caused by Vorinostat, but they were unable to inhibit anti-tumoral activity of Vorinostat plus caspase-8 inhibition.

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

Science.gov (United States)

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

2016-11-01

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

Cetuximab improves AZD6244 antitumor activity in colorectal cancer HT29 cells in vitro and in nude mice by attenuating HER3/Akt pathway activation.

Science.gov (United States)

Zhang, Qin; Xiao, He; Jin, Feng; Li, Mengxia; Luo, Jia; Wang, Ge

2018-07-01

The present study investigated the molecular mechanism by which the epidermal growth factor receptor (EGFR) inhibitor cetuximab enhances the antitumor activity of the mitogen-activated protein kinase kinase (MEK) inhibitor AZD6244 in colorectal cancer HT29 cells. HT29 cells were treated with AZD6244 plus cetuximab and then subjected to the following assays: Cell Counting kit-8, BrdU-incorporation, flow cytometric cell cycle distribution and apoptosis analysis, western blot analysis, and nude mouse xenografts. The combination of AZD6244 and cetuximab significantly reduced HT29 cell viability and proliferation compared with AZD6244 alone. The combination treatment reduced the IC 50 value from 108.12±10.05 to 28.45±1.92 nM. AZD6244 and cetuximab also induced cell cycle arrest at G1 phase and reduced S phase (88.53% vs. 93.39%, P=0.080; 8.73% vs. 4.24%, P=0.082, respectively). Combination of AZD6244 with cetuximab significantly induced tumor cells apoptosis (14.61% vs. 8.99%, P=0.046). Inhibition of EGFR activity using cetuximab partially abrogated the feedback-activation of phosphorylated receptor tyrosine-protein kinase erB-3 (p-HER3) and p-AKT serine/threonine kinase (AKT), as well as prevented reactivation of p-extracellular regulated kinase (ERK) conferred by AZD6244 treatment. Combination of AZD6244 and cetuximab also inhibited HT29 cell xenograft growth in nude mice and suppressed HER3 and p-AKT levels in xenografts. The EGFR inhibitor cetuximab enhanced the antitumor activity of the MEK inhibitor AZD6244 in colorectal cells in vitro and in vivo . Co-inhibition of MEK and EGFR may be a promising treatment strategy in colorectal cancers.

Arctigenin anti-tumor activity in bladder cancer T24 cell line through induction of cell-cycle arrest and apoptosis.

Science.gov (United States)

Yang, Shucai; Ma, Jing; Xiao, Jianbing; Lv, Xiaohong; Li, Xinlei; Yang, Huike; Liu, Ying; Feng, Sijia; Zhang, Yafang

2012-08-01

Bladder cancer is the most common neoplasm in the urinary system. This study assesses arctigenin anti-tumor activity in human bladder cancer T24 cells in vitro and the underlying molecular events. The flow cytometry analysis was used to detect cell-cycle distribution and apoptosis. Western blotting was used to detect changes in protein expression. The data showed that arctigenin treatment reduced viability of bladder cancer T24 cells in a dose- and time-dependent manner after treatment with arctigenin (10, 20, 40, 80, and 100 μmol/L) for 24 hr and 48 hr. Arctigenin treatment clearly arrested tumor cells in the G1 phase of the cell cycle. Apoptosis was detected by hoechst stain and flow cytometry after Annexin-V-FITC/PI double staining. Early and late apoptotic cells were accounted for 2.32-7.01% and 3.07-7.35%, respectively. At the molecular level, arctigenin treatment decreased cyclin D1 expression, whereas CDK4 and CDK6 expression levels were unaffected. Moreover, arctigenin selectively altered the phosphorylation of members of the MAPK superfamily, decreasing phosphorylation of ERK1/2 and activated phosphorylation of p38 significantly in a dose-dependent manner. These results suggest that arctigenin may inhibit cell viability and induce apoptosis by direct activation of the mitochondrial pathway, and the mitogen-activated protein kinase pathway may play an important role in the anti-tumor effect of arctigenin. The data from the current study demonstrate the usefulness of arctigenin in bladder cancer T24 cells, which should further be evaluated in vivo before translation into clinical trials for the chemoprevention of bladder cancer. Copyright © 2012 Wiley Periodicals, Inc.

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

Science.gov (United States)

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

2013-07-25

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

Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity.

Science.gov (United States)

Wang, Dongrui; Aguilar, Brenda; Starr, Renate; Alizadeh, Darya; Brito, Alfonso; Sarkissian, Aniee; Ostberg, Julie R; Forman, Stephen J; Brown, Christine E

2018-05-17

Chimeric antigen receptor-modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2). Upon stimulation with IL13Rα2+ GBM cells, the CD8+ CAR T cells exhibited robust short-term effector function but became rapidly exhausted. By comparison, the CD4+ CAR T cells persisted after tumor challenge and sustained their effector potency. Mixing with CD4+ CAR T cells failed to ameliorate the effector dysfunction of CD8+ CAR T cells, while surprisingly, CD4+ CAR T cell effector potency was impaired when coapplied with CD8+ T cells. In orthotopic GBM models, CD4+ outperformed CD8+ CAR T cells, especially for long-term antitumor response. Further, maintenance of the CD4+ subset was positively correlated with the recursive killing ability of CAR T cell products derived from GBM patients. These findings identify CD4+ CAR T cells as a highly potent and clinically important T cell subset for effective CAR therapy.

Antitumor Effects of Palladium-α-Lipoic Acid Complex Formulation as an Adjunct in Radiotherapy.

Science.gov (United States)

Veena, Ravindran Kalathil; Ajith, Thekkuttuparambil Ananthanarayanan; Janardhanan, Kainoor Krishnankutty; Antonawich, Francis

2016-01-01

Several investigations have been initiated to enhance the antitumor effect of radiation and ameliorate its adverse effects such as reducing blood cell counts and causing DNA damage in normal cells. Compounds that enhance the antitumor activity of radiation without reducing blood cell counts or damaging DNA in normal cells can be of immense use as an adjunct in radiotherapy. We evaluated the antitumor effect of a specific set of minerals, vitamins, and amino acids (Poly-MVA) (2 mL/kg, per os), with and without radiation, against Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines that were transplanted in a solid-tumor model. Whole-body γ-radiation exposure (2 Gy) was performed using 60Co. Poly-MVA enhanced the antitumor effect of radiation when administered beforehand. Furthermore, Poly-MVA administered once daily for 2 wk, immediately after 4 Gy irradiation, protected DNA damage in peripheral blood. It also rendered protection against the radiation-induced reduction of platelet count. The unique electronic and redox properties of palladium-α-lipoic acid complex in Poly-MVA appear to be responsible for the exhibited effect. The results conclude that the antitumor-enhancing and normal cell-protective effect of Poly-MVA warrants additional studies for its potential clinical application.

Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

Science.gov (United States)

Tolcher, Anthony W; Khan, Khurum; Ong, Michael; Banerji, Udai; Papadimitrakopoulou, Vassiliki; Gandara, David R; Patnaik, Amita; Baird, Richard D; Olmos, David; Garrett, Christopher R; Skolnik, Jeffrey M; Rubin, Eric H; Smith, Paul D; Huang, Pearl; Learoyd, Maria; Shannon, Keith A; Morosky, Anne; Tetteh, Ernestina; Jou, Ying-Ming; Papadopoulos, Kyriakos P; Moreno, Victor; Kaiser, Brianne; Yap, Timothy A; Yan, Li; de Bono, Johann S

2015-02-15

KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). ©2014 American Association for Cancer Research.

Artemisinic acid exhibits antitumor activity in MCF-7 breast cancer cells through the inhibition of angiogenesis, VEGF, m-TOR and AKT signalling pathways

Directory of Open Access Journals (Sweden)

Yan Cui

2016-09-01

Full Text Available The aim of the present study was to evaluate the antitumor and anti-angiogenic effects of artemisinic acid in MCF-7 human breast cancer cells. Various cell signalling pathways (VEGF, m-TOR and AKT signalling pathways and MTT assay were used. The in vivo antitumor activity of artemisinic acid was evaluated by means of tumor xenograft mouse model. Transwell cell migration assay was used to examine the chemotactic motility of the human umbilical vascular endothelial cells (HUVECs, while as endothelial cell capillary-like tube formation assay was used to evaluate the effect of artemisinic acid on the tube formation in HUVECs. We found that artemisinic acid considerably reduced both the volume and weight of concrete tumors and reduced angiogenesis in a xenograft mouse tumor model in vivo. Further, artemisinic acid suppressed the VEGF-induced cell migration and capillary-like tube formation of HUVECs in a dose-dependent manner. Artemisinic acid was found to suppress the VEGF-induced phosphorylation of VEGFR2 and also the activity of AKT and m-TOR.

Antitumor Activity and Mechanism of a Reverse Transcriptase Inhibitor, Dapivirine, in Glioblastoma.

Science.gov (United States)

Liu, Weiwen; Song, Xian-Lu; Zhao, Shan-Chao; He, Minyi; Wang, Hai; Chen, Ziyang; Xiang, Wei; Yi, Guozhong; Qi, Songtao; Liu, Yawei

2018-01-01

Dapivirine is one of reverse transcriptase inhibitors (RTIs). It is the prototype of diarylpyrimidines (DAPY), formerly known as TMC120 or DAPY R147681 (IUPAC name: 4- [[4-(2, 4, 6-trimethylphenyl) amino]-2-pyrimidinyl] amino]-benzonitrile; CAS no.244767-67-7). The purpose of this study is to investigate the antitumor activity of dapivirine, one of the RTIs, on U87 glioblastoma (GBM) cells in vitro and in vivo . U87 GBM cells were cultured and treated with or without dapivirine. Cell viability was evaluated by CCK-8 (Cell Counting Kit 8, CCK-8) assay; apoptosis was analyzed by flow cytometry; cell migration was evaluated by Boyden Chamber assay; Western blotting was performed to detect proteins related to apoptosis, epithelial-to-mesenchymal transition and autophagy. PathScan intracellular signaling array kit was used to detect important and well-characterized signaling molecules. Tumor xenograft model in nude mice was used to evaluate the antitumorigenic effect in vivo . Dapivirine weakened proliferation of glioma cells and induced the apoptosis of U87 glioblastoma cells. Furthermore, dapivirine regulated autophagy and induced Akt, Bad and SAPK/JNK activations. Moreover, the inhibition of glioma cell growth by dapivirine was also observed in nude mice in vivo . In summary, in our study dapivirine exposure induces stress, resulting in JNK and PI3K/Akt pathway activation through diminished inhibition of the apoptosis and autophagy cascade in U87 GBM cells, which inhibits cell growth in vitro and in vivo .

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

Directory of Open Access Journals (Sweden)

Guang-Xiong Zhou

2003-11-01

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

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

Science.gov (United States)

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.

Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model.

Science.gov (United States)

Wang, Meng; Yan, Shi-Ju; Zhang, Hong-Tao; Li, Nan; Liu, Tao; Zhang, Ying-Long; Li, Xiao-Xiang; Ma, Qiong; Qiu, Xiu-Chun; Fan, Qing-Yu; Ma, Bao-An

2017-02-01

The treatment of malignant tumors following surgery is important in preventing relapse. Among all the post-surgery treatments, immunomodulators have demonstrated satisfactory effects on preventing recurrence according to recent studies. Ginsenoside is a compound isolated from panax ginseng, which is a famous traditional Chinese medicine. Ginsenoside aids in killing tumor cells through numerous processes, including the antitumor processes of ginsenoside Rh2 and Rg1, and also affects the inflammatory processes of the immune system. However, the role that ginsenoside serves in antitumor immunological activity remains to be elucidated. Therefore, the present study aimed to analyze the effect of ginsenoside Rh2 on the antitumor immunological response. With a melanoma mice model, ginsenoside Rh2 was demonstrated to inhibit tumor growth and improved the survival time of the mice. Ginsenoside Rh2 enhanced T-lymphocyte infiltration in the tumor and triggered cytotoxicity in spleen lymphocytes. In addition, the immunological response triggered by ginsenoside Rh2 could be transferred to other mice. In conclusion, the present study provides evidence that ginsenoside Rh2 treatment enhanced the antitumor immunological response, which may be a potential therapy for melanoma.

Antitumor effects evaluation of a novel porphyrin derivative in photodynamic therapy.

Science.gov (United States)

Li, Jian-Wei; Wu, Zhong-Ming; Magetic, Davor; Zhang, Li-Jun; Chen, Zhi-Long

2015-12-01

In this paper, the antitumor activity of a novel porphyrin-based photosensitizer 5,10,15,20-tetrakis[(5-diethylamino)pentyl] porphyrin (TDPP) was reported in vitro and in vivo. The photophysical and cellular properties of TDPP were investigated. The singlet oxygen generation quantum yield of TDPP was detected; it showed a high singlet oxygen quantum yield of 0.52. The intracellular distribution of photosensitizer was detected with laser scanning confocal microscopy. The efficiency of TDPP-photodynamic therapy (PDT) in vitro was analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and in situ trypan blue exclusion test. Treated with a 630-nm laser, TDPP can kill cultured human esophageal cancer cell line (Eca-109) cells and reduce the growth of Eca-109 xenograft tumors significantly in BABL/c nude mice. And histopathological study was also used to confirm the antitumor effect. It has the perspective to be developed as a new antitumor drug in photodynamic therapy and deserves further investigation.

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

Directory of Open Access Journals (Sweden)

Franco-Molina Moisés A

2010-11-01

Full Text Available Abstract 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 Conclusions The present results showed that colloidal silver might be a potential alternative agent for human breast cancer therapy.

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

Science.gov (United States)

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 colloidal silver. The present results showed that colloidal silver might be a potential alternative agent for human breast cancer therapy.

A new activity of anti-HIV and anti-tumor protein GAP31: DNA adenosine glycosidase - Structural and modeling insight into its functions

Energy Technology Data Exchange (ETDEWEB)

Li, Hui-Guang [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Huang, Philip L. [American Biosciences, Boston, MA 02114 (United States); Zhang, Dawei; Sun, Yongtao [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Chen, Hao-Chia [Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892 (United States); Zhang, John [Department of Chemistry, New York University, New York, NY 10003 (United States); Huang, Paul L. [Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114 (United States); Kong, Xiang-Peng, E-mail: xiangpeng.kong@med.nyu.edu [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Lee-Huang, Sylvia, E-mail: sylvia.lee-huang@med.nyu.edu [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States)

2010-01-01

We report here the high-resolution atomic structures of GAP31 crystallized in the presence of HIV-LTR DNA oligonucleotides systematically designed to examine the adenosine glycosidase activity of this anti-HIV and anti-tumor plant protein. Structural analysis and molecular modeling lead to several novel findings. First, adenine is bound at the active site in the crystal structures of GAP31 to HIV-LTR duplex DNA with 5' overhanging adenosine ends, such as the 3'-processed HIV-LTR DNA but not to DNA duplex with blunt ends. Second, the active site pocket of GAP31 is ideally suited to accommodate the 5' overhanging adenosine of the 3'-processed HIV-LTR DNA and the active site residues are positioned to perform the adenosine glycosidase activity. Third, GAP31 also removes the 5'-end adenine from single-stranded HIV-LTR DNA oligonucleotide as well as any exposed adenosine, including that of single nucleotide dAMP but not from AMP. Fourth, GAP31 does not de-purinate guanosine from di-nucleotide GT. These results suggest that GAP31 has DNA adenosine glycosidase activity against accessible adenosine. This activity is distinct from the generally known RNA N-glycosidase activity toward the 28S rRNA. It may be an alternative function that contributes to the antiviral and anti-tumor activities of GAP31. These results provide molecular insights consistent with the anti-HIV mechanisms of GAP31 in its inhibition on the integration of viral DNA into the host genome by HIV-integrase as well as irreversible topological relaxation of the supercoiled viral DNA.

Sulfamic and succinic acid derivatives of 25-OH-PPD and their activities to MCF-7, A-549, HCT-116, and BGC-823 cell lines.

Science.gov (United States)

Zhou, Wu-Xi; Cao, Jia-Qing; Wang, Xu-De; Guo, Jun-Hui; Zhao, Yu-Qing

2017-02-15

In the search for new anti-tumor agents with higher potency than our previously identified compound 1 (25-OH-PPD, 25-hydroxyprotopanaxadiol), 12 novel sulfamic and succinic acid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 1, compounds 2, 3, and 7 exhibited higher cytotoxic activity on A-549 and BGC-823 cell lines, together with lower toxicity in the normal cell. In particular, compound 2 exhibited the best anti-tumor activity in the in vitro assays, which may provide valuable data for the research and development of new anti-tumor agents. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

International Nuclear Information System (INIS)

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

2010-01-01

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

Transport by SLC5A8 with subsequent inhibition of histone deacetylase 1 (HDAC1) and HDAC3 underlies the antitumor activity of 3-bromopyruvate.

Science.gov (United States)

Thangaraju, Muthusamy; Karunakaran, Senthil K; Itagaki, Shiro; Gopal, Elangovan; Elangovan, Selvakumar; Prasad, Puttur D; Ganapathy, Vadivel

2009-10-15

3-bromopyruvate is an alkylating agent with antitumor activity. It is currently believed that blockade of adenosine triphosphate production from glycolysis and mitochondria is the primary mechanism responsible for this antitumor effect. The current studies uncovered a new and novel mechanism for the antitumor activity of 3-bromopyruvate. The transport of 3-bromopyruvate by sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8), a tumor suppressor and a sodium (Na+)-coupled, electrogenic transporter for short-chain monocarboxylates, was studied using a mammalian cell expression and the Xenopus laevis oocyte expression systems. The effect of 3-bromopyruvate on histone deacetylases (HDACs) was monitored using the lysate of the human breast cancer cell line MCF7 and human recombinant HDAC isoforms as the enzyme sources. Cell viability was monitored by fluorescence-activated cell-sorting analysis and colony-formation assay. The acetylation status of histone H4 was evaluated by Western blot analysis. 3-Bromopyruvate is a transportable substrate for SLC5A8, and that transport process is Na+-coupled and electrogenic. MCF7 cells did not express SLC5A8 and were not affected by 3-bromopyruvate. However, when transfected with SLC5A8 or treated with inhibitors of DNA methylation, these cells underwent apoptosis in the presence of 3-bromopyruvate. This cell death was associated with the inhibition of HDAC1/HDAC3. Studies with different isoforms of human recombinant HDACs identified HDAC1 and HDAC3 as the targets for 3-bromopyruvate. 3-Bromopyruvate was transported into cells actively through the tumor suppressor SLC5A8, and the process was energized by an electrochemical Na+ gradient. Ectopic expression of the transporter in MCF7 cells led to apoptosis, and the mechanism involved the inhibition of HDAC1/HDAC3. Copyright (c) 2009 American Cancer Society.

Naturally occurring immunomodulators with antitumor activity: An insight on their mechanisms of action.

Science.gov (United States)

Mohamed, Shimaa Ibrahim Abdelmonym; Jantan, Ibrahim; Haque, Md Areeful

2017-09-01

Natural products with immunomodulatory activity are widely used in treatment of many diseases including autoimmune diseases, inflammatory disorders in addition to cancer. They gained a great interest in the last decades as therapeutic agents since they provide inexpensive and less toxic products than the synthetic chemotherapeutic agents. Immunomodulators are the agents that have the ability to boost or suppress the host defense response that can be used as a prophylaxis as well as in combination with other therapeutic modalities. The anticancer activity of these immunomodulators is due to their anti-inflammatory, antioxidant, and induction of apoptosis, anti-angiogenesis, and anti-metastasis effect. These natural immunomodulators such as genistein, curcumin, and resveratrol can be used as prophylaxis against the initiation of cancer besides the inhibition of tumor growth and proliferation. Whereas, immunostimulants can elicit and activate humoral and cell-mediated immune responses against the tumor that facilitate the recognition and destruction of the already existing tumor. This review represents the recent studies on various natural immunomodulators with antitumor effects. We have focused on the relationship between their anticancer activity and immunomodulatory mechanisms. The mechanisms of action of various immunomodulators such as polyphenolic compounds, flavonoids, organosulfur compounds, capsaicin, vinca alkaloids, bromelain, betulinic acid and zerumbone, the affected cancerous cell lines in addition to the targeted molecules and transcriptional pathways have been review and critically analyzed. Copyright © 2017 Elsevier B.V. All rights reserved.

Characterization of a Novel Humanized Anti-CD20 Antibody with Potent Anti-Tumor Activity against Non-Hodgkin's Lymphoma

Directory of Open Access Journals (Sweden)

Haifeng Zhang

2013-09-01

Full Text Available Background: Rituximab, a mouse Fab and human Fc chimeric antibody, has been widely used to treat Non-Hodgkin's lymphoma (NHL. However, only 48% of patients respond to the treatment and complete response rate is below 10%. Also, immunogenicity was reported in 17-20% patients receiving the treatment, making it unsuitable for long term diseases such as autoimmune disorders. It has been a hot research field to “humanize” rituximab toward improved efficacy and reduced immunogenicity. Methods: In this study, an advanced antibody humanization technology was applied to the sequence of the anti-CD20 antibody 2B8, its sequence of which was based on the original murine monoclonal antibody of rituximab in Roche. The complementarity-determining regions (CDRs of the humanized antibodies were further optimized through computer-aided molecular dock. Results: Five novel humanized anti-CD20 antibodies 1-5(1635, 1534, 3637, 1634 and 1536 were generated and their immunogenicity was significantly decreased when compared to rituximab. The novel humanized anti-CD20 antibodies 1-5 retained the binding activity of their murine counterpart, as demonstrated by the fluorescence-activated cell-sorting analysis (FACS. When compared to rituximab, the humanized antibodies still have the similar properties on both complement-dependent cytotoxicity (CDC and antibody-dependent cell-mediated cytotoxicity (ADCC. Furthermore, its anti-tumor efficacy in xenograft model is comparable to that of rituximab. Conclusion: The humanized anti-CD20 antibodies 1-5 have lower immunogenicity than rituximab. And at the same time, they still retain the anti-tumor effect both in vitro and vivo.

Mechanisms of reduction of antitumor drug toxicity by liposome encapsulation

Energy Technology Data Exchange (ETDEWEB)

Rahman, Y. E.; Hanson, W. R.; Bharucha, J.; Ainsworth, E. J.; Jaroslow, B.

1977-01-01

The antitumor drug Actinomycin D is effective against the growth of some human solid tumors but its use is limited by its extreme toxicity. The development of a method of administering Act. D to reduce its systemic toxicity by incorporating the drug within liposomes reduced its toxicity but its tumoricidal activity was retained.

Vγ9Vδ2 T cells and zoledronate mediate antitumor activity in an orthotopic mouse model of human chondrosarcoma.

Science.gov (United States)

Sun, L; Li, Y; Jiang, Z; Zhang, J; Li, H; Li, B; Ye, Z

2016-06-01

Chondrosarcoma (CS) is a cartilaginous malignant neoplasm characterized by resistance to conventional adjuvant therapy. The prognosis of unresectable or metastatic CS is poor. Therefore, it is imperative to explore novel therapeutic approaches to improve the treatment efficacy for those CS patients. Emerging data has implicated the synergistic antitumor activity of zoledronate (ZOL) and Vγ9Vδ2 T cells. However, whether ZOL-stimulated Vγ9Vδ2 T cells could infiltrate bone sarcoma and inhibit tumor growth has not been thoroughly answered yet. In this study, Vγ9Vδ2 T cells from healthy donors and CS patients were expanded in the presence of ZOL (1 μM) and IL-2 (400 IU/ml). The antitumor activity of Vγ9Vδ2 T cells to ZOL-pretreated human CS was examined both in vitro and in vivo. ZOL pretreatment substantially enhanced the cytotoxicity of Vγ9Vδ2 T cells to SW1353 and primary CS cells. ZOL potentiated the migration and cytotoxicity of Vγ9Vδ2 T cells to SW1353 in dose- and time-dependent manner. Moreover, weekly intravenous ZOL followed by Vγ9Vδ2 T cells inhibited subcutaneous xenograft growth. Thus, Vγ9Vδ2 T cells were able to infiltrate bone tumor and significantly suppressed the development of orthotopic SW1353 xenografts. Altogether, the study raises the possibility of combining ZOL with Vγ9Vδ2 T cells for CS treatment.

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

Science.gov (United States)

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.

Transport via SLC5A8 with Subsequent Inhibition of Histone Deacetylases HDAC1 and HDAC3 Underlies the Antitumor Activity of 3-Bromopyruvate

Science.gov (United States)

Thangaraju, Muthusamy; Karunakaran, Senthil K.; Itagaki, Shiro; Gopal, Elangovan; Elangovan, Selvakumar; Prasad, Puttur D.; Ganapathy, Vadivel

2009-01-01

Background 3-Bromopyruvate is an alkylating agent with antitumor activity. It is currently believed that blockade of ATP production from glycolysis and mitochondria is the primary mechanism responsible for this antitumor effect. The present studies have uncovered a new and novel mechanism for the antitumor activity of 3-bromopyruvate. Methods Transport of 3-bromopyruvate via SLC5A8, a tumor suppressor and a Na+-coupled electrogenic transporter for short-chain monocarboxylates, was studied using a mammalian cell expression and the Xenopus laevis oocyte expression systems. The effect of 3-bromopyruvate on histone deacetylases (HDACs) was monitored using the lysate of the human breast cancer cell line MCF7 and human recombinant HDAC isoforms as the enzyme sources. Cell viability was monitored by FACS analysis and colony formation assay. Acetylation status of histone H4 was evaluated by Western blot. Results 3-Bromopyruvate is a transportable substrate for SLC5A8, with the transport process being Na+-coupled and electrogenic. MCF7 cells do not express SLC5A8 and are not affected by 3-bromopyruvate. However, when transfected with SLC5A8 or treated with inhibitors of DNA methylation, these cells undergo apoptosis in the presence of 3-bromopyruvate. This cell death is associated with inhibition of HDAC1/HDAC3. Studies with different isoforms of human recombinant HDACs identify HDAC1 and HDAC3 as the targets for 3-bromopyruvate. Conclusions 3-Bromopyruvate is transported into cells actively via the tumor suppressor SLC5A8 and the process is energized by an electrochemical Na+ gradient. Ectopic expression of the transporter in MCF7 cells leads to apoptosis, and the mechanism involves inhibition of HDAC1/HDAC3. PMID:19637353

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

International Nuclear Information System (INIS)

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

2010-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

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

2010-05-26

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

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

Directory of Open Access Journals (Sweden)

Paola Massi

2010-05-01

Full Text Available 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.

Novel biotransformation process of podophyllotoxin to 4 β-sulfur-substituted podophyllum derivates with anti-tumor activity by Penicillium purpurogenum Y.J. Tang.

Science.gov (United States)

Bai, J-K; Zhao, W; Li, H-M; Tang, Y-J

2012-01-01

According to the structure-function relationship of podophyllotoxin (PTOX) and its analogue of 4'- demethylepipodophyllotoxin (DMEP), the 4 β-substitution of sulfur-containing heterocyclic compounds with a carbon-sulfur bond at 4 position of PTOX or DMEP is an essential modification direction for improving the anti-tumor activity. So, four novel 4 β-sulfursubstituted podophyllum derivatives (i.e., 4β -(1,2,4-triazole-3-yl)sulfanyl-4-deoxy-podophyllotoxin (4-MT-PTOX), 4β-(1,3,4- thiadiazole-2-yl)sulfanyl-4-deoxy-podophyllotoxin (4-MTD-PTOX), 4β-(1,2,4-triazole-3-yl)sulfanyl-4-deoxy-4' -demethylepipodophyllotoxin (4-MT-DMEP), and 4β-(1,3,4-thiadiazole-2-yl)sulfanyl-4-deoxy-4'-demethylepipodophyllotoxin (4-MTD-DMEP)) were designed and then successfully biosynthesized in this work. In the novel sulfur-substituted biotransformation processes, PTOX and DMEP was linked with sulfur-containing compounds (i.e., 3-mercapto-1,2,4-triazole (MT) and 2-mercapto-1,3,4-thiadiazole (MTD)) at 4 position of cycloparaffin to produce 4-MT-PTOX (1), 4-MTD-PTOX (2), 4-MT-DMEP (3), and 4-MTD-DMEP (4) by Penicillium purpurogenum Y.J. Tang, respectively, which was screened out from Diphylleia sinensis Li (Hubei, China). All the novel compounds exhibited promising in vitro bioactivity, especially 4-MT-PTOX (1). Compared with etoposide (i.e., a 50 % effective concentration [EC(50)] of 25.72, 167.97, and 1.15 M), the EC(50) values of 4-MT-PTOX (1) against tumor cell line BGC-823, A549 and HepG2 (i.e., 0.28, 0.76, and 0.42 M) were significantly improved by 91, 221 and 2.73 times, respectively. Moreover, the EC(50) value of 4-MT-PTOX (1) against the normal human cell line HK-2 (i.e., 182.4 μM) was 19 times higher than that of etoposide (i.e., 9.17 μM). Based on the rational design, four novel 4 β-sulfur-substituted podophyllum derivatives with superior in vitro anti-tumor activity were obtained for the first time. The correctness of structure-function relationship and rational drug

Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases.

Science.gov (United States)

Wan, Xinhai; Corn, Paul G; Yang, Jun; Palanisamy, Nallasivam; Starbuck, Michael W; Efstathiou, Eleni; Li Ning Tapia, Elsa M; Tapia, Elsa M Li-Ning; Zurita, Amado J; Aparicio, Ana; Ravoori, Murali K; Vazquez, Elba S; Robinson, Dan R; Wu, Yi-Mi; Cao, Xuhong; Iyer, Matthew K; McKeehan, Wallace; Kundra, Vikas; Wang, Fen; Troncoso, Patricia; Chinnaiyan, Arul M; Logothetis, Christopher J; Navone, Nora M

2014-09-03

Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell-bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in serum prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors. Copyright © 2014, American Association for the Advancement of Science.

Synthesis and antitumor evaluation of arctigenin derivatives based on antiausterity strategy.

Science.gov (United States)

Kudou, Naoki; Taniguchi, Akira; Sugimoto, Kenji; Matsuya, Yuji; Kawasaki, Masashi; Toyooka, Naoki; Miyoshi, Chika; Awale, Suresh; Dibwe, Dya Fita; Esumi, Hiroyasu; Kadota, Shigetoshi; Tezuka, Yasuhiro

2013-02-01

A series of new (-)-arctigenin derivatives with variably modified O-alkyl groups were synthesized and their preferential cytotoxicity was evaluated against human pancreatic cancer cell line PANC-1 under nutrient-deprived conditions. The results showed that monoethoxy derivative 4i (PC(50), 0.49 μM), diethoxy derivative 4h (PC(50), 0.66 μM), and triethoxy derivative 4m (PC(50), 0.78 μM) showed the preferential cytotoxicities under nutrient-deprived conditions, which were identical to or more potent than (-)-arctigenin (1) (PC(50), 0.80 μM). Among them, we selected the triethoxy derivative 4m and examined its in vivo antitumor activity using a mouse xenograft model. Triethoxy derivative 4m exhibited also in vivo antitumor activity with the potency identical to or slightly more than (-)-arctigenin (1). These results would suggest that a modification of (-)-arctigenin structure could lead to a new drug based on the antiausterity strategy. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

ChLpMab-23: Cancer-Specific Human-Mouse Chimeric Anti-Podoplanin Antibody Exhibits Antitumor Activity via Antibody-Dependent Cellular Cytotoxicity.

Science.gov (United States)

Kaneko, Mika K; Nakamura, Takuro; Kunita, Akiko; Fukayama, Masashi; Abe, Shinji; Nishioka, Yasuhiko; Yamada, Shinji; Yanaka, Miyuki; Saidoh, Noriko; Yoshida, Kanae; Fujii, Yuki; Ogasawara, Satoshi; Kato, Yukinari

2017-06-01

Podoplanin is expressed in many cancers, including oral cancers and brain tumors. The interaction between podoplanin and its receptor C-type lectin-like receptor 2 (CLEC-2) has been reported to be involved in cancer metastasis and tumor malignancy. We previously established many monoclonal antibodies (mAbs) against human podoplanin using the cancer-specific mAb (CasMab) technology. LpMab-23 (IgG 1 , kappa), one of the mouse anti-podoplanin mAbs, was shown to be a CasMab. However, we have not shown the usefulness of LpMab-23 for antibody therapy against podoplanin-expressing cancers. In this study, we first determined the minimum epitope of LpMab-23 and revealed that Gly54-Leu64 peptide, especially Gly54, Thr55, Ser56, Glu57, Asp58, Arg59, Tyr60, and Leu64 of podoplanin, is a critical epitope of LpMab-23. We further produced human-mouse chimeric LpMab-23 (chLpMab-23) and investigated whether chLpMab-23 exerts antibody-dependent cellular cytotoxicity (ADCC) and antitumor activity. In flow cytometry, chLpMab-23 showed high sensitivity against a podoplanin-expressing glioblastoma cell line, LN319, and an oral cancer cell line, HSC-2. chLpMab-23 also showed ADCC activity against podoplanin-expressing CHO cells (CHO/podoplanin). In xenograft models with HSC-2 and CHO/podoplanin, chLpMab-23 exerts antitumor activity using human natural killer cells, indicating that chLpMab-23 could be useful for antibody therapy against podoplanin-expressing cancers.

The anti-tumor effect of ACNU and x-irradiation on mouse glioma

International Nuclear Information System (INIS)

Nakagawa, Hidemitsu; Hori, Masaharu; Hasegawa, Hiroshi; Mogami, Heitaro; Hayakawa, Toru.

1979-01-01

Anti-tumor activities of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and x-irradiation on methylcholanthrene induced glioma in C 57 BL mice were studied in vitro and in vivo. In vitro experiments using cultured glioma cells (MGB cells), the synchronization of cell cycle was done by excess addition of thymidine, and the anti-tumor cell effect were investigated by mean of determinations of DNA synthesis, mitotic index and the number of the living cells following the treatments. As the results, it appeared obvious that ACNU was most effective on MGB cells in S phase and x-irradiation in M phase. As to the combined therapy of ACNU and x-irradiation, the anti-tumor effect was most remarkable when the cells were treated by x-irradiation in the G 2 , M phase, which were hervested by addition of ACNU 44 hours before irradiation. However simultaneous treatment of ACNU and x-irradiation on the cells in G 1 phase was not so remarkable. In vivo experiments the anti-tumor effect of ACNU and x-irradiation on subcutaneously or intracranially transplanted glioma in mice was investigated. Either ACNU 10 mg/kg or local x-irradiation 1240 rads showed inhibitory effect on the tumor growth and prolonged the survival time of the tumor bearing mice. The combination therapy was more effective than ACNU or x-irradiation alone, particularly combination therapy of ACNU and repeated small doses irradiation of x-ray was remarkably effective. Evidence obtained indicated that the combination therapy of ACNU and x-irradiation have synergistic anti-tumor effect on experimental mouse glioma. (author)

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

Science.gov (United States)

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

2011-06-15

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

Inhibition of protein kinase CK2 reduces CYP24A1 expression and enhances 1,25-dihydroxyvitamin D3 anti-tumor activity in human prostate cancer cells

Science.gov (United States)

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

2013-01-01

Vitamin D has broad range of physiological functions and anti-tumor effects. 24-hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D3. Inhibition of CYP24A1 enhances 1,25D3 anti-tumor activity. In order to isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D3 in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D3 induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D3 mediated target gene expression. Lastly, inhibition of CK2 by TBBz or CK2 siRNA significantly enhanced 1,25D3 mediated anti-proliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D3 and CK2 inhibitor enhances 1,25D3 mediated anti-tumor effect. PMID:23358686

The role of radiotherapy for the induction of antitumor immune responses

International Nuclear Information System (INIS)

Multhoff, G.; Helmholtz-Zentrum Muenchen; Gaipl, U.S.; Niedermann, G.

2012-01-01

Effective radiotherapy is aimed to control the growth of the primary carcinoma and to induce a long-term specific antitumor immune response against the primary tumor, recurrence and metastases. The contribution covers the following issues: T cells and tumor specific immune responses, dendritic cells (DCs) start adaptive immune responses, NK (natural killer) cells for HLA independent tumor control, abscopal effects of radiotherapy, combination of radiotherapy and immune therapy, radiotherapy contribution to the induction of immunogenic cell death, combinability of radiotherapy and DC activation, combinability of radiotherapy and NK cell therapy. It turns out that the combination of radio-chemotherapy and immune therapy can change the microenvironment initiating antitumor immune reactions that inhibit the recurrence risk and the development of metastases.

Chemical composition, in vitro antitumor and pro-oxidant activities of Glandora rosmarinifolia (Boraginaceae) essential oil.

Science.gov (United States)

Poma, Paola; Labbozzetta, Manuela; Notarbartolo, Monica; Bruno, Maurizio; Maggio, Antonella; Rosselli, Sergio; Sajeva, Maurizio; Zito, Pietro

2018-01-01

The biological properties of essential oils have been demonstrated in the treatment of several diseases and to enhance the bioavailability of other drugs. In natural habitats the essential oils compounds may play important roles in the protection of the plants as antibacterials, antivirals, antifungals, insecticides and also against herbivores by reducing their appetite for such plants or by repelling undesirable others. We analyzed by gas-chromatography mass spectrometry the chemical composition of the essential oil of aerial parts of Glandora rosmarinifolia (Ten.) D.C. Thomas obtained by hydrodistillation and verified some biological activities on a panel of hepatocellular carcinoma cell lines (HA22T/VGH, HepG2, Hep3B) and triple negative breast cancer cell lines (SUM 149, MDA-MB-231). In the essential oil we detected 35 compounds. The results of the biological assays indicate that essential oil of G. rosmarinifolia induces cell growth inhibition at concentration-dependent way in all cell line models. This oil does not seem to possess antioxidant activity, while the cytotoxicity of G. rosmarinifolia essential oil appeared to involve, at least in part, a pro-oxidant mechanism. Our results show for the first time the antitumoral and pro-oxidant activities of G. rosmarinifolia essential oil and suggest that it may represent a resource of pharmacologically active compounds.

Anti-tumor activity of metformin: from metabolic and epigenetic perspectives

Science.gov (United States)

Zhai, Yansheng; Tong, Chong; Liu, Min; Ma, Lixin; Yu, Xiaolan; Li, Shanshan

2017-01-01

Metformin has been used to treat type 2 diabetes for over 50 years. Epidemiological, preclinical and clinical studies suggest that metformin treatment reduces cancer incidence in diabetes patients. Due to its potential as an anti-cancer agent and its low cost, metformin has gained intense research interest. Its traditional anti-cancer mechanisms involve both indirect and direct insulin-dependent pathways. Here, we discussed the anti-tumor mechanism of metformin from the aspects of cell metabolism and epigenetic modifications. The effects of metformin on anti-cancer immunity and apoptosis were also described. Understanding these mechanisms will shed lights on application of metformin in clinical trials and development of anti-cancer therapy. PMID:27902459

Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells

International Nuclear Information System (INIS)

Rhee, Yun-Hee; Jeong, Soo-Jin; Lee, Hyo-Jeong; Lee, Hyo-Jung; Koh, Wonil; Jung, Ji Hoon; Kim, Sun-Hee; Sung-Hoon, Kim

2012-01-01

Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells. Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control. These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells

Antitumor and angiostatic peptides from frog skin secretions.

Science.gov (United States)

van Zoggel, Hanneke; Hamma-Kourbali, Yamina; Galanth, Cécile; Ladram, Ali; Nicolas, Pierre; Courty, José; Amiche, Mohamed; Delbé, Jean

2012-01-01

The discovery of new molecules with potential antitumor activity continues to be of great importance in cancer research. In this respect, natural antimicrobial peptides isolated from various animal species including humans and amphibians have been found to be of particular interest. Here, we report the presence of two anti-proliferative peptides active against cancer cells in the skin secretions of the South American tree frog, Phyllomedusa bicolor. The crude skin exudate was fractioned by size exclusion gel followed by reverse-phase HPLC chromatography. After these two purification steps, we identified two fractions that exhibited anti-proliferative activity. Sequence analysis indicated that this activity was due to two antimicrobial α-helical cationic peptides of the dermaseptin family (dermaseptins B2 and B3). This result was confirmed using synthetic dermaseptins. When tested in vitro, synthetic B2 and B3 dermaseptins inhibited the proliferation of the human prostatic adenocarcinoma PC-3 cell line by more than 90%, with an EC(50) of around 2-3 μM. No effect was observed on the growth of the NIH-3T3 non-tumor mouse cell line with Drs B2, whereas a slight inhibiting effect was observed with Drs B3 at high dose. In addition, the two fractions obtained after size exclusion chromatography also inhibited PC-3 cell colony formation in soft agar. Interestingly, inhibition of the proliferation and differentiation of activated adult bovine aortic endothelial cells was observed in cells treated with these two fractions. Dermaseptins B2 and B3 could, therefore, represent interesting new pharmacological molecules with antitumor and angiostatic properties for the development of a new class of anticancer drugs.

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

Science.gov (United States)

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

2015-04-01

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

Production of interferon-gamma by in vivo tumor-sensitized T cells: Association with active antitumor immunity

International Nuclear Information System (INIS)

Bursuker, I.; Pearce, M.T.

1990-01-01

The state of active immunity to Meth A fibrosarcoma in mice immunized with an admixture of Meth A cells and Propionibacterium acnes is associated with possession by the host of spleen cells capable of producing interferon-gamma (IFN-gamma) upon in vitro restimulation with irradiated tumor cells. The ability of spleen cells from immunized mice to produce IFN-gamma in response to irradiated Meth A cells decays as active antitumor immunity is replaced by a state of immunological memory. The IFN-producing cells are L3T4+Ly2+, cyclophosphamide-sensitive and radiosensitive T cells, as determined by their sensitivity to corresponding monoclonal antibodies and complement. The induction of IFN-gamma production by in vivo tumor-sensitized T cells is tumor specific, in that spleen cells from mice immunized against Meth A fibrosarcoma can produce IFN in response to irradiated Meth A cells but not in response to another syngeneic tumor M109 lung carcinoma

Effect of Paris saponin on antitumor and immune function in U14 ...

African Journals Online (AJOL)

bearing mice, and reduced the serum IL-4 level. The Paris saponin can inhibit U14 cell growth and prolong survival time of mice; it is speculated that the Paris saponin may express its anti-tumor activity by improving the body's immune system.

The anti-tumor effect and biological activities of the extract JMM6 from the stem-barks of the Chinese Juglans mandshurica Maxim on human hepatoma cell line BEL-7402.

Science.gov (United States)

Zhang, Yongli; Cui, Yuqiang; Zhu, Jiayong; Li, Hongzhi; Mao, Jianwen; Jin, Xiaobao; Wang, Xiangsheng; Du, Yifan; Lu, Jiazheng

2013-01-01

Juglans mandshurica Maxim is a traditional herbal medicines in China, and its anti-tumor bioactivities are of research interest. Bioassay-guided fractionation method was employed to isolate anti-tumor compounds from the stem barks of the Juglans mandshurica Maxim. The anti-tumor effect and biological activities of the extracted compound JMM6 were studied in BEL-7402 cells by MTT, Cell cycle analysis, Hoechst 33342 staining, Annexin V-FITC/PI assay and Detection of mitochondrial membrane potential (ΔΨm). After treatment with the JMM6, the growth of BEL-7402 cells was inhibited and cells displayed typical morphological apoptotic characteristics. Further investigations revealed that treatment with JMM6 mainly caused G2/M cell cycle arrest and induced apoptosis in BEL-7402 cells. To evaluate the alteration of mitochondria in JMM6 induced apoptosis. The data showed that JMM6 decreased significantly the ΔΨm, causing the depolarization of the mitochondrial membrane. Our results show that the JMM6 will have a potential advantage of anti-tumor, less harmful to normal cells. This paper not only summarized the JMM6 pick-up technology from Juglans mandshurica Maxim and biological characteristic, but also may provide further evidence to exploit the potential medicine compounds from the stem-barks of the Chinese Juglans mandshurica Maxim.

Prostate Cancer Cell–Stromal Cell Cross-Talk via FGFR1 Mediates Antitumor Activity of Dovitinib in Bone Metastases

Science.gov (United States)

Wan, Xinhai; Corn, Paul G.; Yang, Jun; Palanisamy, Nallasivam; Starbuck, Michael W.; Efstathiou, Eleni; Li-Ning Tapia, Elsa M.; Zurita, Amado J.; Aparicio, Ana; Ravoori, Murali K.; Vazquez, Elba S.; Robinson, Dan R.; Wu, Yi-Mi; Cao, Xuhong; Iyer, Matthew K.; McKeehan, Wallace; Kundra, Vikas; Wang, Fen; Troncoso, Patricia; Chinnaiyan, Arul M.; Logothetis, Christopher J.; Navone, Nora M.

2015-01-01

Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell–bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors. PMID:25186177

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

Directory of Open Access Journals (Sweden)

Srivastava MK

2012-10-01

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

Improved antitumor activity and reduced cardiotoxicity of epirubicin using hepatocyte-targeted nanoparticles combined with tocotrienols against hepatocellular carcinoma in mice.

Science.gov (United States)

Nasr, Magda; Nafee, Noha; Saad, Hoda; Kazem, Amani

2014-09-01

Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. Epirubicin (EPI), an anthracycline derivative, is one of the main line treatments for HCC. However, serious side effects including cardiomyopathy and congestive heart failure limit its long term administration. Our main goal is to develop a delivery strategy that ensures improved efficacy of the chemotherapeutic agent together with reduced cardiotoxicity. In this context, EPI was loaded in chitosan-PLGA nanoparticles linked with asialofetuin (EPI-NPs) selectively targeting hepatocytes. In an attempt to reduce cardiotoxicity, targeted EPI-NPs were coadministered with tocotrienols. EPI-NPs significantly enhanced the antiproliferative effect compared to free EPI as studied on Hep G2 cell line. Nanoencapsulated EPI injected in HCC mouse model revealed higher p53-mediated apoptosis and reduced angiogenesis in the tumor. Combined therapy of EPI-NPs with tocotrienols further enhanced apoptosis and reduced VEGF level in a dose dependent manner. Assessment of cardiotoxicity indicated that EPI-NPs diminished the high level of proinflammatory cytokine tumor necrosis factor-α (TNF-α) as well as oxidative stress-induced cardiotoxicity as manifested by reduced level of lipid peroxidation products (TBARS) and nitric oxide (NO). EPI-NPs additionally restored the diminished level of superoxide dismutase (SOD) and reduced glutathione (GSH) in the heart. Interestingly, tocotrienols provided both antitumor activity and higher protection against oxidative stress and inflammation induced by EPI in the heart. This hepatocyte-targeted biodegradable nanoparticle/tocotrienol combined therapy represents intriguing therapeutic strategy for EPI providing not only superior efficacy but also higher safety levels. Copyright © 2014 Elsevier B.V. All rights reserved.

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

Directory of Open Access Journals (Sweden)

Zong Sheng eGuo

2014-04-01

Full Text Available Oncolytic viruses (OVs are novel immunotherapeutic agents whose anticancer effects come from both oncolysis and elicited antitumor immunity. OVs induce mostly immunogenic cancer cell death (ICD, including immunogenic apoptosis, necrosis/necroptosis, pyroptosis and autophagic cell death, leading to exposure of calreticulin and heat-shock proteins to the cell surface, and/or released ATP, high mobility group box-1 [HMGB1], uric acid, and other DAMPs as well as PAMPs as danger signals, along with tumor-associated antigens, to activate dendritic cells (DCs and elicit adaptive antitumor immunity. Dying the right way may greatly potentiate adaptive antitumor immunity. The mode of cancer cell death may be modulated by individual OVs and cancer cells as they often encode and express genes that inhibit/promote apoptosis, necroptosis or autophagic cell death. We can genetically engineer OVs with death-pathway-modulating genes and thus skew the infected cancer cells towards certain death pathways for the enhanced immunogenicity. Strategies combining with some standard therapeutic regimens may also change the immunological consequence of cancer cell death. In this review, we discuss recent advances in our understanding of danger signals, modes of cancer cell death induced by OVs, the induced danger signals and functions in eliciting subsequent antitumor immunity. We also discuss potential combination strategies to target cells into specific modes of ICD and enhance cancer immunogenicity, including blockade of immune checkpoints, in order to break immune tolerance, improve antitumor immunity and thus the overall therapeutic efficacy.

Theoretical Study of Phosphoethanolamine: A Synthetic Anticancer Agent with Broad Antitumor Activity

Directory of Open Access Journals (Sweden)

Vitor Prates Lorenzo

2016-01-01

Full Text Available Cancer is a major public health problem with limited success of available treatments, pointing to the need for new strategies to be developed. Phosphoethanolamine exhibits broad antitumor activity in a variety of tumor cells and potent inhibitor effects on tumor progress in vivo. Once-used organophosphates inhibit acetylcholinesterase (AChE, resulting in toxic effects to the user. As this group is present in phosphoethanolamine, we perform prediction of the in silico metabolism of phosphoethanolamine and submit this series to a docking study on AChE. A total of 10 metabolites were indicated by the prediction, including ammonia and hydroxylamine, which were not included in the study. Using a group of 8 organophosphorus whose pIC50 values ranged from 5.92 to 9.47 as template, we observed that no compound present in the phosphoethanolamine series had a binding energy lower than that of organophosphorus, suggesting that the series has low inhibitory power on AChE. In light of this, we conclude that phosphoethanolamine and its predicted metabolites do not significantly inhibit AChE to cause a cholinergic crisis. This finding highlights the importance of investigating this compound as lead for potential anticancer agents.

Docetaxel-loaded single-wall carbon nanohorns using anti-VEGF antibody as a targeting agent: characterization, in vitro and in vivo antitumor activity

Science.gov (United States)

Zhao, Qian; Li, Nannan; Shu, Chang; Li, Ruixin; Ma, Xiaona; Li, Xuequan; Wang, Ran; Zhong, Wenying

2015-05-01

A novel antitumor drug delivery system, docetaxel (DTX)-loaded oxidized single-wall carbon nanohorns (oxSWNHs) with anti-VEGF monoclonal antibody (mAb) as a target agent was constructed. DTX was absorbed onto the oxSWNHs via the physical adsorption or π-π interaction. DSPE-PEG-COOH was non-covalently wrapped to the hydrophobic surface of oxSWNHs to improve its water solubility and biocompatibility. The mAb was bonded to the PEG through amide bond. The DTX@oxSWNHs-PEG-mAb (DDS) exhibited suitable particle size (191.2 ± 2.1 nm), good particle size distribution (PDI: 0.196), and negative zeta potential (-24.3 ± 0.85 mV). These features enhanced permeability and retention (EPR) effect and reduced the drug molecule uptake by the reticuloendothelial system. The in vitro drug release followed non-Fickian diffusion ( n = 0.6857, R = 0.9924) with the cumulative release of DTX 59 ± 1.35 % at 72 h. Compared with free DTX, the DDS enhanced the cytotoxicity in MCF-7 cell lines in vitro efficiently (IC50: 2.96 ± 0.6 μg/ml), and provided higher antitumor efficacy (TGI: 69.88 %) in vivo. The histological analysis indicated that the DDS had no significant side effect. Therefore, the new DDS is promising to attain higher pharmaceutical efficacy and lower side effects than free DTX for cancer therapy. The research demonstrated that DTX@oxSWNHs-PEG-mAb might have promising biomedical applications for future cancer therapy.

Synthesis and Biological Evaluation of Novel Furozan-Based Nitric Oxide-Releasing Derivatives of Oridonin as Potential Anti-Tumor Agents

Directory of Open Access Journals (Sweden)

Hao Cai

2012-06-01

Full Text Available To search for novel nitric oxide (NO releasing anti-tumor agents, a series of novel furoxan/oridonin hybrids were designed and synthesized. Firstly, the nitrate/nitrite levels in the cell lysates were tested by a Griess assay and the results showed that these furoxan-based NO-releasing derivatives could produce high levels of NO in vitro. Then the anti-proliferative activity of these hybrids against four human cancer cell lines was also determined, among which, 9h exhibited the most potential anti-tumor activity with IC₅₀ values of 1.82 µM against K562, 1.81 µM against MGC-803 and 0.86 µM against Bel-7402, respectively. Preliminary structure-activity relationship was concluded based on the experimental data obtained. These results suggested that NO-donor/natural product hybrids may provide a promising approach for the discovery of novel anti-tumor agents.

Anti-tumor and anti-angiogenic ergosterols from Ganoderma lucidum

Science.gov (United States)

Chen, Shaodan; Yong, Tianqiao; Zhang, Yifang; Su, Jiyan; Jiao, Chunwei; Xie, Yizhen

2017-10-01

This study was carried out to isolate chemical constituents from the lipid enriched fraction of Ganoderma lucidum extract and to evaluate their anti-proliferative effect on cancer cell lines and human umbilical vein endothelial cells. Ergosterol derivatives (1-14) were isolated from the lipid enriched fraction of G. lucidum. Their structures were established on the basis of spectroscopic analyses or by comparison of mass and NMR spectral data with those reported previously. Amongst, compound 1 was isolated and identified as a new compound. All the compounds were evaluated for their inhibitory effect on tumor cells and human umbilical vein endothelial cells in vitro. Compounds 9-13 displayed inhibitory activity against two tumor cell lines and human umbilical vein endothelial cells, which indicated that these four compounds had both anti-tumor and anti-angiogenesis activities. Compound 2 had significant selective inhibition against two tumor cell lines, while 3 exhibited selective inhibition against human umbilical vein endothelial cells. The structure–activity relationships for inhibiting human HepG2 cells were revealed by 3D-QASR. Ergosterol content in different parts of the raw material and products of G. lucidum was quantified. This study provides a basis for further development and utilization of ergosterol derivatives as natural nutraceuticals and functional food ingredients, or as source of new potential antitumor or anti-angiogenesis chemotherapy agent.

Antitumor Action of a Novel Histone Deacetylase Inhibitor, YF479, in Breast Cancer

Directory of Open Access Journals (Sweden)

Tao Zhang

2014-08-01

Full Text Available Accumulating evidence demonstrates important roles for histone deacetylase in tumorigenesis (HDACs, highlighting them as attractive targets for antitumor drug development. Histone deactylase inhibitors (HDACIs, which have shown favorable anti-tumor activity with low toxicity in clinical investigations, are a promising class of anticancer therapeutics. Here, we screened our compound library to explore small molecules that possess anti-HDAC activity and identified a novel HDACI, YF479. Suberoylanilide hydroxamic acid (SAHA, which was the first approved HDAC inhibitor for clinical treatment by the FDA, was as positive control in our experiments. We further demonstrated YF479 abated cell viability, suppressed colony formation and tumor cell motility in vitro. To investigate YF479 with superior pharmacodynamic properties, we developed spontaneous and experimental breast cancer animal models. Our results showed YF479 significantly inhibited breast tumor growth and metastasis in vivo. Further study indicated YF479 suppressed both early and end stages of metastatic progression. Subsequent adjuvant chemotherapy animal experiment revealed the elimination of local-regional recurrence (LRR and distant metastasis by YF479. More important, YF479 remarkably prolonged the survival of tumor-bearing mice. Intriguingly, YF479 displayed more potent anti-tumor activity in vitro and in vivo compared with SAHA. Together, our results suggest that YF479, a novel HDACI, inhibits breast tumor growth, metastasis and recurrence. In light of these results, YF479 may be an effective therapeutic option in clinical trials for patients burdened by breast cancer.

Antitumor evaluation of epigallocatechin gallate by colorimetric methods

Energy Technology Data Exchange (ETDEWEB)

Baek, Soon Ok [Korean Ginseng and Tobacco Research institute, Daejon (Korea, Republic of); Kim, Il Kwang; Baek, Seung Hwa; Han, Du Seok [Wonkwang Unvi., Iksan (Korea, Republic of)

1998-08-01

In the present study, we were evaluated cytotoxic effects of epigallocatechin gallate in human skin melanoma cells such as HTB-69. The light microscopic study showed morphological changes of the treated cells. Disruptions in cell organelles were determined by colorimetric methods; 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, neutral red (NR) assay and sulforhodamine B protein (SRB) as-say. These results suggest that epigallocatechin gallate retains a potential antitumor activity.

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

Science.gov (United States)

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

2017-06-01

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

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

Directory of Open Access Journals (Sweden)

Chao Liu

2016-06-01

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

Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

Science.gov (United States)

Chen, Lili; He, Zhengxiang; Qin, Li; Li, Qinyan; Shi, Xibao; Zhao, Siting; Chen, Ling; Zhong, Nanshan; Chen, Xiaoping

2011-01-01

Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+) T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer

Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

Directory of Open Access Journals (Sweden)

Lili Chen

Full Text Available BACKGROUND: Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL staining and decreased Ki-67 expression in tumors. Through natural killer (NK cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+ T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. CONCLUSIONS/SIGNIFICANCE: Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria

Antitumor activity and inhibitory effects on cancer stem cell-like properties of Adeno-associated virus (AAV) -mediated Bmi-1 interference driven by Bmi-1 promoter for gastric cancer

Science.gov (United States)

Wang, Xiaofeng; Liu, Xinyang; Huang, Mingzhu; Gan, Lu; Cheng, Yufan; Li, Jin

2016-01-01

Bmi-1 is aberrantly activated in various cancers and plays a vital role in maintaining the self-renewal of stem cells. Our previous research revealed that Bmi-1 was overexpressed in gastric cancer (GC) and it's overexpression was an independent negative prognostic factor, suggesting it can be a therapeutic target. The main purpose of this investigation was to explore the antitumor activity of Bmi-1 interference driven by its own promoter (Ad-Bmi-1i) for GC. In this study, we used adenoviral vector to deliver Bmi-1 shRNA driven by its own promoter to treat GC. Our results revealed that Ad-Bmi-1i could selectively silence Bmi-1 in GC cells which overexpress Bmi-1 and suppress the malignant phenotypes and stem-like properties of GC cells in vitro and in vivo. Moreover, direct injection of Ad-Bmi-1i into xenografts suppressed tumor growth and destroyed cancer cells in vivo. Ad-Bmi-1i inhibited the proliferation of GC cells mainly via inducing senescence in vitro, but it suppressed tumor through inducing senescence and apoptosis, and inhibiting angiogenesis in vivo. Bmi-1 knockdown by Ad-Bmi-1i downregulated VEGF via inhibiting AKT activity. These results suggest that Ad-Bmi-1i not only inhibits tumor growth and stem cell-like phenotype by inducing cellular senescence directly, but also has an indirect anti-tumor activity by anti-angiogenesis effects via regulating PTEN/AKT/VEGF pathway. Transfer of gene interference guided by its own promoter by an adeno-associated virus (AAV) vector might be a potent antitumor approach for cancer therapy. PMID:27009837

SYNTHESIS AND ANTITUMOR ACTIVITY OF COPPER, NICKEL AND COBALT COORDINATION COMPOUNDS WITH 1-(2-HYDROXYPHENYL)ETHANONE N(4)-ALLYL-3-THIOSEMICARBAZONE

OpenAIRE

Vasilii GRAUR; Serghei SAVCIN; Victor TSAPKOV; Aurelian GULEA

2015-01-01

The paper presents the synthesis of the ligand 1-(2-hydroxyphenyl)ethanone N(4)-allyl-3-thiosemicarbazone (H2L) and six coordination compounds of copper, nickel and cobalt with this ligand. The structure of thiosemicarbazone H2L was studied using 1H and 13С NMR spectroscopy. The synthesized coordination compounds were studied using elemental analysis, gravimetric analysis of water content, molar conductivity, and magnetochemistry. For H2L the antitumor activity towards human leukemia HL-60 ce...

Selective activation of human heat shock gene transcription by nitrosourea antitumor drugs mediated by isocyanate-induced damage and activation of heat shock transcription factor.

Science.gov (United States)

Kroes, R A; Abravaya, K; Seidenfeld, J; Morimoto, R I

1991-01-01

Treatment of cultured human tumor cells with the chloroethylnitrosourea antitumor drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) selectively induces transcription and protein synthesis of a subset of the human heat shock or stress-induced genes (HSP90 and HSP70) with little effect on other stress genes or on expression of the c-fos, c-myc, or beta-actin genes. The active component of BCNU and related compounds appears to be the isocyanate moiety that causes carbamoylation of proteins and nucleic acids. Transcriptional activation of the human HSP70 gene by BCNU is dependent on the heat shock element and correlates with the level of heat shock transcription factor and its binding to the heat shock element in vivo. Unlike activation by heat or heavy metals, BCNU-mediated activation is strongly dependent upon new protein synthesis. This suggests that BCNU-induced, isocyanate-mediated damage to newly synthesized protein(s) may be responsible for activation of the heat shock transcription factor and increased transcription of the HSP90 and HSP70 genes. Images PMID:2052560

Comparison of the fibronectin-binding ability and antitumor efficacy of various mycobacteria.

Science.gov (United States)

Hudson, M A; Ritchey, J K; Catalona, W J; Brown, E J; Ratliff, T L

1990-07-01

Although the mechanism by which Bacillus Calmette-Guerin (BCG) exerts an antitumor effect on superficial bladder tumors is not fully understood, recent evidence has implicated binding of BCG organisms to fibronectin (FN) as requisite for this antitumor efficacy. Various substrains of BCG and other mycobacteria were tested in vitro for their relative capacities to bind both matrix and soluble FN. A substrain of Mycobacterium kansasii, designated the "high-binding strain," was found to bind FN more readily (P less than 0.05) in in vitro studies, when compared to commercially available substrains of BCG (Tice, Connaught, and Armand Frappier). The binding by the three commercial strains of BCG to FN in vitro appeared to be equivalent. The high-binding strain was further demonstrated to attach more readily in vivo to the acutely injured murine bladder (P less than 0.005) than the Armand Frappier substrain. Finally, using the MB49 murine bladder tumor model, an enhanced antitumor effect (P less than 0.05) was noted in mice treated with intravesical high-binding strain, in comparison to the Armand Frappier substrain, during five weekly treatments. It appears not only that the commercial substrains of BCG bind FN in an equivalent manner but also that the relative binding capacities of the substrains correlate directly with antitumor activity. A substrain of M. kansasii appears to have been identified which may prove more clinically effective than the currently available strains of BCG.

Enhancement of antitumor activity by using a fully human gene encoding a single-chain fragmented antibody specific for carcinoembryonic antigen

Directory of Open Access Journals (Sweden)

Shibaguchi H

2017-08-01

Full Text Available Hirotomo Shibaguchi,1,* Naixiang Luo,1,* Naoto Shirasu,1,* Motomu Kuroki,2 Masahide Kuroki1 1Department of Biochemistry, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; 2School of Nursing, Faculty of Medicine, Fukuoka University, Fukuoka, Japan *These authors equally contributed to this work Abstract: Human leukocyte antigen and/or costimulatory molecules are frequently lacking in metastatic tumor cells, and thus tumor cells are able to escape from the immune system. Although lymphocytes with a chimeric antigen receptor (CAR is a promising approach for overcoming this challenge in cancer immunotherapy, administration of modified T cells alone often demonstrates little efficacy in patients. Therefore, in order to enhance the antitumor activity of immune cells in the cancer microenvironment, we used lymphocytes expressing CAR in combination with a fusion protein of IL-2 that contained the single-chain fragmented antibody (scFv specific for the carcinoembryonic antigen. Among a series of CAR constructs, with or without a spacer and the intracellular domain of CD28, the CAR construct containing CD8α, CD28, and CD3ζ most effectively activated and expressed INF-γ in CAR-bearing T cells. Furthermore, in comparison with free IL-2, the combination of peripheral blood mononuclear cells expressing CAR and the fusion protein containing IL-2 significantly enhanced the antitumor activity against MKN-45 cells, a human gastric cancer cell line. In conclusion, this novel combination therapy of CAR and a fusion protein consisting of a functional cytokine and a fully human scFv may be a promising approach for adoptive cancer immunotherapy. Keywords: chimeric antigen receptor, fusion protein, human scFv, CEA, combination therapy

Evaluation of tetrazolium-based semiautomatic colorimetric assay for measurement of human antitumor cytotoxicity

International Nuclear Information System (INIS)

Heo, D.S.; Park, J.G.; Hata, K.; Day, R.; Herberman, R.B.; Whiteside, T.L.

1990-01-01

A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-based colorimetric assay was developed and compared with 51Cr release from different adherent tumor cell targets (human squamous cell carcinoma lines of the head and neck established in our laboratory, melanoma, and colorectal carcinoma) using 5-7-day human lymphokine-activated killer cells and monocyte-depleted peripheral blood lymphocytes as effectors. With adherent tumor cell targets, MTT colorimetry was more sensitive than the 51Cr release assay in measuring the antitumor activity of effectors: median, 4385 (range, 988-8144) versus median, 1061 (range, 582-7294) lytic units (the number of effector cells required to lyse 20% of 5 x 10(3) targets)/10(7) effectors (P less than 0.01). Background effects (without effector cells) were comparable in 4-h assays (9% versus 10%) between MTT colorimetry and 51Cr release. In 24-h assays, MTT colorimetry showed higher antitumor activity (70-100% versus 40-60% lysis at 1:1 effector:target cell ratio) but lower background effects (6% versus 38%) than 51Cr release assay. Thus, MTT colorimetry was more sensitive, did not use radiolabeled targets, required fewer effector cells, and was easier, less expensive, and better adaptable to serial monitoring of effector cell function in cancer patients. This colorimetric assay is especially well suited to adherent tumor cell targets. The use of adherent tumor cell monolayers, as opposed to trypsinized single cell suspensions, provides an opportunity to measure interactions of effector cells with enzymatically unaltered solid tumor targets. Because of the greater sensitivity of the colorimetric assay, the transformation of MTT data into lytic units, as commonly used for 51Cr release assays, required an adjustment to avoid the extrapolation based on the exponential fit equation

Antioxidants Impair Anti-Tumoral Effects of Vorinostat, but Not Anti-Neoplastic Effects of Vorinostat and Caspase-8 Downregulation

OpenAIRE

Bergadà, Laura; Yeramian, Andree; Sorolla, Annabel; Matias-Guiu, Xavier; Dolcet, Xavier

2014-01-01

We have recently demonstrated that histone deacetylase inhibitor, Vorinostat, applied as a single therapy or in combination with caspase-8 downregulation exhibits high anti-tumoral activity on endometrial carcinoma cell lines. In the present study, we have assessed the signalling processes underlying anti-tumoral effects of Vorinostat. Increasing evidence suggests that reactive oxygen species are responsible for histone deacetylase inhibitor-induced cell killing. We have found that Vorinostat...

Immunopotentiation by a new antitumor polysaccharide, DMG, a degraded D-manno-D-glucan from Microellobosporia grisea culture fluid.

Science.gov (United States)

Nakajima, H; Kita, Y; Takashi, T; Akasaki, M; Yamaguchi, F; Ozawa, S; Tsukada, W; Abe, S; Mizuno, D

1984-03-01

The immunopharmacological behavior of DMG, an antitumor polysaccharide, was studied in mice. DMG administered ip or sc stimulated peritoneal macrophages to produce high levels of interleukin-1 activity, which can amplify successive immune responses. DMG dose-dependently and schedule-dependently increased the cellular immune response against allogeneic tumor cells and the humoral immune response to sheep erythrocytes. DMG also enhanced nonspecific antitumor effector functions, such as natural killer activity of spleen and peritoneal cells, and the cytostatic activity of peritoneal macrophages. Peritoneal macrophages activated by ip or sc injection of DMG exhibited high cytostatic activity, especially after exposure in vitro to lymphokine supernatants containing macrophage activation factor. Moreover, granulocyte/macrophage colony-stimulating activity in the serum increased 2-10 hr after DMG administration. Thus, DMG potentiated antigen-specific immunological functions and nonspecific functions of host defense systems against cancer both qualitatively and quantitatively.

Antitumor Properties of the Essential Oil From the Leaves of Duguetia gardneriana.

Science.gov (United States)

Rodrigues, Ana Carolina B C; Bomfim, Larissa M; Neves, Sara P; Menezes, Leociley R A; Dias, Rosane B; Soares, Milena B P; Prata, Ana Paula N; Rocha, Clarissa A Gurgel; Costa, Emmanoel V; Bezerra, Daniel P

2015-07-01

Duguetia gardneriana, popularly known in the Brazilian northeast as "jaquinha", is a species belonging to the family Annonaceae. The aim of this work was to assess the chemical composition and antitumor properties of the essential oil from the leaves of D. gardneriana in experimental models. The chemical composition of the essential oil was analyzed via gas chromatography-flame ionization detector and gas chromatography-mass spectrometry. In vitro cytotoxic activity was determined in cultured tumor cells, and in vivo antitumor activity was assessed in B16-F10-bearing mice. The identified compounds were β-bisabolene (80.99%), elemicin (8.04%), germacrene D (4.15%), and cyperene (2.82%). The essential oil exhibited a cytotoxic effect, with IC50 values of 16.89, 19.16, 13.08, and 19.33 µg/mL being obtained for B16-F10, HepG2, HL-60, and K562 cell lines, respectively. On the other hand, β-bisabolene was inactive in all of the tested tumor cell lines (showing IC50 values greater than 25 µg/mL). The in vivo analysis revealed tumor growth inhibition rates of 5.37-37.52% at doses of 40 and 80 mg/kg/day, respectively. Herein, the essential oil from the leaves of D. gardneriana presented β-bisabolene as the major constituent and showed cytotoxic and antitumor potential. Georg Thieme Verlag KG Stuttgart · New York.

Antitumor effect of the essential oil from leaves of Guatteria pogonopus (Annonaceae).

Science.gov (United States)

do N Fontes, José Eraldo; Ferraz, Rosana P C; Britto, Anny C S; Carvalho, Adriana A; Moraes, Manoel O; Pessoa, Claudia; Costa, Emmanoel V; Bezerra, Daniel P

2013-04-01

Guatteria pogonopus Martius, a plant belonging to the Annonaceae family, is found in the remaining Brazilian Atlantic Forest. In this study, the chemical composition and antitumor effects of the essential oil isolated from leaves of G. pogonopus was investigated. The chemical composition of the oil was determined by GC-FID and GC/MS analyses. The in vitro cytotoxicity was evaluated against three different tumor cell lines (OVCAR-8, NCI-H358M, and PC-3M), and the in vivo antitumor activity was tested in mice bearing sarcoma 180 tumor. A total of 29 compounds was identified and quantified in the oil. The major compounds were γ-patchoulene (13.55%), (E)-caryophyllene (11.36%), β-pinene (10.37%), germacrene D (6.72%), bicyclogermacrene (5.97%), α-pinene (5.33%), and germacrene B (4.69%). The essential oil, but neither (E)-caryophyllene nor β-pinene, displayed in vitro cytotoxicity against all three tumor cell lines tested. The obtained average IC50 values ranged from 3.8 to 20.8 μg/ml. The lowest and highest values were obtained against the NCI-H358M and the OVCAR-8 cell lines, respectively. The in vivo tumor-growth-inhibition rates in the tumor-bearing mice treated with essential oil (50 and 100 mg/kg/d) were 25.3 and 42.6%, respectively. Hence, the essential oil showed significant in vitro and in vivo antitumor activity. Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.

Novel Therapeutic Strategies for Solid Tumor Based on Body's Intrinsic Antitumor Immune System.

Science.gov (United States)

Duan, Haifeng

2018-05-22

The accumulation of mutated somatic cells due to the incompetency of body's immune system may lead to tumor onset. Therefore, enhancing the ability of the system to eliminate such cells should be the core of tumor therapy. The intrinsic antitumor immunity is triggered by tumor-specific antigens (TSA) or TSA-sensitized dendritic cells (DC). Once initiated, specific anti-tumor antibodies are produced and tumor-specific killer immune cells, including cytotoxic T lymphocytes (CTL), NK cells, and macrophages, are raised or induced. Several strategies may enhance antitumor action of immune system, such as supplying tumor-targeted antibody, activating T cells, enhancing the activity and tumor recognition of NK cells, promoting tumor-targeted phagocytosis of macrophages, and eliminating the immunosuppressive myeloid-derived suppressor cells (MDSCs) and Treg cells. Apart from the immune system, the removal of tumor burden still needs to be assisted by drugs, surgery or radiation. And the body's internal environment and tumor microenvironment should be improved to recover immune cell function and prevent tumor growth. Multiple microenvironment modulatory therapies may be applied, including addressing hypoxia and oxidative stress, correcting metabolic disorders, and controlling chronic inflammation. Finally, to cure tumor and prevent tumor recurrence, repairing or supporting therapy that consist of tissue repair and nutritional supplement should be applied properly. © 2018 The Author(s). Published by S. Karger AG, Basel.

Telmisartan Exerts Anti-Tumor Effects by Activating Peroxisome Proliferator-Activated Receptor-γ in Human Lung Adenocarcinoma A549 Cells

Directory of Open Access Journals (Sweden)

Juan Li

2014-03-01

Full Text Available Telmisartan, a member of the angiotensin II type 1 receptor blockers, is usually used for cardiovascular diseases. Recent studies have showed that telmisartan has the property of PPARγ activation. Meanwhile, PPARγ is essential for tumor proliferation, invasion and metastasis. In this work we explore whether telmisartan could exert anti-tumor effects through PPARγ activation in A549 cells. MTT and trypan blue exclusion assays were included to determine the survival rates and cell viabilities. RT-PCR and western blotting were used to analyze the expression of ICAM-1, MMP-9 and PPARγ. DNA binding activity of PPARγ was evaluated by EMSA. Our data showed that the survival rates and cell viabilities of A549 cells were all reduced by telmisartan in a time- and concentration-dependent manner. Meanwhile, our results also demonstrated that telmisartan dose-dependently inhibited the expression of ICAM-1 and MMP-9. Moreover, the cytotoxic and anti-proliferative effects, ICAM-1 and MMP-9 inhibitive properties of telmisartan were totally blunted by the PPARγ antagonist GW9662. Our findings also showed that the expression of PPARγ was up-regulated by telmisartan in a dose dependent manner. And, the EMSA results also figured out that DNA binding activity of PPARγ was dose-dependently increased by telmisartan. Additionally, our data also revealed that telmisartan-induced PPARγ activation was abrogated by GW9662. Taken together, our results indicated that telmisartan inhibited the expression of ICAM-1 and MMP-9 in A549 cells, very likely through the up-regulation of PPARγ synthesis.

Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways.

Directory of Open Access Journals (Sweden)

Canhui Yi

Full Text Available Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy.

Melatonin Enhances the Anti-Tumor Effect of Fisetin by Inhibiting COX-2/iNOS and NF-κB/p300 Signaling Pathways

Science.gov (United States)

Yu, Zhenlong; Xiao, Yao; Wang, Jingshu; Qiu, Huijuan; Yu, Wendan; Tang, Ranran; Yuan, Yuhui; Guo, Wei; Deng, Wuguo

2014-01-01

Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy. PMID:25000190

The Antitumor Effects of Triterpenoid Saponins from the Anemone flaccida and the Underlying Mechanism

Directory of Open Access Journals (Sweden)

Lin-Tao Han

2013-01-01

Full Text Available Anemone flaccida Fr. Schmidt, a family of ancient hopanoids, have been used as traditional Asian herbs for the treatments of inflammation and convulsant diseases. Previous study on HeLa cells suggested that triterpenoid saponins from Anemone flaccida Fr. Schmidt may have potential antitumor effect due to their apoptotic activities. Here, we confirmed the apoptotic activities of the following five triterpenoid saponins: glycoside St-I4a (1, glycoside St-J (2, anhuienoside E (3, hedera saponin B (4, and flaccidoside II (5 on human BEL-7402 and HepG2 hepatoma cell lines, as well as the model of HeLa cells treated with lipopolysaccharide (LPS. We found that COX-2/PGE2 signaling pathway, which plays key roles in the development of cancer, is involved in the antitumor activities of these saponins. These data provide the evidence that triterpenoid saponins can induce apoptosis via COX-2/PGE2 pathway, implying a preventive role of saponins from Anemone flaccida in tumor.

Anti-podocalyxin antibody exerts antitumor effects via antibody-dependent cellular cytotoxicity in mouse xenograft models of oral squamous cell carcinoma.

Science.gov (United States)

Itai, Shunsuke; Ohishi, Tomokazu; Kaneko, Mika K; Yamada, Shinji; Abe, Shinji; Nakamura, Takuro; Yanaka, Miyuki; Chang, Yao-Wen; Ohba, Shun-Ichi; Nishioka, Yasuhiko; Kawada, Manabu; Harada, Hiroyuki; Kato, Yukinari

2018-04-27

Podocalyxin (PODXL) overexpression is associated with progression, metastasis, and poor outcomes in cancers. We recently produced the novel anti-PODXL monoclonal antibody (mAb) PcMab-47 (IgG 1 , kappa). Herein, we engineered PcMab-47 into 47-mG 2a , a mouse IgG 2a -type mAb, to add antibody-dependent cellular cytotoxicity (ADCC). We further developed 47-mG 2a -f, a core fucose-deficient type of 47-mG 2a to augment its ADCC. Immunohistochemical analysis of oral cancer tissues using PcMab-47 and 47-mG 2a revealed that the latter stained oral squamous cell carcinoma (OSCC) cells in a cytoplasmic pattern at a much lower concentration. PcMab-47 and 47-mG 2a detected PODXL in 163/201 (81.1%) and in 197/201 (98.0%) OSCC samples, respectively. 47-mG 2a -f also detected PODXL in OSCCs at a similar frequency as 47-mG 2a . In vitro analysis revealed that both 47-mG 2a and 47-mG 2a -f exhibited strong complement-dependent cytotoxicity (CDC) against CHO/hPODXL cells. In contrast, 47-mG 2a -f exhibited much stronger ADCC than 47-mG 2a against OSCC cells, indicating that ADCC and CDC of those anti-PODXL mAbs depend on target cells. In vivo analysis revealed that both 47-mG 2a and 47-mG 2a -f exerted antitumor activity in CHO/hPODXL xenograft models at a dose of 100 μg or 500 μg/mouse/week administered twice. 47-mG 2a -f, but not 47-mG 2a , exerted antitumor activity in SAS and HSC-2 xenograft models at a dose of 100 μg/mouse/week administered three times. Although both 47-mG 2a and 47-mG 2a -f exerted antitumor activity in HSC-2 xenograft models at a dose of 500 μg/mouse/week administered twice, 47-mG 2a -f also showed higher antitumor activity than 47-mG 2a . These results suggested that a core fucose-deficient anti-PODXL mAb could be useful for antibody-based therapy against PODXL-expressing OSCCs.

Meroterpenoids with Antitumor Activities from Guava (Psidium guajava).

Science.gov (United States)

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

2017-06-21

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

Andrographolide enhanced 5-fluorouracil-induced antitumor effect in colorectal cancer via inhibition of c-MET pathway

Directory of Open Access Journals (Sweden)

Su M

2017-11-01

Full Text Available Meng Su,1 Baoli Qin,1 Fang Liu,2 Yuze Chen,2 Rui Zhang2 1Department of Internal Medicine, 2Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Liaoning, China Abstract: Colorectal cancer (CRC is the third most common malignant neoplasm worldwide. 5-Fluorouracil (5-Fu is the most important chemotherapeutic drug used for the treatment of CRC. However, resistance to 5-Fu therapies is a growing concern in CRC clinical practice recently. Andrographolide (Andro is a main bioactive constituent of the herb Andrographis paniculata, which has various biological effects including anti-inflammation and antitumor activities. In the present study, we investigated the effects of combined Andro with 5-Fu against CRC HCT-116 cells. In vitro studies showed that Andro synergistically enhanced the anti-proliferation effect of 5-Fu on HCT-116 cells due to increased apoptotic cells. Meanwhile, results of the enzyme linked immunosorbent assay indicated that the level of phosphorylated cellular-mesenchymal to epithelial transition factor (p-MET was decreased by the combination treatment. Further study suggested that Andro promoted the antitumor effect of 5-Fu by downregulating the level of p-MET. In conclusion, these results confirmed the synergistic antitumor activity of Andro on CRC and provide evidence for possible clinical application of Andro for enhancing the antitumor effect of 5-Fu in CRC treatment. Keywords: Andro, 5-Fu, HCT-116 cells, apoptosis, p-MET

MiR-143 enhances the antitumor activity of shikonin by targeting BAG3 expression in human glioblastoma stem cells.

Science.gov (United States)

Liu, Jing; Qu, Cheng-Bin; Xue, Yi-Xue; Li, Zhen; Wang, Ping; Liu, Yun-hui

Therapeutic applications of microRNAs (miRNAs) in chemotherapy were confirmed to be valuable, but there is rare to identify their specific roles and functions in shikonin treatment toward tumors. Here, for the first time, we reported that miR-143 played a critical role in the antitumor activity of shikonin in glioblastoma stem cells (GSCs). The results showed that the expression of miR-143 was downregulated in shikonin treated GSCs within 24 h. MiR-143 overexpression significantly enhanced the inhibitory effect of shikonin toward GSCs on cell viability. Besides, miR-143 overexpression caused a significant increase in the apoptotic fraction and made apoptosis occur earlier. Further investigation identified that BAG3, an apoptotic regulator, was a functional target of miR-143 in shikonin treated GSCs. The expression of BAG3 was upregulated in shikonin treated GSCs within 24 h. MiR-143 overexpression significantly reversed the high expression of BAG3 in shikonin treated GSCs. Moreover, it was confirmed that the enhanced cytotoxicity of shikonin by miR-143 overexpression was reversed by BAG3 overexpression both in vitro and in vivo, suggesting that the enhanced tumor suppressive effects by miR-143 overexpression was at least partly through the regulation of BAG3. Taken together, for the first time, our results demonstrate that miR-143 could enhance the antitumor activity of shikonin toward GSCs through reducing BAG3 expression, which may provide a novel therapeutic strategy for enhancing the treatment efficacy of shikonin toward GSCs. Copyright © 2015 Elsevier Inc. All rights reserved.

Enhanced antitumor efficacy and counterfeited cardiotoxicity of combinatorial oral therapy using Doxorubicin- and Coenzyme Q10-liquid crystalline nanoparticles in comparison with intravenous Adriamycin

DEFF Research Database (Denmark)

Swarnakar, Nitin K; Thanki, Kaushik; Jain, Sanyog

2014-01-01

and strong synergism for combination at 1:10 dose ratio owing to higher cellular uptake, nuclear colocalization, higher apoptotic index and 8-OHdG levels. The prophylactic antitumor efficacy of the CoQ10-LCNPs was also established using tumor induction and progression studies. Finally, therapeutic antitumor......, with Dox-induced-cardiotoxicity was completely counterfeited in combination. In nutshell, LCNPs pose great potential in improving the therapeutic efficacy of drugs by oral route of administration. FROM THE CLINICAL EDITOR: This study describes the use of liquid crystalline nanoparticles containing coenzyme...

Induction of anti-tumor immunity by trifunctional antibodies in patients with peritoneal carcinomatosis

Directory of Open Access Journals (Sweden)

Lindhofer Horst

2009-02-01

Full Text Available Abstract Peritoneal carcinomatosis (PC from epithelial tumors is a fatal diagnosis without efficient treatment. Trifunctional antibodies (trAb are novel therapeutic approaches leading to a concerted anti-tumor activity resulting in tumor cell destruction. In addition, preclinical data in mouse tumor models demonstrated the induction of long lasting tumor immunity after treatment with trAb. We describe the induction of anti-tumor specific T-lymphocytes after intraperitoneal administration of trAb in patients with PC. 9 patients with progressive PC from gastric (n = 6 and ovarian cancer (n = 2, and cancer of unknown primary (n = 1 received 3 escalating doses of trAb after surgery and/or ineffective chemotherapy. The trAb EpCAM × CD3 (10, 20, 40 μg or HER2/neu × CD3 (10, 40, 80 μg were applicated by intraperitoneal infusion. Four weeks after the last trAb application, all patients were restimulated by subdermal injection of trAb + autologous PBMC + irradiated autologous tumor cells. Immunological reactivity was tested by analyzing PBMC for specific tumor reactive CD4+/CD8+ T lymphocytes using an IFN-γ secretion assay. In 5 of 9 patients, tumor reactive CD4+/CD8+ T-lymphocytes increased significantly, indicating specific anti-tumor immunity. A clinical response (stable disease, partial regression has been observed in 5 of 9 patients, with a mean time to progression of 3.6 months. Follow-up showed a mean survival of 11.8 months (median 8.0 months after trAb therapy. TrAb are able to induce anti-tumor immunity after intraperitoneal application and restimulation. The induction of long-lasting anti-tumor immunity may provide an additional benefit of the intraperitoneal therapy with trAb and should be further elevated in larger clinical trials.

Antivascular and antitumor properties of the tubulin-binding chalcone TUB091.

Science.gov (United States)

Canela, María-Dolores; Noppen, Sam; Bueno, Oskía; Prota, Andrea E; Bargsten, Katja; Sáez-Calvo, Gonzalo; Jimeno, María-Luisa; Benkheil, Mohammed; Ribatti, Domenico; Velázquez, Sonsoles; Camarasa, María-José; Díaz, J Fernando; Steinmetz, Michel O; Priego, Eva-María; Pérez-Pérez, María-Jesús; Liekens, Sandra

2017-02-28

We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3''-amino-4''-methoxyphenyl)-1-(5'-methoxy-3',4'-methylendioxyphenyl)-2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-to-straight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs.

New benzimidazoles and their antitumor effects with Aurora A kinase and KSP inhibitory activities.

Science.gov (United States)

Abd El-All, Amira S; Magd-El-Din, Asmaa A; Ragab, Fatma A F; ElHefnawi, Mahmoud; Abdalla, Mohamed M; Galal, Shadia A; El-Rashedy, Ahmed A

2015-07-01

A newly synthesized series of anticancer compounds comprising thiazolo[3,2-a]pyrimidine derivatives 6a-q bearing a benzimidazole moiety was produced via a one-pot reaction of N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-2-cyanoacetamide 5 with 2-aminothiazole and an appropriate aromatic aldehyde. Compound 7 was obtained via the reaction of 4-(1H-benzo[d]imidazol-2yl)benzenamide 1 with carbon disulphide and methyl iodide in the presence of concentrated aqueous solution of NaOH, then treated with o-phenylenediamine to give N-(4-1H-benzo[d]imidazol-2-yl)phenyl)-1H-benzo[d]imidazol-2-amine 8. The structures of the newly synthesized compounds were confirmed by analytical and spectroscopic measurements (IR, MS, and (1) H NMR). The synthesized products were screened and studied for their in vitro antitumor activity against three human cancer cell lines (namely colorectal cancer cell line HCT116, human liver cancer cell line HepG2, and human ovarian cancer cell line A2780) and their Aurora A kinase and KSP inhibitory activities. All newly synthesized compounds revealed marked results comparable with the standard drug CK0106023. The compounds 6e and 6k of the thiazolopyrimidine derivatives were the most active compounds when tested against the three cell lines in comparison with the standard drug CK0106023, and showed potent dual KSP and Aurora A kinase inhibition. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.

Directory of Open Access Journals (Sweden)

Sachiko Hirai

Full Text Available Up-regulated sirtuin 1 (SIRT1, an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53. Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5. In the KatoIII cell line (TP53-null, DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.

Anti-tumor effects of Egr-IFN gamma gene therapy combined with {sup 125}I-UdR radionuclide therapy

Energy Technology Data Exchange (ETDEWEB)

Jingguo, Zhao [No.403 Hospital of PLA, Dalian (China); Yanjun, Ni; Xiangfu, Song; Yanyi, Li; Wei, Yang; Ting, Sun; Qingjie, Ma; Fengtong, Gao

2008-12-15

Objective: To explore the anti-tumor effects of Egr-IFNgamma gene therapy combined with {sup 125}I-UdR radionuclide therapy in mice bearing H22 hepatocarcinoma and its mechanism. Methods: The recombinant plasmid pcDNAEgr-IFNgamma mixed with liposome was injected into tumor. 48 h later, 370 kBq {sup 125}I-UdR was injected into tumor. The tumor growth rates at different times were observed. After 3 d gene-radionuclide therapy, the concentration of IFNgamma in cytoplasm of H22 cells and cytotoxic activities of splenic CTL of the mice in different groups were examined. Results: The tumor growth rates of pcDNAEgr-IFNgamma + {sup 125}I-UdR group were obviously lower than those of control group, {sup 125}I-UdR group and pcDNAEgr-1 + {sup 125}I-UdR group 6-15 d after gene-radionuclide therapy. IFNgamma protein was found in cytoplasm of H22 cells in pcDNAEgr-IFNgamma + {sup 125}I-UdR group after 3 d gene-radionuclide therapy. Cytotoxic activity of splenic CTL in pcDNAEgr-IFNgamma + {sup 125}I-UdR group was significantly higher than that in the other groups (P<0.01). Conclusions: The anti-tumor effects in vivo of pcDNAEgr-IFNgamma gene therapy combined with {sup 125}I-UdR radionuclide therapy are better than those of {sup 125}I-UdR therapy. (authors)

Immunomodulatory and antitumor effects in vivo by the cytoplasmic fraction of Lactobacillus casei and Bifidobacterium longum.

Science.gov (United States)

Lee, Jung-Woo; Shin, Jung-Gul; Kim, Eun Hee; Kang, Hae Eun; Yim, In Been; Kim, Ji Yeon; Joo, Hong-Gu; Woo, Hee Jong

2004-03-01

The immunomodulatory and antitumor effects of lactic acid bacteria (LABs) were investigated. Cytoplasmic fraction of Lactobacillus acidophilus, Lactobacillus casei and Bifidobacterium longum were tested for the antiproliferative activity in vitro to SNUC2A, SNU1, NIH/3T3 and Jurkat cell lines by crystal violet assay. All cytoplasmic fraction suppressed proliferation of tumor cells, though L. casei and B. longum were more effective. From these results, cytoplasmic fraction of L. casei and B. longum with Y400 as a control were administered as dietary supplements to Balb/c mice for 2, and 4 consecutive wks. Administration for 4 wks enhanced the number of total T cells, NK cells and MHC class II+ cells, and CD4-CD8+ T cells in flow cytometry analysis. To determine of antitumor activity of LABs preparation in vivo, F9 teratocarcinoma cells were inoculated on mice at 14th day. Body weight was decreased with increased survival rate in all groups with the cytoplasm of LABs. Our results showed that cytoplasmic fraction of LABs had direct antiproliferative effects on tumor cell lines in vitro, effects on immune cells in vivo, and antitumor effects on tumor-bearing mice with prolonged survival periods.

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

Directory of Open Access Journals (Sweden)

Xi-Shi Tai

2015-11-01

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

Potential Antitumor Effects of Pomegranates and Its Ingredients.

Science.gov (United States)

Rahmani, Arshad H; Alsahli, Mohammed A; Almatroodi, Saleh A

2017-01-01

The treatment based on plant or plant derivatives is a promising strategy in the killing of cancers cells. Moreover, wide-ranging finding has established that medicinal plant and its ingredient modulate several cells signaling pathways or inhibiting the carcinogenesis process. In this vista, pomegranates fruits, seeds and peels illustrate cancer preventive role seems to be due to rich source of antioxidant and other valuable ingredients. Furthermore, anti-tumour activities of pomegranates have been evidences through the modulation of cell signaling pathways including transcription factor, apoptosis and angiogenesis. In this review article, anti-tumor activity of pomegranates and its components or its different type of extracts are described to understand the mechanism of action of pomegranates in cancer therapy.

Development of CAR T cells designed to improve antitumor efficacy and safety

OpenAIRE

Jaspers, Janneke E.; Brentjens, Renier J.

2017-01-01

Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are ‘on-target, off-tumor’ toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how ...

Anti-tumor effect of polysaccharides from rhizome of Curculigo ...

African Journals Online (AJOL)

The anti-tumor effect of PDC on cervical cancer was investigated in vivo in mice injected with Hela cells. The parameters measured were tumor volume and weight. In vitro anti-tumor effects of PDC were assessed by measuring expressions of caspase-3, caspase-9 and P53 proteins in Hela cells via ELISA assay. Thymus ...

Antitumor activity of ginseng sapogenins, 25-OH-PPD and 25-OCH3-PPD, on gastric cancer cells.

Science.gov (United States)

Zhao, Chen; Su, Guangyue; Wang, Xude; Zhang, Xiaoshu; Guo, Shuang; Zhao, Yuqing

2016-01-01

25-Hydroxyprotopanaxadiol (25-OH-PPD) and 25-methoxylprotopanaxadiol (25-OCH3-PPD), two ginseng sapogenins, have potent antitumor activity and their effects on gastric cancer (BGC-823, SGC-7901, MKN-28) cells and a gastric mucosa (GES-1) cell line are reported. Both compounds significantly inhibited the growth of gastric cancer cells, while having lesser inhibitory effects on GES-1 cells by MTT assay. A mechanistic study revealed that the two ginseng sapogenins could induce apoptosis in BGC-823 cells by morphological observation, DNA fragmentation, flow cytometry and western blot analysis. Besides, the apoptosis was inhibited by Ac-DEVD-CHO, a caspase 3 inhibitor, which was confirmed by cell viability analysis. These results indicate that 25-OH-PPD and 25-OCH3-PPD have potential to be promising agents for the treatment of gastric cancer.

A new compound of thiophenylated pyridazinone IMB5043 showing potent antitumor efficacy through ATM-Chk2 pathway.

Directory of Open Access Journals (Sweden)

Jianhua Gong

Full Text Available Through cell-based screening models, we have identified a new compound IMB5043, a thiophenylated pyridazinone, which exerted cytotoxicity against cancer cells. In the present study, we evaluated its antitumor efficacy and the possible mechanism. By MTT assay, IMB5043 inhibited the proliferation of various human cancer cells lines, especially hepatocarcinoma SMMC-7721 cells. IMB5043 blocked cell cycle with G2/M arrest, induced cell apoptosis, and inhibited the migration and invasion of SMMC-7721 cells. As verified by comet assay and γ-H2AX foci formation, IMB5043 caused DNA damage and activated ATM, Chk2 and p53 through phosphorylation. As shown by Gene microarray analysis, the differentially expressed genes in SMMC-7721 cells treated with IMB5043 were highly related to cell death and apoptosis. IMB5043 suppressed the growth of hepatocarcinoma SMMC-7721 xenograft in athymic mice. By histopathological examination, no lesions were found in bone marrow and various organs of the treated mice. Our findings reveal that IMB5043 as an active compound consisting of both pyridazinone and thiophene moieties exerts antitumor efficacy through activation of ATM-Chk2 pathway. IMB5043 may serve as a promising leading compound for the development of antitumor drugs.

Melittin exerts an antitumor effect on non‑small cell lung cancer cells.

Science.gov (United States)

Zhang, Su-Fang; Chen, Zhe

2017-09-01

Lung cancer accounts for a significant percentage of all cancer‑associated mortalities in men and women, with non‑small cell lung cancer being the most frequently occurring type of lung cancer. Melittin is the principal active component of apitoxin (bee venom) that has been reported to exert anti‑chronic inflammatory and anti‑cancer effects. In the present study, the antitumor effect of melittin was evaluated using in vivo and in vitro analyses. The results demonstrated that melittin significantly inhibited the epidermal growth factor‑induced invasion and migration of non‑small cell lung cancer cells. Subcutaneous injection of melittin at doses of 1 and 10 mg/kg significantly suppressed non‑small cell lung cancer tumor growth by 27 and 61%, respectively. In addition, melittin significantly inhibited the secretion of vascular endothelial growth factor (VEGF) in non‑small cell lung cancer cells. Furthermore, melittin decreased the protein expression of VEGF and hypoxia‑inducible factor 1‑α. Therefore, the antitumor activity of melittin may be associated with the anti‑angiogenic actions of inhibiting the VEGF and hypoxia‑inducible factor signaling pathways.

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

Science.gov (United States)

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

2011-01-01

Wnt/β-catenin pathway activation caused by APC mutations occurs in approximately 80% of sporadic colorectal cancers. The anti-helminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined if niclosamide could inhibit the Wnt/ β-catenin pathway in human colorectal cancers and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/ β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling and exerted anti-proliferative effects in human colon cancer cell lines and colorectal cancer cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar anti-proliferative effects in these colorectal cancer model systems. In mice implanted with human colorectal cancer xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity and led to tumor control. Our findings support clinical explorations to reposition niclosamide for treatment of colorectal cancer. PMID:21531761

Evaluation of the antitumor activity of platinum nanoparticles in the treatment of hepatocellular carcinoma induced in rats.

Science.gov (United States)

Medhat, Amina; Mansour, Somaya; El-Sonbaty, Sawsan; Kandil, Eman; Mahmoud, Mustafa

2017-07-01

This study aimed to evaluate the antitumor activity of platinum nanoparticles compared with cis-platin both in vitro and in vivo in the treatment of hepatocellular carcinoma induced in rats. The treatment efficacy of platinum nanoparticles was evaluated by measuring antioxidant activities against oxidative stress caused by diethylnitrosamine in liver tissue. The measurements included reduced glutathione content and superoxide dismutase activity, as well as malondialdehyde level. Liver function tests were also determined, in addition to the evaluation of serum alpha-fetoprotein, caspase-3, and cytochrome c in liver tissue. Total RNA extraction from liver tissue samples was also done for the relative quantification of B-cell lymphoma 2, matrix metallopeptidase 9, and tumor protein p53 genes. Histopathological examination was also performed for liver tissue. Results showed that platinum nanoparticles are more potent than cis-platin in treatment of hepatocellular carcinoma induced by diethylnitrosamine in rats as it ameliorated the investigated parameters toward normal control animals. These findings were well appreciated with histopathological studies of diethylnitrosamine group treated with platinum nanoparticles, suggesting that platinum nanoparticles can serve as a good therapeutic agent for the treatment of hepatocellular carcinoma which should attract further studies.

Activation of professional antigen presenting cells by acharan sulfate isolated from giant African snail, Achatina fulica.

Science.gov (United States)

Kim, Hyun-Sun; Lee, Young-Hee; Lee, Young-Ran; Im, Sun-A; Lee, Jae-Kwon; Kim, Yeong Shik; Sim, Joon-Soo; Choi, Hyung Seok; Lee, Chong-Kil

2007-07-01

Acharan sulfate isolated from the giant African snail, Achatina fulica, has been reported to have antitumor activity in vivo. In an effort to determine the mechanisms of its antitumor activity, we examined the effects of acharan sulfate on professional antigen presenting cells (APCs). Acharan sulfate increased the phagocytic activity, the production of cytokines such as TNF-alpha and IL-1beta, and the release of nitric oxide on a macrophage cell line, Raw 264.7 cells. In addition, acharan sulfate induced phenotypic and functional maturation of immature dendritic cells (DCs). Immature DCs cultured with acharan sulfate expressed higher levels of class II MHC molecules and major co-stimulatory molecules such as B7-1, B7-2, and CD40. Functional maturation of immature DCs cultured in the presence of acharan sulfate was confirmed by the increased allostimulatory capacity and IL-12 production. These results suggest that the antitumor activity of acharan sulfate is partly due to the activation of professional antigen presenting cells.

Apigenin potentiates the antitumor activity of 5-FU on solid Ehrlich carcinoma: Crosstalk between apoptotic and JNK-mediated autophagic cell death platforms

Energy Technology Data Exchange (ETDEWEB)

Gaballah, Hanaa H., E-mail: hanaahibishy@hotmail.com [Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Tanta University, Tanta, 3111 (Egypt); Gaber, Rasha A. [Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Tanta University, Tanta, 3111 (Egypt); Mohamed, Darin A. [Histopathology Department, Faculty of Medicine, Tanta University, Tanta, 3111 (Egypt)

2017-02-01

Background: Although 5- Fluorouracil (5-FU) has exhibited effectiveness against cancer, novel therapeutic strategies are needed to enhance its antitumor efficiency and modulate its cytotoxity. Apigenin, a flavonoid present in fruits and vegetables, is a potent dietary phytochemical effective in cancer chemoprevention. Aim: This study was undertaken to investigate the potential synergistic antitumor activity of apigenin and 5-FU on Solid Ehrlich carcinoma (SEC). Methods: Eighty Swiss albino male mice were divided into four equal groups: vehicle treated control SEC, SEC + 5-FU, SEC + apigenin, SEC + 5-FU + apigenin. Beclin-1 and caspases 3, 9 and JNK activities were estimated by ELISA; mRNA expression levels of the antiapoptotic gene Mcl-1 were estimated using quantitative real-time RT-PCR, while tissue malondialdehyde (MDA), glutathione peroxidase and total antioxidant capacity were evaluated spectrophotometrically. A part of the tumor was examined for histopathological and Ki-67 immunohistochemistry analysis. Results: 5-FU and/or apigenin caused significant increase in tissue levels of Beclin-1, caspases 3, 9 and JNK activities, MDA with significant decrease in tumor volume, Mcl-1expression, tissue glutathione peroxidase and total antioxidant capacity and alleviated the histopathological changes with significant decrease of Ki-67 proliferation index compared to vehicle treated SEC control group. In conclusion: The combination of 5-FU and apigenin had a greater effect than each of 5-FU or apigenin alone against solid Ehrlich carcinoma in mice. - Highlights: • Apigenin potentiated 5-FU cytotoxicity in EAC solid tumor models in vivo. • It acted via autophagy stimulation, downregulating MCL-1 and Ki-67 expression. • It caused JNK activation and ROS accumulation; resulted in tumor growth inhibition. • Apigenin can be used as a co-adjuvant agent in cancer therapy.

Synthesis and antitumor activity evaluation of a novel combi-nitrosourea prodrug: Designed to release a DNA cross-linking agent and an inhibitor of O(6)-alkylguanine-DNA alkyltransferase.

Science.gov (United States)

Sun, Guohui; Zhang, Na; Zhao, Lijiao; Fan, Tengjiao; Zhang, Shufen; Zhong, Rugang

2016-05-01

The drug resistance of CENUs induced by O(6)-alkylguanine-DNA alkyltransferase (AGT), which repairs the O(6)-alkylated guanine and subsequently inhibits the formation of dG-dC cross-links, hinders the application of CENU chemotherapies. Therefore, the discovery of CENU analogs with AGT inhibiting activity is a promising approach leading to novel CENU chemotherapies with high therapeutic index. In this study, a new combi-nitrosourea prodrug 3-(3-(((2-amino-9H-purin-6-yl)oxy)methyl)benzyl)-1-(2-chloroethyl)-1-nitrosourea (6), designed to release a DNA cross-linking agent and an inhibitor of AGT, was synthesized and evaluated for its antitumor activity and ability to induce DNA interstrand cross-links (ICLs). The results indicated that 6 exhibited higher cytotoxicity against mer(+) glioma cells compared with ACNU, BCNU, and their respective combinations with O(6)-benzylguanine (O(6)-BG). Quantifications of dG-dC cross-links induced by 6 were performed using HPLC-ESI-MS/MS. Higher levels of dG-dC cross-link were observed in 6-treated human glioma SF763 cells (mer(+)), whereas lower levels of dG-dC cross-link were observed in 6-treated calf thymus DNA, when compared with the groups treated with BCNU and ACNU. The results suggested that the superiority of 6 might result from the AGT inhibitory moiety, which specifically functions in cells with AGT activity. Molecular docking studies indicated that five hydrogen bonds were formed between the O(6)-BG analogs released from 6 and the five residues in the active pocket of AGT, which provided a reasonable explanation for the higher AGT-inhibitory activity of 6 than O(6)-BG. Copyright © 2016 Elsevier Ltd. All rights reserved.

Docetaxel-loaded single-wall carbon nanohorns using anti-VEGF antibody as a targeting agent: characterization, in vitro and in vivo antitumor activity

Energy Technology Data Exchange (ETDEWEB)

Zhao, Qian; Li, Nannan; Shu, Chang; Li, Ruixin; Ma, Xiaona; Li, Xuequan; Wang, Ran; Zhong, Wenying, E-mail: wyzhong@cpu.edu.cn [China Pharmaceutical University, Department of Analytical Chemistry (China)

2015-05-15

A novel antitumor drug delivery system, docetaxel (DTX)-loaded oxidized single-wall carbon nanohorns (oxSWNHs) with anti-VEGF monoclonal antibody (mAb) as a target agent was constructed. DTX was absorbed onto the oxSWNHs via the physical adsorption or π–π interaction. DSPE–PEG–COOH was non-covalently wrapped to the hydrophobic surface of oxSWNHs to improve its water solubility and biocompatibility. The mAb was bonded to the PEG through amide bond. The DTX@oxSWNHs-PEG-mAb (DDS) exhibited suitable particle size (191.2 ± 2.1 nm), good particle size distribution (PDI: 0.196), and negative zeta potential (−24.3 ± 0.85 mV). These features enhanced permeability and retention (EPR) effect and reduced the drug molecule uptake by the reticuloendothelial system. The in vitro drug release followed non-Fickian diffusion (n = 0.6857, R = 0.9924) with the cumulative release of DTX 59 ± 1.35 % at 72 h. Compared with free DTX, the DDS enhanced the cytotoxicity in MCF-7 cell lines in vitro efficiently (IC{sub 50}: 2.96 ± 0.6 μg/ml), and provided higher antitumor efficacy (TGI: 69.88 %) in vivo. The histological analysis indicated that the DDS had no significant side effect. Therefore, the new DDS is promising to attain higher pharmaceutical efficacy and lower side effects than free DTX for cancer therapy. The research demonstrated that DTX@oxSWNHs-PEG-mAb might have promising biomedical applications for future cancer therapy.

Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody.

Science.gov (United States)

Fallon, Jonathan K; Vandeveer, Amanda J; Schlom, Jeffrey; Greiner, John W

2017-03-28

The combined therapeutic potential of an immunocytokine designed to deliver IL-12 to the necrotic regions of solid tumors with an anti-PD-L1 antibody that disrupts the immunosuppressive PD-1/PD-L1 axis yielded a combinatorial benefit in multiple murine tumor models. The murine version of the immunocytokine, NHS-muIL12, consists of an antibody (NHS76) recognizing DNA/DNA-histone complexes, fused with two molecules of murine IL-12 (NHS-muIL12). By its recognition of exposed DNA, NHS-muIL12 targets IL-12 to the necrotic portions of tumors; it has a longer plasma half-life and better antitumor efficacy against murine tumors than recombinant murine IL-12. It is shown here that NHS-muIL12, in an IFN-γ‒dependent mechanism, upregulates mPD-L1 expression on mouse tumors, which could be construed as an immunosuppressive action. Yet concurrent therapy with NHS-muIL12 and an anti-PD-L1 antibody resulted in additive/synergistic antitumor effects in PD-L1‒expressing subcutaneously transplanted tumors (MC38, MB49) and in an intravesical bladder tumor model (MB49). Antitumor efficacy correlated with (a) with a higher frequency of tumor antigen-specific splenic CD8+ T cells and (b) enhanced T cell activation over a wide range of NHS-muIL12 concentrations. These findings suggest that combining NHS-muIL12 and an anti-PD-L1 antibody enhances T cell activation and T cell effector functions within the tumor microenvironment, significantly improving overall tumor regression. These results should provide the rationale to examine the combination of these agents in clinical studies.

Increasing antitumor effects of chemoradiotherapy by drug efflux inhibition with encapsulated anti-RLIP-76

International Nuclear Information System (INIS)

Harada, Satoshi; Ehara, Shigeru; Ishii, Keizo

2011-01-01

Microencapsulated anti-RLIP76 was tested in vivo using C3He/J mice to determine the increasing of antitumor effects by chemotherapeutic agent efflux inhibition during chemoradiotherapy. Microcapsules were produced by spraying a mixture of 3.0% hyaluronic acid, 2.0% alginate, 3.0% H 2 O 2 , and 0.3 mmol carboplatin onto a mixture of 0.3 mol FeCl 2 and 0.15 mol CaCl 2 . Microcapsules were subcutaneously injected into MM46 tumors previously inoculated into the left hind legs of C3He/J mice. Subsequent radiotherapy consisted of tumor irradiation with 10 Gy or 20 Gy 60 Co. The antitumor effects of microcapsules were tested by measuring tumor size and monitoring tumor growth. Three types of adverse effects were considered: fuzzy hair, loss of body weight, and mortality. Carboplatin levels were monitored using particle-induced X-ray emission (PIXE) and a micro-PIXE camera. Anti-RLIP76 inhibited the efflux of carboplatin from tumor tissue, which led to an increase in the concentration of carboplatin. Higher carboplatin concentration significantly increased the combined antitumor effect of radiation and chemotherapy. A significant decrease in adverse effects was also observed with microencapsulated anti-RLIP76. (author)

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

Science.gov (United States)

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

2013-09-01

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

Stimulation of granulocytic cell iodination by pine cone antitumor substances

International Nuclear Information System (INIS)

Unten, S.; Sakagami, H.; Konno, K.

1989-01-01

Antitumor substances (Fractions VI and VII) prepared from the NaOH extract of pine cone significantly stimulated the iodination (incorporation of radioactive iodine into an acid-insoluble fraction) of human peripheral blood adherent mononuclear cells, polymorphonuclear cells (PMN), and human promyelocytic leukemic HL-60 cells. In contrast, these fractions did not significantly increase the iodination of nonadherent mononuclear cells, red blood cells, other human leukemic cell lines (U-937, THP-1, K-562), human diploid fibroblast (UT20Lu), or mouse cell lines (L-929, J774.1). Iodination of HL-60 cells, which were induced to differentiate by treatment with either retinoic acid or tumor necrosis factor, were stimulated less than untreated cells. The stimulation of iodination of both PMN and HL-60 cells required the continuous presence of these fractions and was almost completely abolished by the presence of myeloperoxidase inhibitors. The stimulation activity of these fractions was generally higher than that of various other immunopotentiators. Possible mechanisms of extract stimulation of myeloperoxidase-containing cell iodination are discussed

An Eco-Friendly Ultrasound-Assisted Synthesis of Novel Fluorinated Pyridinium Salts-Based Hydrazones and Antimicrobial and Antitumor Screening

Science.gov (United States)

Rezki, Nadjet; Al-Sodies, Salsabeel A.; Aouad, Mohamed R.; Bardaweel, Sanaa; Messali, Mouslim; El Ashry, El Sayed H.

2016-01-01

The present work reports an efficient synthesis of fluorinated pyridinium salts-based hydrazones under both conventional and eco-friendly ultrasound procedures. The synthetic approach first involves the preparation of halogenated pyridinium salts through the condensation of isonicotinic acid hydrazide (1) with p-fluorobenzaldehyde (2) followed by the nucleophilic alkylation of the resulting N-(4-fluorobenzylidene)isonicotinohydrazide (3) with a different alkyl iodide. The iodide counteranion of 5–10 was subjected to an anion exchange metathesis reaction in the presence of an excess of the appropriate metal salts to afford a new series of fluorinated pyridinium salts tethering a hydrazone linkage 11–40. Ultrasound irradiation led to higher yields in considerably less time than the conventional methods. The newly synthesized ILs were well-characterized with FT-IR, 1H NMR, 13C NMR, 11B, 19F, 31P and mass spectral analyses. The ILs were also screened for their antimicrobial and antitumor activities. Within the series, the salts tethering fluorinated counter anions 11–13, 21–23, 31–33 and 36–38 were found to be more potent against all bacterial and fungal strains at MIC 4–8 µg/mL. The in vitro antiproliferative activity was also investigated against four tumor cell lines (human ductal breast epithelial tumor T47D, human breast adenocarcinoma MCF-7, human epithelial carcinoma HeLa and human epithelial colorectal adenocarcinoma Caco-2) using the MTT assay, which revealed that promising antitumor activity was exhibited by compounds 5, 12 and 14. PMID:27213367

Reprogramming antitumor immunity against chemoresistant ovarian cancer by a CXCR4 antagonist-armed viral oncotherapy

Directory of Open Access Journals (Sweden)

Marcin P Komorowski

2016-01-01

Full Text Available Ovarian cancer remains the most lethal gynecologic malignancy owing to late detection, intrinsic and acquired chemoresistance, and remarkable heterogeneity. Here, we explored approaches to inhibit metastatic growth of murine and human ovarian tumor variants resistant to paclitaxel and carboplatin by oncolytic vaccinia virus expressing a CXCR4 antagonist to target the CXCL12 chemokine/CXCR4 receptor signaling axis alone or in combination with doxorubicin. The resistant variants exhibited augmented expression of the hyaluronan receptor CD44 and CXCR4 along with elevated Akt and ERK1/2 activation and displayed an increased susceptibility to viral infection compared with the parental counterparts. The infected cultures were more sensitive to doxorubicin-mediated killing both in vitro and in tumor-challenged mice. Mechanistically, the combination treatment increased apoptosis and phagocytosis of tumor material by dendritic cells associated with induction of antitumor immunity. Targeting syngeneic tumors with this regimen increased intratumoral infiltration of antitumor CD8+ T cells. This was further enhanced by reducing the immunosuppressive network by the virally-delivered CXCR4 antagonist, which augmented antitumor immune responses and led to tumor-free survival. Our results define novel strategies for treatment of drug-resistant ovarian cancer that increase immunogenic cell death and reverse the immunosuppressive tumor microenvironment, culminating in antitumor immune responses that control metastatic tumor growth.

Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity.

Science.gov (United States)

Schettini, Jorge; Kidiyoor, Amritha; Besmer, Dahlia M; Tinder, Teresa L; Roy, Lopamudra Das; Lustgarten, Joseph; Gendler, Sandra J; Mukherjee, Pinku

2012-11-01

Monoclonal antibodies (mAbs) against tumor-associated antigens are useful anticancer agents. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG-2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo.

Anti-tumor effects of an engineered “killer” transfer RNA

International Nuclear Information System (INIS)

Zhou, Dong-hui; Lee, Jiyoung; Frankenberger, Casey; Geslain, Renaud; Rosner, Marsha; Pan, Tao

2012-01-01

Highlights: ► tRNA with anti-cancer effects. ► tRNA induced protein misfolding. ► tRNA as anti-tumor agent. -- Abstract: A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA Ser (AAU) is an engineered human tRNA Ser with an anticodon coding for isoleucine. Here we test the possibility that tRNA Ser (AAU) can be an effective killing agent of breast cancer cells and can effectively inhibit tumor-formation in mice. We found that tRNA Ser (AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA Ser (AAU) in both tumorigenic and non-tumorigenic cells. tRNA Ser (AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA Ser (AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA Ser (AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA Ser (AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.

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

Directory of Open Access Journals (Sweden)

Aisha Ashraf

2015-03-01

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

Flavonoids Isolated From the Flowers of Limonium bicolor and their In vitro Antitumor Evaluation.

Science.gov (United States)

Chen, Jian; Teng, Jiehui; Ma, Li; Tong, Haiying; Ren, Bingru; Wang, Linshan; Li, Weilin

2017-01-01

Limonium bicolor , a halophytic species, can grow in saline or saline-alkali soil, is well known as a traditional Chinese medicine. Recently it attracted much attention for its treatment for cancer. The present study was performed to evaluate this species from the phytochemical standpoint and the possible relationship between the antitumor activity and its natural products. The chemical constituents from the flowers of L. bicolor were investigated through bioassay-guided fractionation and isolation. All the individual compounds were characterized by spectroscopic analysis and their potential antitumor activity was tested against three different human tumor cell lines by MTT assays. The EtOAc extract was proven as the most potent fraction and further fractionation led to the isolation of 15 natural flavonoids, which were characterized as luteolin (1), acacetin (2), quercetin (3), isorhamnetin (4), kaempferol (5), eriodictyol (6), kaempferol-3-O-α-L-rhamnoside (7), kaempferol-3-O-β-D-glucoside (8), quercetin-3-O-α-L-rhamnoside (9), quercetin-3-O-β-D-glucoside (10), quercetin-3-O-β-D-galactoside (11), myricetin-3-O-α-L-rhamnoside (12), kaempferol-3-O-(6″-O-galloyl)-β-D-glucoside (13), hesperidin (14) and rutin (15). The biotesting results demonstrated that both compounds 1 and 3 showed good cytotoxicity against human colon cancer cells (LOVO). Compound 5 exhibited relative greater growth inhibition against both human breast cancer cells (MCF-7) and osteosarcoma cell lines (U2-OS) at the concentration of 100 μg/mL. On the basis of these findings, the flavonoids were deduced to be potentially responsible for the antitumor activity of L. bicolor . The preliminary structure-activity relationship analysis suggests that the 3-O-glycosylation moiety in natural flavonoids was not essential for the antiproliferative activity on LOVO and U2-OS cells. The phytochemical investigation of Limonium bicolor led to the isolation of 15 flavonoids.The biotesting of the

Novel histone deacetylase inhibitor AR-42 exhibits antitumor activity in pancreatic cancer cells by affecting multiple biochemical pathways.

Directory of Open Access Journals (Sweden)

Yi-Jin Chen

Full Text Available Pancreatic cancer is one of the most lethal types of cancer with a 5-year survival rate of ~5%. Histone deacetylases (HDACs participate in many cellular processes, including carcinogenesis, and pharmacological inhibition of HDACs has emerged as a potential therapeutic strategy. In this study, we explored antitumor activity of the novel HDAC inhibitor AR-42 in pancreatic cancer.Human pancreatic cancer cell lines BxPC-3 and PANC-1 were used in this study. Real-time PCR, RT-PCR, and western blotting were employed to investigate expression of specific genes and proteins, respectively. Translocation of apoptosis-inducing factor was investigated by immunofluorescence and subcellular fractionation. The number of apoptotic cells, cell cycle stages, and reactive oxygen species (ROS generation levels were determined by flow cytometry. Cell invasiveness was examined by the Matrigel invasion assay. Efficacy of AR-42 in vivo was evaluated by utilizing BxPC-3 xenograft mouse model.AR-42 inhibited pancreatic cancer cell proliferation by causing G2/M cell cycle arrest via regulating expression levels of genes and proteins involved in cell cycle. AR-42 also induced ROS generation and DNA damage, triggering apoptosis of pancreatic cancer cells via both caspase-3-dependent and caspase-3-independent pathways. In addition, AR-42 increased expression levels of negative regulators of p53 (miR-125b, miR-30d, and miR33, which could contribute to lower expression level of mutant p53 in pancreatic cancer cells. Cell invasion assay showed that AR-42 reduced cancer cell aggressiveness and significantly diminished BxPC-3 xenograft tumor growth in vivo.AR-42, a novel HDAC inhibitor, inhibited pancreatic cancer cells by regulating p53 expression, inducing cell cycle arrest, particularly at the G2/M stage, and activating multiple apoptosis pathways. Additionally, AR-42 inhibited cell invasiveness and potently suppressed pancreatic cancer tumors in vivo. We conclude that by

In vitro and in vivo antitumor effects of 50 to 100-KDa components from B16 melanoma culture supernatant.

Science.gov (United States)

Qin, Ying-Song; Zhang, X U; Zhang, Xiang-Yu

2015-07-01

The development of immunological therapies for melanoma has been of considerable concern in recent years. Whole tumor cell lysates have been used to develop antitumor vaccines, but the effective components of the lysates have not been identified. In the present study, protein elements were purified from the B16 supernatant to analyze the in vitro chemotaxis towards mouse spleen lymphocytes using a Boyden chamber. Prior to establishing a B16 melanoma model, C57BL/6 mice were vaccinated with these proteins, and melanoma growth, tumor appearance time and behavioral changes were observed. Next, the cytotoxicity and subsets of the tumor infiltrating lymphocytes, and the histological characteristics of the melanoma were analyzed. The isolated purified fragments of B16 melanoma culture supernatant had strong antitumor effects. The possible antitumor mechanism was delineated, and was identified to possibly be through the activation of cluster of differentiation 8-positive T cells and the promotion of B16 cell differentiation. These methods will provide a novel insight into understanding antitumor immunological mechanisms and provide a potential avenue for immunotherapy.

T lymphocytes derived from human cord blood provide effective antitumor immunotherapy against a human tumor

Directory of Open Access Journals (Sweden)

Kim Tae-Sik

2011-06-01

Full Text Available Abstract Background Although the graft-versus-tumor (GVT effect of donor-derived T cells after allogeneic hematopoietic stem cell transplantation has been used as an effective adoptive immunotherapy, the antitumor effects of cord blood (CB transplantation have not been well studied. Methods We established the animal model by transplantation of CB mononuclear cells and/or tumor cells into NOD/SCID mice. The presence of CB derived T cells in NOD/SCID mice or tumor tissues were determined by flow cytometric and immunohistochemical analysis. The anti-tumor effects of CB derived T cells against tumor was determined by tumor size and weight, and by the cytotoxicity assay and ELISPOT assay of T cells. Results We found dramatic tumor remission following transfer of CB mononuclear cells into NOD/SCID mice with human cervical tumors with a high infiltration of CD3+ T cells in tumors. NOD/SCID mice that receive neonatal CB transplants have reconstituted T cells with significant antitumor effects against human cervical and lung tumors, with a high infiltration of CD3+ T cells showing dramatic induction of apoptotic cell death. We also confirmed that T cells showed tumor specific antigen cytotoxicity in vitro. In adoptive transfer of CD3+ T cells into mice with pre-established tumors, we observed much higher antitumor effects of HPV-specific T cells by ELISPOT assays. Conclusions Our results show that CB derived T lymphocytes will be useful for novel immunotherapeutic candidate cells for therapy of several tumors in clinic.

Investigation of HIFU-induced anti-tumor immunity in a murine tumor model

Directory of Open Access Journals (Sweden)

Lyerly H Kim

2007-07-01

Full Text Available Abstract Background High intensity focused ultrasound (HIFU is an emerging non-invasive treatment modality for localized treatment of cancers. While current clinical strategies employ HIFU exclusively for thermal ablation of the target sites, biological responses associated with both thermal and mechanical damage from focused ultrasound have not been thoroughly investigated. In particular, endogenous danger signals from HIFU-damaged tumor cells may trigger the activation of dendritic cells. This response may play a critical role in a HIFU-elicited anti-tumor immune response which can be harnessed for more effective treatment. Methods Mice bearing MC-38 colon adenocarcinoma tumors were treated with thermal and mechanical HIFU exposure settings in order to independently observe HIFU-induced effects on the host's immunological response. In vivo dendritic cell activity was assessed along with the host's response to challenge tumor growth. Results Thermal and mechanical HIFU were found to increase CD11c+ cells 3.1-fold and 4-fold, respectively, as compared to 1.5-fold observed for DC injection alone. In addition, thermal and mechanical HIFU increased CFSE+ DC accumulation in draining lymph nodes 5-fold and 10-fold, respectively. Moreover, focused ultrasound treatments not only caused a reduction in the growth of primary tumors, with tumor volume decreasing by 85% for thermal HIFU and 43% for mechanical HIFU, but they also provided protection against subcutaneous tumor re-challenge. Further immunological assays confirmed an enhanced CTL activity and increased tumor-specific IFN-γ-secreting cells in the mice treated by focused ultrasound, with cytotoxicity induced by mechanical HIFU reaching as high as 27% at a 10:1 effector:target ratio. Conclusion These studies present initial encouraging results confirming that focused ultrasound treatment can elicit a systemic anti-tumor immune response, and they suggest that this immunity is closely related to

Two photon microscopy intravital study of DC-mediated anti-tumor response of NK cells

Science.gov (United States)

Caccia, Michele; Gorletta, Tatiana; Sironi, Laura; Zanoni, Ivan; Salvetti, Cristina; Collini, Maddalena; Granucci, Francesca; Chirico, Giuseppe

2010-02-01

Recent studies have demonstrated that dendritic cells (DCs) play a crucial role in the activation of Natural Killer cells (NKs) that are responsible for anti-tumor innate immune responses. The focus of this report is on the role of pathogen associated molecular pattern (PAMP) activated-DCs in inducing NK cell-mediated anti-tumor responses. Mice transplanted sub-cute (s.c.) with AK7 cells, a mesothelioma cell line sensitive to NK cell responses, are injected with fluorescent NK cells and DC activation is then induced by s.c. injection of Lipopolysaccharide (LPS). Using 4 dimensional tracking we follow the kinetic behavior of NK cells at the Draining Lymph-Node (DLN). As control, noninflammatory conditions are also evaluated. Our data suggest that NK cells are recruited to the DLN where they can interact with activated-DCs with a peculiar kinetic behavior: short lived interactions interleaved by rarer longer ones. We also found that the changes in the NK dynamic behavior in inflammatory conditions clearly affect relevant motility parameters such as the instantaneous and average velocity and the effective diffusion coefficient. This observation suggests that NK cells and activated-DCs might efficiently interact in the DLN, where cells could be activated. Therefore the interaction between activated-DCs and NK cells in DLN is not only a reality but it may be also crucial for the start of the immune response of the NKs.

In vitro testing of curcumin based composites coatings as antitumoral systems against osteosarcoma cells

Science.gov (United States)

Tirca, I.; Mitran, V.; Marascu, V.; Brajnicov, S.; Ion, V.; Stokker-Cheregi, F.; Popovici, I. A.; Cimpean, A.; Dinca, V.; Dinescu, M.

2017-12-01

In this work, we propose a new design for biodegradable composite coatings obtained by laser methods, which are aimed at evaluating the effects of active antitumoral elements on osteosarcoma cells. Our approach relies on embedding curcumin, which is a natural polyphenol having antitumoral properties, within biodegradable copolymer coatings (i.e. polyvinyl alcohol-polyethylene glycol - PVA-PEG) by using matrix assisted pulsed laser evaporation (MAPLE). The structural and morphological characteristics of the coatings were tailored by using different solvents (water, ethanol, benzene, dimethylsufoxide) as deposition matrix. The morphological characteristics of the resulting films were investigated by atomic force microscopy (AFM), whereas their chemical composition was characterized by Fourier transform infrared spectroscopy (FTIR). These characteristics were correlated with the degradation behavior by using ellipsometry (SE) and AFM measurements data. The in vitro study of the MG-63 osteosarcoma cell behavior indicates that the developed hybrid coatings significantly decreased osteosarcoma cell viability and proliferation potential. The physico-chemical characteristics of the thin films, along with the preliminary in vitro analyses, suggest that our developed polymeric hybrid coatings represent an efficient way to tackle the design of antitumoral surfaces, with applications in biomedicine.

Characterization and anti-tumor effects of chondroitin sulfate-chitosan nanoparticles delivery system

Science.gov (United States)

Hu, Chieh-Shen; Tang, Sung-Ling; Chiang, Chiao-Hsi; Hosseinkhani, Hossein; Hong, Po-Da; Yeh, Ming-Kung

2014-11-01

We prepared chondroitin sulfate (ChS)-chitosan (CS) nanoparticles (NPs) as a delivery carrier, and doxorubicin (Dox) was used as a model drug. The physicochemical properties and biological activities of the Dox-ChS-CS NPs including the release profile, cell cytotoxicity, cellular internalization, and in vivo anti-tumor effects were evaluated. The ChS-CS NPs and Dox-ChS-CS NPs had a mean size of 262.0 ± 15.0 and 369.4 ± 77.4 nm, and a zeta potential of 30.2 ± 0.9 and 20.6 ± 3.1 mV, respectively. In vitro release tests showed that the 50 % release time for the Dox-ChS-CS NPs was 20 h. Two hepatoma cell models, HepG2 and HuH6, were used for evaluating the cytotoxicity and cell uptake efficiency of the Dox-ChS-CS NPs. A significant difference was observed between doxorubicin solution and the Dox-ChS-CS NPs in the cellular uptake within 60 min ( p < 0.01). For the in vivo human xenograft-nude mouse model, the Dox-ChS-CS NPs were more effective with less body weight loss and anti-tumor growth suppression in comparison with the Dox solution. The prepared Dox-ChS-CS NPs offer a new effective targeting nanoparticle delivery system platform for anti-tumor therapy.

Antitumor properties of (5E,7E) analogs of vitamin D3.

Science.gov (United States)

Filip, B; Milczarek, M; Wietrzyk, J; Chodyński, M; Kutner, A

2010-07-01

Geometric isomers (5E,7E) of major active metabolites of vitamin D3 [1alpha,25(OH)2D3 and (24R)-1,24(OH)2D3] were synthesized by a new convenient procedure. Vitamin D triene system of the metabolites was first derivatized as a Diels-Alder adduct. Removal of the triene protecting group, in a key synthetic step, yielded the title compounds PRI-2208 and PRI-2209, respectively. The analogs were examined for their antiproliferative activity in vitro against human breast cancer cells (MCF-7) and promyelocytic leukemia (HL-60) cells. The activity was compared with one of the parent compounds. Both analogs examined revealed similar or higher antiproliferative activity compared to 1alpha,25(OH)2D3 or to (24R)-1,24(OH)2D3. The studies of calcemic activity in vivo showed that analogs PRI-2208 and PRI-2209 did not influence the serum calcium level in doses, in which 1alpha,25(OH)2D3 or (24R)-1,24(OH)2D3 significantly increased this level. The antitumor activity of these analogs in the LLC mice tumor model was studied. Analog PRI-2208 was found to be more active in inhibiting LLC tumor growth than 1alpha,25(OH)2D3, as well as than PRI-2191 and PRI-2209. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Homeostatic T Cell Expansion to Induce Anti-Tumor Autoimmunity in Breast Cancer

National Research Council Canada - National Science Library

Baccala, Roberto

2007-01-01

... that (a) homeostatic T-cell proliferation consistently elicits anti-tumor responses; (b) irradiation is more effective than Tcell depletion by antibodies in inducing anti-tumor responses mediated by homeostatic T-cell proliferation...

The Whole-Genome Sequence of Bacillus velezensis Strain SB1216 Isolated from the Great Salt Plains of Oklahoma Reveals the Presence of a Novel Extracellular RNase with Antitumor Activity

OpenAIRE

Marasini, Daya; Cornell, Carolyn R.; Oyewole, Opeoluwa; Sheaff, Robert J.; Fakhr, Mohamed K.

2017-01-01

ABSTRACT The whole-genome sequence of Bacillus velezensis strain SB1216, isolated from the Great Salt Plains of Oklahoma, showed the presence of a 3,814,720-bp circular chromosome and no plasmids. The presence of a novel 870-bp extracellular RNase gene is predicted to be responsible for this strain’s antitumor activity.

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

Science.gov (United States)

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

2018-03-28

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

Antitumor function and mechanism of phycoerythrin from Porphyra haitanensis

Directory of Open Access Journals (Sweden)

Qunwen Pan

2013-01-01

Full Text Available The anti-tumor effect of R-Phycoerythrin (R-PE from Porphyra haitanensis was studied using cell line HeLa as an in vitro model and Sarcoma-180 (S180 tumor-bearing mice as an in vivo model. The results showed that the combination treatment of R-PE and photodynamic therapy PDT significantly inhibited the growth of HeLa cells up to 81.5%, with a fair dose-effect relationship, but did not inhibit endothelial cells. The annexin v-fitc/PI fluorescence staining experiments demonstrated that at doses between 0~60µg/mL, apoptosis cells and later stage apoptosis cells or necrosis cells increased significantly as the R-PE dosage increased. DNA electrophoresis showed that after R-PE+PDT treatment of HeLa cells for 24 hours, a light "smear" band between 100~400bp appeared to indicate the degradation of genomic DNA. The QRT-PCR results showed that R-PE+PDT treatment increased caspase-3 and caspase-10 gene expression and decreased the Bcl-2 gene expression level significantly as the R-PE dose increased, implying that R-PE promoted HeLa cell apoptosis. Compared with untreated S180 tumor-bearing mice, R-PE injection significantly inhibited the growth of S180 in tumor-bearing mice up to 41.3% at a dose of 300mg-kg-1. Simultaneously, the significant increase of superoxide dismutase (SOD activity in serum (p < 0.01 and the decrease of the malondialdehyde (MDA level in liver suggests that R-PE improved the anti-oxidant ability of the S180 tumor-bearing mice, which may related to its antitumor effect. In addition, the R-PE caused a significant increase (p < 0.05 in the spleen index and thymus index, and a significant increase (p < 0.01 in lymphocyte proliferation, NK cell kill activity and the TNF-α level in the serum of S180 tumor-bearing mice. These results strongly suggest that the antitumor effect of R-PE from Porphyra haitanensis functioned by increasing the immunity and antioxidant ability of S180 tumor-bearing mice, promoting apoptosis by increasing protease

OFFICIAL MEDICATIONS FOR ANTI-TUMOR GENE THERAPY

Directory of Open Access Journals (Sweden)

E. R. Nemtsova

2016-01-01

Full Text Available This is a review of modern literature data of official medications for anti-tumor gene therapy as well as of medications that finished clinical trials.The article discusses the concept of gene therapy, the statistical analysis results of initiated clinical trials of gene products, the most actively developing directions of anticancer gene therapy, and the characteristics of anti-tumor gene medications.Various delivery systems for gene material are being examined, including viruses that are defective in  replication (Gendicine™ and Advexin and oncolytic (tumor specific conditionally replicating viruses (Oncorine™, ONYX-015, Imlygic®.By now three preparations for intra-tumor injection have been introduced into oncology clinical practice: two of them – Gendicine™ and Oncorine™ have been registered in China, and one of them – Imlygic® has been registered in the USA. Gendicine™ and Oncorine™ are based on the wild type p53 gene and are designed for treatment of patients with head and neck malignancies. Replicating adenovirus is the delivery system in Gendicine™, whereas oncolytic adenovirus is the vector for gene material in Oncorine™. Imlygic® is based on the  recombinant replicating HSV1 virus with an introduced GM–CSF gene and is designed for treatment of  melanoma patients. These medications are well tolerated and do not cause any serious adverse events. Gendicine™ and Oncorine™ are not effective in monotherapy but demonstrate pronounced synergism with chemoand radiation therapy. Imlygic® has just started the post marketing trials.

Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

Directory of Open Access Journals (Sweden)

Lin YL

2015-09-01

Full Text Available Yu-Ling Lin,1,2,* Kai-Fu Chang,3,* Xiao-Fan Huang,3 Che-Lun Hung,4 Shyh-Chang Chen,5 Wan-Ru Chao,6,7 Kuang-Wen Liao,1,8 Nu-Man Tsai3,9 1College of Biological Science and Technology, 2Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, 3School of Medical Laboratory and Biotechnology, Chung Shan Medical University, 4Department of Computer Science and Communication Engineering, Providence University, 5Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, 6Institute of Medicine, Chung Shan Medical University, 7Department of Pathology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, 8Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, 9Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan *These authors contributed equally to this work Background: The natural compound n-butylidenephthalide (BP can pass through the blood–brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.Objective: The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery.Methods: To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC. Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.Results: When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than

The Whole-Genome Sequence of Bacillus velezensis Strain SB1216 Isolated from the Great Salt Plains of Oklahoma Reveals the Presence of a Novel Extracellular RNase with Antitumor Activity.

Science.gov (United States)

Marasini, Daya; Cornell, Carolyn R; Oyewole, Opeoluwa; Sheaff, Robert J; Fakhr, Mohamed K

2017-11-22

The whole-genome sequence of Bacillus velezensis strain SB1216, isolated from the Great Salt Plains of Oklahoma, showed the presence of a 3,814,720-bp circular chromosome and no plasmids. The presence of a novel 870-bp extracellular RNase gene is predicted to be responsible for this strain's antitumor activity. Copyright © 2017 Marasini et al.

Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts.

Directory of Open Access Journals (Sweden)

Kiersten Marie Miles

Full Text Available The Notch ligand Delta-like 4 (Dll4 is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth. Given the cross-talk between the vascular endothelial growth factor (VEGF and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a function-blocking Dll4 antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC.Severe combined immunodeficiency (SCID mice bearing patient-derived clear cell RCC xenografts were treated with REGN1035 and in combination with the multi-targeted tyrosine kinase inhibitor sunitinib or the VEGF blocker ziv-aflibercept. Immunohistochemical and immunofluorescent analyses were carried out, as well as magnetic resonance imaging (MRI examinations pre and 24 hours and 2 weeks post treatment. Single agent treatment with REGN1035 resulted in significant tumor growth inhibition (36-62% that was equivalent to or exceeded the single agent anti-tumor activity of the VEGF pathway inhibitors sunitinib (38-54% and ziv-aflibercept (46%. Importantly, combination treatments with REGN1035 plus VEGF inhibitors resulted in enhanced anti-tumor effects (72-80% growth inhibition, including some tumor regression. Magnetic resonance imaging showed a marked decrease in tumor perfusion in all treatment groups. Interestingly, anti-tumor efficacy of the combination of REGN1035 and ziv-aflibercept was also observed in a sunitinib resistant ccRCC model.Overall, these findings demonstrate the potent anti-tumor activity of Dll4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll4 and VEGF signaling pathways, highlighting the therapeutic potential of this treatment modality in RCC.

Antisense oligonucleotides and all-trans retinoic acid have a synergistic anti-tumor effect on oral squamous cell carcinoma

International Nuclear Information System (INIS)

Xu, Qin; Zhang, Zhiyuan; Zhang, Ping; Chen, Wantao

2008-01-01

Antisense oligonucleotides against hTR (As-ODN-hTR) have shown promising results as treatment strategies for various human malignancies. All-trans retinoic acid (ATRA) is a signalling molecule with important roles in differentiation and apoptosis. Biological responses to ATRA are currently used therapeutically in various human cancers. The aim of this study was to evaluate the anti-tumor effects of As-ODN-hTR combined with ATRA in vivo. In situ human oral squamous cell carcinoma (OSCC) models were established by subcutaneous injection of Tca8113 cells. Mice were treated with sense oligonucleotides against hTR(S-ODN-hTR) alone, As-ODN-hTR alone, ATRA alone, As-ODN-hTR plus ATRA, or S-ODN-hTR plus ATRA. Tumor size and weight were assessed in the mice. Telomerase activity was detected by a TRAP assay, apoptotic cells were evaluated with a Tunel assay, the expression of apoptosis-related proteins (Bcl-2 and Bax) was evaluated by immunohistochemistry and ultrastructural morphological changes in the tumor specimen were examined. Both As-ODN-hTR and ATRA can significantly inhibit tumor growth in this OSCC xenograft solid-tumor model, and the combination of the two agents had a synergistic anti-tumorogenic effect. We also demonstrated that this anti-tumor effect correlated with inhibition of telomerase activity. Furthermore, significant increases in the number of apoptotic cells, typical apoptotic morphology and a downregulation of the anti-apoptotic protein, bcl-2 were observed in the treated tissues. The combination of As-ODN-hTR and ATRA has a synergistic anti-tumor effect. This anti-tumor effect can be mainly attributed to apoptosis induced by a decrease in telomerase activity. Bcl-2 plays an important role in this process. Therefore, combining As-ODN-hTR and ATRA may be an approach for the treatment of human oral squamous cell carcinoma

Fluorescent nanodiamonds engage innate immune effector cells: A potential vehicle for targeted anti-tumor immunotherapy.

Science.gov (United States)

Suarez-Kelly, Lorena P; Campbell, Amanda R; Rampersaud, Isaac V; Bumb, Ambika; Wang, Min S; Butchar, Jonathan P; Tridandapani, Susheela; Yu, Lianbo; Rampersaud, Arfaan A; Carson, William E

2017-04-01

Fluorescent nanodiamonds (FNDs) are nontoxic, infinitely photostable, and emit fluorescence in the near infrared region. Natural killer (NK) cells and monocytes are part of the innate immune system and are crucial to the control of carcinogenesis. FND-mediated stimulation of these cells may serve as a strategy to enhance anti-tumor activity. FNDs were fabricated with a diameter of 70±28 nm. Innate immune cell FND uptake, viability, surface marker expression, and cytokine production were evaluated in vitro. Evaluation of fluorescence emission from the FNDs was conducted in an animal model. In vitro results demonstrated that treatment of immune cells with FNDs resulted in significant dose-dependent FND uptake, no compromise in cell viability, and immune cell activation. FNDs were visualized in an animal model. Hence, FNDs may serve as novel agents with "track and trace" capabilities to stimulate innate immune cell anti-tumor responses, especially as FNDs are amenable to surface-conjugation with immunomodulatory molecules. Copyright © 2016 Elsevier Inc. All rights reserved.

Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti-Tumor Necrosis Factor Alpha Agents: A Systematic Review and Meta-analysis.

Science.gov (United States)

Yang, Chen; Huang, Junlin; Huang, Xiaowen; Huang, Shaozhuo; Cheng, Jiaxin; Liao, Weixin; Chen, Xuewen; Wang, Xueyi; Dai, Shixue

2018-05-12

The association between anti-tumor necrosis factor alpha agents and the risk of lymphoma in patients with inflammatory bowel disease has already been sufficiently reported. However, the results of these studies are inconsistent. Hence, this analysis was conducted to investigate whether anti-tumor necrosis factor alpha agents can increase the risk of lymphoma in inflammatory bowel disease patients. MEDLINE, EMBASE and the Cochrane Library were searched to identify relevant studies which evaluated the risk of lymphoma in inflammatory bowel disease patients treated with anti-tumor necrosis factor alpha agents. A random-effects meta-analysis was performed to calculate the pooled incidence rate ratios as well as risk ratios. Twelve studies comprising 285811 participants were included. The result showed that there was no significantly increased risk of lymphoma between anti-tumor necrosis factor alpha agents exposed and anti-tumor necrosis factor alpha agents unexposed groups (random effects: incidence rate ratio [IRR], 1.43 95%CI, 0.91-2.25, p= 0.116; random effects: risk ratio [RR], 0.83 95%CI, 0.47-1.48, p=0.534). However, monotherapy of anti-tumor necrosis factor alpha agents (random effects: IRR=1.65, 95%CI, 1.16-2.35; p=0.006; random effects: RR=1.00, 95%CI, 0.39-2.59; p=0.996) or combination therapy (random effects: IRR=3.36, 95%CI, 2.23-5.05; ptumor necrosis factor alpha agents in patients with inflammatory bowel disease is not associated with a higher risk of lymphoma. Combination therapy and anti-tumor necrosis factor alpha agents monotherapy can significantly increase the risk of lymphoma in patients with inflammatory bowel disease.

Enhanced antitumor efficacy of folate-linked liposomal doxorubicin with TGF-β type I receptor inhibitor

International Nuclear Information System (INIS)

Taniguchi, Yukimi; Kawano, Kumi; Minowa, Takuya; Shimojo, Yuki; Maitani, Yoshie; Sugino, Takashi

2010-01-01

Tumor cell targeting of drug carriers is a promising strategy and uses the attachment of various ligands to enhance the therapeutic potential of chemotherapy agents. Folic acid is a high-affinity ligand for folate receptor, which is a functional tumor-specific receptor. The transforming growth factor (TGF)-β type I receptor (TβR-I) inhibitor A-83-01 was expected to enhance the accumulation of nanocarriers in tumors by changing the microvascular environment. To enhance the therapeutic effect of folate-linked liposomal doxorubicin (F-SL), we co-administrated F-SL with A-83-01. Intraperitoneally injected A-83-01-induced alterations in the cancer-associated neovasculature were examined by magnetic resonance imaging (MRI) and histological analysis. The targeting efficacy of single intravenous injections of F-SL combined with A-83-01 was evaluated by measurement of the biodistribution and the antitumor effect in mice bearing murine lung carcinoma M109. A-83-01 temporarily changed the tumor vasculature around 3 h post injection. A-83-01 induced 1.7-fold higher drug accumulation of F-SL in the tumor than liposome alone at 24 h post injection. Moreover F-SL co-administrated with A-83-01 showed significantly greater antitumor activity than F-SL alone. This study shows that co-administration of TβR-I inhibitor will open a new strategy for the use of folate receptor (FR)-targeting nanocarriers for cancer treatment. (author)

Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via an apoptosis-independent pathway

Energy Technology Data Exchange (ETDEWEB)

An, Hyunsook; Kim, Ji Young; Lee, Nahyun; Cho, Youngkwan; Oh, Eunhye [Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703 (Korea, Republic of); Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul 152-703 (Korea, Republic of); Seo, Jae Hong, E-mail: cancer@korea.ac.kr [Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703 (Korea, Republic of); Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul 152-703 (Korea, Republic of)

2015-10-30

Cancer stem cells (CSCs) play important roles in the formation, growth and recurrence of tumors, particularly following therapeutic intervention. Salinomycin has received recent attention for its ability to target breast cancer stem cells (BCSCs), but the mechanisms of action involved are not fully understood. In the present study, we sought to investigate the mechanisms responsible for salinomycin's selective targeting of BCSCs and its anti-tumor activity. Salinomycin suppressed cell viability, concomitant with the downregulation of cyclin D1 and increased p27{sup kip1} nuclear accumulation. Mammosphere formation assays revealed that salinomycin suppresses self-renewal of ALDH1-positive BCSCs and downregulates the transcription factors Nanog, Oct4 and Sox2. TUNEL analysis of MDA-MB-231-derived xenografts revealed that salinomycin administration elicited a significant reduction in tumor growth with a marked downregulation of ALDH1 and CD44 levels, but seemingly without the induction of apoptosis. Our findings shed further light on the mechanisms responsible for salinomycin's effects on BCSCs. - Highlights: • Salinomycin suppresses mammosphere formation. • Salinomycin reduces ALDH1 activity and downregulates Nanog, Oct4 and Sox2. • Salinomycin targets BCSCs via an apoptosis-independent pathway.

The antitumor effect of bromophenol derivatives in vitro and Leathesia nana extract in vivo

Science.gov (United States)

Shi, Dayong; Li, Jing; Guo, Shuju; Su, Hua; Fan, Xiao

2009-05-01

To investigate the antitumor effect of bromophenol derivatives in vitro and Leathesia nana extract in vivo, six bromophenol derivatives 6-(2,3-dibromo-4,5-dihydroxybenzyl)-2,3-dibromo-4,5-dihydroxy benzyl methyl ether (1), (+)-3-(2,3-dibromo-4,5-dihydroxyphenyl)-4-bromo-5,6-dihydroxy-1,3-dihydroisobenzofuran (2), 3-bromo-4-(2,3-dibromo-4,5-dihydroxybenzyl)-5-methoxymethyl-pyrocatechol (3), 2,2',3,3'-tetrabromo-4,4',5,5'-tetrahydroxy-diphenylmethane (4), bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (5), 2,2',3-tribromo-3',4,4',5-tetrahydroxy-6'-ethyloxymethyldiphenylmethane (6) were isolated from brown alga Leathesia nana, and their cytotoxicity were tested by MTT assays in human cancer cell lines A549, BGC-823, MCF-7, B16-BL6, HT-1080, A2780, Bel7402 and HCT-8. Their inhibitory activity against protein tyrosine kinase (PTK) with over-expression of c-kit was analyzed also by ELISA. The antitumor activity of ethanolic extraction of Leathesia nana (EELN) was evaluated on S180-bearing mice. All compounds showed very potent cytotoxicity against all of the eight cancer cell lines with IC50 below 10 μg/mL. In PTK inhibition study, all bromophenol derivatives showed moderate inhibitory activity and compounds 2, 5 and 6 showed significant bioactivity with the inhibition ratio of 77.5%, 80.1% and 71.4%, respectively. Pharmacological studies reveal that EELN could inhibit the growth of Sarcoma 180 tumor and increase the indices of thymus and spleen to improve the immune system remarkably in vivo. Results indicated that the bromophenol derivatives and EELN can be used as potent antitumor agents for PTK over-expression of c-kit and considered in a new therapeutic strategy for treatment of cancer.

In vitro and in vivo antitumor activity of the halogenated boroxine dipotassium-trioxohydroxytetrafluorotriborate (K2[B3O3F4OH]).

Science.gov (United States)

Ivankovic, Sinisa; Stojkovic, Ranko; Galic, Zoran; Galic, Borivoj; Ostojic, Jelena; Marasovic, Maja; Milos, Mladen

2015-06-01

Dipotassium-trioxohydroxytetrafluorotriborate K2[B3O3F4OH] was listed as a promising new therapeutic for cancer diseases. For in vitro and in vivo investigation of its antitumor effects 4T1 mammary adenocarcinoma, B16F10 melanoma and squamous cell carcinoma SCCVII were used. The detailed in vitro investigation undoubtedly showed that K2[B3O3F4OH] affects the growth of cancer cells. The proliferation of cells depends on the concentration so that aqueous solution of K2[B3O3F4OH], the concentrations of 10(-4) M and less, does not affect cell growth, but the concentrations of 10(-3) M or more, significantly slows cells growth. B16F10 and SCCVII cells show higher sensitivity to the cytotoxic effects of K2[B3O3F4OH] compared to 4T1 cells. Under in vivo conditions, K2[B3O3F4OH] slows the growth of all three tumors tested compared to the control, and the inhibitory effect was most pronounced during the application of the substance. There is almost no difference if K2[B3O3F4OH] was applied intraperitoneally, intratumor, peroral or as ointment. Addition of 5-FU did not further increase the antitumor efficacy of K2[B3O3F4OH].

Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors.

Science.gov (United States)

Herbst, Roy S; Hong, David; Chap, Linnea; Kurzrock, Razelle; Jackson, Edward; Silverman, Jeffrey M; Rasmussen, Erik; Sun, Yu-Nien; Zhong, Don; Hwang, Yuying C; Evelhoch, Jeffrey L; Oliner, Jonathan D; Le, Ngocdiep; Rosen, Lee S

2009-07-20

PURPOSE AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. PATIENTS AND METHODS Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg. Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti-AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (K(trans); measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks. CONCLUSION Weekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor-axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient

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

Science.gov (United States)

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.

[Structural analysis and anti-tumor activity in vivo of polysaccharide APS-2a from Angelica sinensis].

Science.gov (United States)

Cao, Wei; Li, Xiao-Qiang; Hou, Ying; Fan, Hui-Ting; Zhang, Xiao-Nan; Mei, Qi-Bing

2008-02-01

The polysaccharide APS-2a was isolated from Angelica sinensis (Oliv.) Diels through water extraction, deprotein, ethanol precipitation and DEAE-sephades A-25 column chromatography respectively,and was further purified by Sephacryl S-400 and Sephadex G-100 column chromatography. The phenol-sulfuric acid assay and Bradford method were used to determine the contents of carbohydrate and protein, respectively. The molecular weight was carried out with high-performance size exclusion chromatography (HPSEC) combined with a differential refractometer detector. The monosaccharide compositions were determined by gas chromatography after complete hydrolysis with acid. The models of mice transplanted sarcoma S-180 were used to study the anti-tumor effects in vivo. Thymus indexes, spleen indexes were determined. The HPSEC result showed the APS-2a was a single homogeneous component and its weight average molecular weight was 7.4 x 10(5) Da. The monosaccharide composition of APS-2a was glucose, galactose, arabinose, rhamnose, galcturonic acid. Furthermore, APS-2a (20.50 mg/kg) could inhibit the proliferation of tumor cells in mice transplanted S-180. The thymus indexes and spleen indexes in the groups treated with APS-2a were higher than control group.

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

DEFF Research Database (Denmark)

Overdijk, M. B.; Verploegen, S.; Bogels, M.

2015-01-01

Daratumumab (DARA) is a human CD38-specific IgG1 antibody that is in clinical development for the treatment of multiple myeloma (MM). The potential for IgG1 antibodies to induce macrophage-mediated phagocytosis, in combination with the known presence of macrophages in the tumor microenvironment...... in MM and other hematological tumors, led us to investigate the contribution of antibody-dependent, macrophage-mediated phagocytosis to DARA's mechanism of action. Live cell imaging revealed that DARA efficiently induced macrophage-mediated phagocytosis, in which individual macrophages rapidly...... and sequentially engulfed multiple tumor cells. DARA-dependent phagocytosis by mouse and human macrophages was also observed in an in vitro flow cytometry assay, using a range of MM and Burkitt's lymphoma cell lines. Phagocytosis contributed to DARA's anti-tumor activity in vivo, in both a subcutaneous...

Chimeric antigen receptors with human scFvs preferentially induce T cell anti-tumor activity against tumors with high B7H6 expression.

Science.gov (United States)

Gacerez, Albert T; Hua, Casey K; Ackerman, Margaret E; Sentman, Charles L

2018-05-01

B7H6 is emerging as a promising tumor antigen that is known to be expressed on a wide array of tumors and is reported to stimulate anti-tumor responses from the immune system. As such, B7H6 presents a good target for tumor-specific immunotherapies. B7H6-specific chimeric antigen receptors (CAR) based on a murine antibody showed successful targeting and elimination of tumors expressing B7H6. However, mouse single chain variable fragments (scFvs) have the potential to induce host anti-CAR responses that may limit efficacy, so human scFvs specific for B7H6 were selected by yeast surface display. In this study, we validate the functionality of these human scFvs when formatted into chimeric antigen receptors. The data indicate that T cells expressing these B7H6-specific human scFvs as CARs induced potent anti-tumor activity in vitro and in vivo against tumors expressing high amounts of B7H6. Importantly, these human scFv-based CARs are sensitive to changes in B7H6 expression which may potentially spare non-tumor cells that express B7H6 and provides the foundation for future clinical development.

Novel production method of innovative antiangiogenic and antitumor small peptides in Escherichia coli

Directory of Open Access Journals (Sweden)

Setrerrahmane S

2017-11-01

Full Text Available Sarra Setrerrahmane,1 Jian Yu,1 Jingchao Hao,1,2 Heng Zheng,3 Hanmei Xu1,3 1The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing, Jiangsu, 2College of Pharmacy & the Provincial Key Laboratory of Natural Drug and Pharmacology, Kunming, Yunnan, 3State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China Background: Developing innovative drugs with potent efficacy, specificity, and high safety remains an ongoing task in antitumor therapy development. In the last few years, peptide drugs have become attractive agents in cancer therapy. HM-3, mainly with antiangiogenic effect, and AP25, with an additional antiproliferative effect, are two peptides designed in our laboratory targeting αvβ3 and α5β1 integrins, respectively. The low molecular weight of the two peptides renders their recombinant expression very difficult, and the complicated structure of AP25 makes its chemical synthesis restricted, which presents a big challenge for its development.Methods: Bifunctional peptides designed by the ligation of HM-3 and AP25, using linkers with different flexibility, were prepared using recombinant DNA technology in Escherichia coli. The fusion peptides were expressed in a modified auto-induction medium based on a mixture of glucose, glycerol, and lactose as carbon substrates and NH4+ as nitrogen source without any amino acid or other elements. Subsequently, the antiangiogenic, antiproliferative, and cell adhesion assays were conducted to evaluate the bioactivity of the two fusion peptides.Results: The peptides were successfully expressed in a soluble form without any induction, which allows the culture to reach higher cell density before protein expression occurs. Human umbilical vein endothelial cell migration assay and chick embryo chorioallantoic membrane assay showed, at low doses, a significantly

Immunotherapeutic effect of Concholepas hemocyanin in the murine bladder cancer model: evidence for conserved antitumor properties among hemocyanins.

Science.gov (United States)

Moltedo, Bruno; Faunes, Fernando; Haussmann, Denise; De Ioannes, Pablo; De Ioannes, Alfredo E; Puente, Javier; Becker, María Inés

2006-12-01

We determined the antitumor properties of a newly available hemocyanin obtained from the Chilean gastropod Concholepas concholepas (Biosonda Corp., Santiago, Chile) in a syngeneic heterotopic mouse bladder carcinoma model. Since keyhole limpet hemocyanin (Pierce, Rockford, Illinois) is used increasingly in biomedicine as a carrier for vaccines and an immunotherapeutic agent for bladder transitional cell carcinoma, there is a growing interest in finding new substances that share its potent immunomodulatory properties. Considering that keyhole limpet hemocyanin and Concholepas concholepas hemocyanin differ significantly, it was not possible to predict a priori the antitumor properties of Concholepas concholepas hemocyanin. C3H/He mice were primed with Concholepas concholepas hemocyanin before subcutaneous implantation of mouse bladder tumor-2 cells. Treatment consisted of a subcutaneous dose of Concholepas concholepas hemocyanin (1 mg or 100 mug) at different intervals after implantation. Keyhole limpet hemocyanin and phosphate buffered saline served as positive and negative controls, respectively. In addition, experiments were designed to determine which elements of the immune response were involved in its adjuvant immunostimulatory effect. Mice treated with Concholepas concholepas hemocyanin showed a significant antitumor effect, as demonstrated by decreased tumor growth and incidence, prolonged survival and lack of toxic effects. These effects were similar to those achieved with keyhole limpet hemocyanin. We found that each hemocyanin increased natural killer cell activity but the effect of Concholepas concholepas hemocyanin was stronger. Analysis of serum from treated mice showed an increased interferon-gamma and low interleukin-4, which correlated with antibody isotypes, confirming that hemocyanins induce a T helper type 1 cytokine profile. To our knowledge our results are the first demonstration of the antitumor effect of a hemocyanin other than keyhole limpet

Redox cycling of potential antitumor aziridinylquinones

NARCIS (Netherlands)

Lusthof, Klaas J.; de Mol, Nicolaas J.; Richter, Wilma; Janssen, Lambert H.M.; Butler, John; Hoey, Brigid M.; Verboom, Willem; Reinhoudt, David

1992-01-01

The formation of reactive oxygen intermediates (ROI) during redox cycling of newly synthetized potential antitumor 2,5-bis (1-aziridinyl)-1,4-benzoquinone (BABQ) derivatives has been studied by assaying the production of ROI (superoxide, hydroxyl radical, and hydrogen peroxide) by xanthine oxidase

Extraction, Preliminary Characterization and Evaluation of in Vitro Antitumor and Antioxidant Activities of Polysaccharides from Mentha piperita

Directory of Open Access Journals (Sweden)

Xin Liu

2014-09-01

Full Text Available This study describes the extraction, preliminary characterization and evaluation of the in vitro antitumor and antioxidant activities of polysaccharides extracted from Mentha piperita (MPP. The optimal parameters for the extraction of MPP were obtained by Box-Behnken experimental design and response surface methodology (RSM at the ratio of water to raw material of 20, extraction time of 1.5 h and extraction temperature at 80 °C. Chemical composition analysis showed that MPP was mainly composed of glucuronic acid, galacturonic acid, glucose, galactose and arabinose, and the molecular weight of its two major fractions were estimated to be about 2.843 and 1.139 kDa, respectively. In vitro bioactivity experiments showed that MPP not only inhibited the growth of A549 cells but possessed potent inhibitory action against DNA topoisomerase I (topo I, and an appreciative antioxidant action as well. These results indicate that MPP may be useful for developing safe natural health products.

Synthesis, structural characterization and antitumor activity of a Ca(II) coordination polymer based on 4-formyl-1,3-benzenedisulfonate-2-furoic acid hydrazide ligands

Energy Technology Data Exchange (ETDEWEB)

Tai, Xi-Shi, E-mail: taixs@wfu.edu.cn [Weifang University, College of Chemistry and Chemical Engineering (China); Wang, Xin [Qinghai Normal University, Department of Chemistry (China)

2017-03-15

A new Ca(II) coordination polymer, ([CaL(H{sub 2}O){sub 4}] · (H{sub 2}O){sub 4}){sub n} (L = 4-formyl-1,3-benzenedisulfonate-2-furoic acid hydrazide) has been prepared by one-pot synthesis method. And it was characterized by elemental analysis, IR and thermal analysis. The result of X-ray single-crystal diffraction analysis shows that the Ca(II) complex molecules form one-dimensional chain structure by the bridging oxygen atoms. The anti-tumor activity of L ligand and the Ca(II) coordination polymer has also been studied.

Anti-tumor activity of high-dose EGFR tyrosine kinase inhibitor and sequential docetaxel in wild type EGFR non-small cell lung cancer cell nude mouse xenografts

OpenAIRE

Tang, Ning; Zhang, Qianqian; Fang, Shu; Han, Xiao; Wang, Zhehai

2016-01-01

Treatment of non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is still a challenge. This study explored antitumor activity of high-dose icotinib (an EGFR tyrosine kinase inhibitor) plus sequential docetaxel against wild-type EGFR NSCLC cells-generated nude mouse xenografts. Nude mice were subcutaneously injected with wild-type EGFR NSCLC A549 cells and divided into different groups for 3-week treatment. Tumor xenograft volumes were monitored and record...

Screening and analysis of potential anti-tumor components from the stipe of Ganoderma sinense using high-performance liquid chromatography/time-of-flight mass spectrometry with multivariate statistical tool.

Science.gov (United States)

Chan, Kar-Man; Yue, Grace Gar-Lee; Li, Ping; Wong, Eric Chun-Wai; Lee, Julia Kin-Ming; Kennelly, Edward J; Lau, Clara Bik-San

2017-03-03

According to Chinese Pharmacopoeia 2015 edition, Ganoderma (Lingzhi) is a species complex that comprise of Ganoderma lucidum and Ganoderma sinense. The bioactivity and chemical composition of G. lucidium had been studied extensively, and it was shown to possess antitumor activities in pharmacological studies. In contrast, G. sinense has not been studied in great detail. Our previous studies found that the stipe of G. sinense exhibited more potent antitumor activity than the pileus. To identify the antitumor compounds in the stipe of G. sinense, we studied its chemical components by merging the bioactivity results with liquid chromatography-mass spectrometry-based chemometrics. The stipe of G. sinense was extracted with water, followed by ethanol precipitation and liquid-liquid partition. The resulting residue was fractionated using column chromatography. The antitumor activity of these fractions were analysed using MTT assay in murine breast tumor 4T1 cells, and their chemical components were studied using the LC-QTOF-MS with multivariate statistical tools. The chemometric and MS/MS analysis correlated bioactivity with five known cytotoxic compounds, 4-hyroxyphenylacetate, 9-oxo-(10E,12E)-octadecadienoic acid, 3-phenyl-2-propenoic acid, 13-oxo-(9E,11E)-octadecadienoic acid and lingzhine C, from the stipe of G. sinense. To the best of our knowledge, 4-hyroxyphenylacetate, 3-phenyl-2-propenoic acid and lingzhine C are firstly reported to be found in G. sinense. These five compounds will be investigated for their antitumor activities in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

Preliminary evaluation of the encapsulation of new antidiabetic sulphonylhydrazone and antitumor N-acylhydrazone derivatives using PLGA nanoparticles

International Nuclear Information System (INIS)

Costa, F N; Ibiapino, A L; De Figueiredo, L P; De Castro, C E; Giacomelli, F C; Ferreira, F F; Barreiro, E J; Lima, L M; Do Amaral, D N

2015-01-01

It has been demonstrated the feasibly of using PLGA nanoparticles to promote the encapsulation of novel anti-diabetic sulphonylhydrazone and antitumor N-acylhydrazone derivatives. The motivation is to further demonstrate the possibility of long-term release of anti-diabetic as well as higher accumulation of the antitumor derivative by using the nanotechnology-based production. The produced nanoparticles were obtained by the nanoprecipitation method, which revealed to be effective in the encapsulation of the bioactive compounds. The determined sizes were in the range of ∼100 nm, which are supposed to be suitable for both potential applications. The preliminary experimental data demonstrated the formation of stable nanosystems and further experiments are underway in order to determine the loading content, encapsulation efficiency and release profile of the hydrophobic bioactive compounds. (paper)

Assessment of antitumoral and antimicrobial effects of a maslinic acid derivative

Directory of Open Access Journals (Sweden)

Ioana Z. Pavel

2016-12-01

Full Text Available INTRODUCTION Maslinic acid, a naturally occurring triterpene, has been reported to possess several therapeutic effects including antioxidant, anti-inflammatory and antiparasitic properties. Structural changes of the compound led to the development of new derivatives in order to expand the spectrum of activities. OBJECTIVES AND BACKGROUND The present study was purposed to assess the in vitro antitumoral and antibacterial effects of a maslinic acid derivative, namely benzyl (2α, 3β 2,3-diacetoxy-olean-12- en-28-amide (EM2. MATERIALS AND METHODS Four compound concentrations (12.5, 25, 50 and 100 µM were evaluated for their cytotoxic effect on A375 human melanoma and B164A5 murine melanoma cell lines using the MTT assay. Furthermore, EM2 was tested on ten bacterial strains by means of agar disk diffusion method with the assessment of the inhibition zone diameters at 24h period of time. RESULTS EM2 elicited a dose-dependent cytotoxic effect on both melanoma cell lines. Regarding the antibacterial activity, EM2 determined a significant growth inhibition on Streptococcus pyogenes (20 ± 0.26 mm and Staphylococcus aureus (13 ± 0.19 mm. CONCLUSIONS The tested maslinic acid derivative is a promising antitumoral agent against skin cancer and antimicrobial agent against cocci bacteria. Graphical abstract: EM2 in vitro effects

Antitumor Activity of Portulaca Oleracea L. Polysaccharide on HeLa Cells Through Inducing TLR4/NF-κB Signaling.

Science.gov (United States)

Zhao, Rui; Zhang, Tao; Ma, Baoling; Li, Xing

2017-01-01

Abstarct We have previously shown that Portulaca oleracea L. polysaccharide (POL-P3b) possesses the ability to inhibit cervical cancer cell growth in vitro and in vivo. In this study, we explored how toll-like receptor 4 (TLR4) signaling correlated with the antitumor mechanism of POL-P3b. Western blotting was utilized to detect the expression of TLR4 and the downstream signaling pathway. The level of inflammatory mediator was quantified using enzyme-linked immunosorbent assay (ELISA) kits. The effects of POL-P3b on the proliferation and apoptosis in HeLa cells were determined by WST-8 assay and Hoechst 33342/propidium iodide (PI) assay. Our results demonstrated that lipopolysaccharide (LPS) binding to TLR4 on tumor cells could enhance HeLa cell proliferation and increase the expression of TLR4 and the downstream molecules. Treating HeLa cells with POL-P3b could decrease the proliferation of HeLa cells, and upregulate Bax level and downregulate Bcl-2 level in a concentration-dependent manner. In addition, POL-P3b inhibited the protein expression levels of TLR4, MyD88, TRAF6, Activator Protein-1 (AP-1) and nuclear factor-κB (NF-κB) subunit P65 in HeLa cells. Furthermore, POL-P3b also reduced the production of cytokine/chemokine. Taken together, the present work suggested the antitumor mechanism of POL-P3b by downregulating TLR4 downstream signaling pathway and inducing cell apoptosis. Our results may provide direct evidence to suggest that POL-P3b should be considered as a potent nutrient supplement for oncotherapy.

Systemic treatment with n-6 polyunsaturated fatty acids attenuates EL4 thymoma growth and metastasis through enhancing specific and non-specific anti-tumor cytolytic activities and production of TH1 cytokines.

Science.gov (United States)

Salem, Mohamed Labib

2005-06-01

Recently, there has been a great interest in the effects of different types of n-6 polyunsaturated acids (n-6 PUFAs) upon the immune system and cancer development. However, the effects of n-6 PUFAs are still controversial and as yet undefined. The present study aimed to investigate the anti-tumor effects of n-6 PUFAs against EL4 thymoma and the associated immune mechanisms. To this, sesame oil, a vegetable oil enriched with n-6 PUFAs, or free linoleic acid (LA) were administered intraperitoneally into C57BL/6 mice before and after challenge with EL4 lymphoma cells. Treatment with either sesame oil or LA attenuated the growth and metastasis of EL4 lymphoma. The anti-tumor effect of LA was superior to that of sesame oil, and associated with an increase in the survival rate of the tumor-bearing mice. In addition, both sesame oil and LA showed dose-dependent anti-lymphoma growth in vitro. Treatment with LA generated significant increases in the anti-lymphoma cytolytic and cytostatic activities of T cells and macrophages, respectively, and enhanced production of IL-2 and IFN-gamma while decreased production of IL-4, IL-6 and IL-10. In summation, the results suggest that n-6 PUFAs, represented by LA, can attenuate EL4 lymphoma growth and metastasis through enhancing the specific and non-specific anti-tumor cytolytic activities and production of TH1 cytokines. These findings might be of great importance for a proper design of systemic nourishment with PUFAs emulsions for cancer patients.

Antitumor-promoting activity of scopadulcic acid B, isolated from the medicinal plant Scoparia dulcis L.

Science.gov (United States)

Nishino, H; Hayashi, T; Arisawa, M; Satomi, Y; Iwashima, A

1993-01-01

Scopadulcic acid B (SDB), a tetracyclic diterpenoid isolated from a medicinal plant, Scoparia dulcis L., inhibited the effects of tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in vitro and in vivo; SDB inhibited TPA-enhanced phospholipid synthesis in cultured cells, and also suppressed the promoting effect of TPA on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene. The potency of SDB proved to be stronger than that of other natural antitumor-promoting terpenoids, such as glycyrrhetinic acid.

STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors.

Science.gov (United States)

Deng, Liufu; Liang, Hua; Xu, Meng; Yang, Xuanming; Burnette, Byron; Arina, Ainhoa; Li, Xiao-Dong; Mauceri, Helena; Beckett, Michael; Darga, Thomas; Huang, Xiaona; Gajewski, Thomas F; Chen, Zhijian J; Fu, Yang-Xin; Weichselbaum, Ralph R

2014-11-20

Ionizing radiation-mediated tumor regression depends on type I interferon (IFN) and the adaptive immune response, but several pathways control I IFN induction. Here, we demonstrate that adaptor protein STING, but not MyD88, is required for type I IFN-dependent antitumor effects of radiation. In dendritic cells (DCs), STING was required for IFN-? induction in response to irradiated-tumor cells. The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) mediated sensing of irradiated-tumor cells in DCs. Moreover, STING was essential for radiation-induced adaptive immune responses, which relied on type I IFN signaling on DCs. Exogenous IFN-? treatment rescued the cross-priming by cGAS or STING-deficient DCs. Accordingly, activation of STING by a second messenger cGAMP administration enhanced antitumor immunity induced by radiation. Thus radiation-mediated antitumor immunity in immunogenic tumors requires a functional cytosolic DNA-sensing pathway and suggests that cGAMP treatment might provide a new strategy to improve radiotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Role of CD1A and HSP60 in the antitumoral response of oesophageal cancer

Directory of Open Access Journals (Sweden)

Simona Corrao

2011-12-01

Full Text Available Oesophageal cancer (OC is one of the most common and severe forms of tumor. A wider knowledge of molecular mechanisms which lead to a normal epithelium becoming a neoplasm may reveal new strategies to improve treatment and outcome of this disease. In this review, we report recent findings concerning molecular events which take place during carcinogenesis of the oesophagus. In particular, we focus on the role of two molecules, CD1a and Hsp60, which are overexpressed in oesophageal and many other types of tumor. Both molecules may present tumor antigens and promote in situ the stimulation of an antitumoral immune activity. We suggest there is a synergistic action between these molecules. Further knowledge about their intracellular pathways and extracellular roles may help develop new antitumoral tools for OC.

Chimeric HCMV/HSV-1 and Δγ134.5 oncolytic herpes simplex virus elicit immune mediated antigliomal effect and antitumor memory

Directory of Open Access Journals (Sweden)

Mohammed G. Ghonime

2018-02-01

Full Text Available Malignant gliomas are the most common primary brain tumor and are characterized by rapid and highly invasive growth. Because of their poor prognosis, new therapeutic strategies are needed. Oncolytic virotherapy (OV is a promising strategy for treating cancer that incorporates both direct viral replication mediated and immune mediated mechanisms to kill tumor cells. C134 is a next generation Δγ134.5 oHSV-1 with improved intratumoral viral replication. It remains safe in the CNS environment by inducing early IFN signaling which restricts its replication in non-malignant cells. We sought to identify how C134 performed in an immunocompetent tumor model that restricts its replication advantage over first generation viruses. To achieve this we identified tumors that have intact IFN signaling responses that restrict C134 and first generation virus replication similarly. Our results show that both viruses elicit a T cell mediated anti-tumor effect and improved animal survival but that subtle difference exist between the viruses effect on median survival despite equivalent in vivo viral replication. To further investigate this we examined the anti-tumor activity in immunodeficient mice and in syngeneic models with re-challenge. These studies show that the T cell response is integral to C134 replication independent anti-tumor response and that OV therapy elicits a durable and circulating anti-tumor memory. The studies also show that repeated intratumoral administration can extend both OV anti-tumor effects and induce durable anti-tumor memory that is superior to tumor antigen exposure alone.

A Novel Paclitaxel Microemulsion Containing a Reduced Amount of Cremophor EL: Pharmacokinetics, Biodistribution, and In Vivo Antitumor Efficacy and Safety

Science.gov (United States)

Wang, Ying; Wu, Ke-Chun; Zhao, Bing-Xiang; Zhao, Xin; Wang, Xin; Chen, Su; Nie, Shu-Fang; Pan, Wei-San; Zhang, Xuan; Zhang, Qiang

2011-01-01

The purpose of this study was to prepare a novel paclitaxel (PTX) microemulsion containing a reduced amount of Cremophor EL (CrEL) which had similar pharmacokinetics and antitumor efficacy as the commercially available PTX injection, but a significantly reduced allergic effect due to the CrEL. The pharmacokinetics, biodistribution, in vivo antitumor activity and safety of PTX microemulsion was evaluated. The results of pharmacokinetic and distribution properties of PTX in the microemulsion were similar to those of the PTX injection. The antitumor efficacy of the PTX microemulsion in OVCRA-3 and A 549 tumor-bearing animals was similar to that of PTX injection. The PTX microemulsion did not cause haemolysis, erythrocyte agglutination or simulative reaction. The incidence and degree of allergic reactions exhibited by the PTX microemulsion group, with or without premedication, were significantly lower than those in the PTX injection group (P microemulsion had similar pharmacokinetics and anti-tumor efficacy to the PTX injection, but a significantly reduced allergic effect due to CrEL, indicating that the PTX microemulsion overcomes the disadvantages of the conventional PTX injection and is one way of avoiding the limitations of current injection product while providing suitable therapeutic efficacy. PMID:21331356

Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug

Directory of Open Access Journals (Sweden)

Maria P. Crespo-Ortiz

2012-01-01

Full Text Available Improvement of quality of life and survival of cancer patients will be greatly enhanced by the development of highly effective drugs to selectively kill malignant cells. Artemisinin and its analogs are naturally occurring antimalarials which have shown potent anticancer activity. In primary cancer cultures and cell lines, their antitumor actions were by inhibiting cancer proliferation, metastasis, and angiogenesis. In xenograft models, exposure to artemisinins substantially reduces tumor volume and progression. However, the rationale for the use of artemisinins in anticancer therapy must be addressed by a greater understanding of the underlying mechanisms involved in their cytotoxic effects. The primary targets for artemisinin and the chemical base for its preferential effects on heterologous tumor cells need yet to be elucidated. The aim of this paper is to provide an overview of the recent advances and new development of this class of drugs as potential anticancer agents.

Antitumor effects of pristimerin on human osteosarcoma cells in vitro and in vivo.

Science.gov (United States)

Mori, Yuki; Shirai, Toshiharu; Terauchi, Ryu; Tsuchida, Shinji; Mizoshiri, Naoki; Hayashi, Daichi; Arai, Yuji; Kishida, Tunao; Mazda, Osam; Kubo, Toshikazu

2017-01-01

There are very few treatments for musculoskeletal tumors, compared to other cancers; thus, novel therapeutic drugs are needed. Pristimerin (PM) is a triterpene compound isolated from plant extracts that reportedly has antitumor effects on various cancers, such as of the breast and prostate. The purpose of this study was to evaluate the antitumor effects of PM on human osteosarcoma cells. Treatment of the human osteosarcoma cell lines, MNNG and 143B, with PM led to a dose-dependent decrease in cell viability. The effects of PM on apoptosis were evaluated with the Annexin V/propidium iodide assay and analysis of caspases 3, 8, and 9 activities. Western blot analysis showed that PM caused a decrease in the expression of Akt, mTOR, and NF-κB. The volumes and weights of human osteosarcoma xenografts decreased significantly with PM treatment. The results of this study revealed that PM can inhibit human osteosarcoma growth in vitro and in vivo, and may be a novel therapeutic agent for the disease.

Anti-tumor effects of an engineered 'killer' transfer RNA

Energy Technology Data Exchange (ETDEWEB)

Zhou, Dong-hui [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States); Lee, Jiyoung; Frankenberger, Casey [Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637 (United States); Geslain, Renaud, E-mail: rgeslain@depaul.edu [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States); Department of Biology, DePaul University, Chicago, IL 60614 (United States); Rosner, Marsha, E-mail: m-rosner@uchicago.edu [Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637 (United States); Pan, Tao, E-mail: taopan@uchicago.edu [Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637 (United States)

2012-10-12

Highlights: Black-Right-Pointing-Pointer tRNA with anti-cancer effects. Black-Right-Pointing-Pointer tRNA induced protein misfolding. Black-Right-Pointing-Pointer tRNA as anti-tumor agent. -- Abstract: A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA{sup Ser}(AAU) is an engineered human tRNA{sup Ser} with an anticodon coding for isoleucine. Here we test the possibility that tRNA{sup Ser}(AAU) can be an effective killing agent of breast cancer cells and can effectively inhibit tumor-formation in mice. We found that tRNA{sup Ser}(AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA{sup Ser}(AAU) in both tumorigenic and non-tumorigenic cells. tRNA{sup Ser}(AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA{sup Ser}(AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA{sup Ser}(AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA{sup Ser}(AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.

Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.

Directory of Open Access Journals (Sweden)

Shujing Shi

Full Text Available INTRODUCTION: Cytokine-induced killer cells (CIK cells are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. METHODS: We combined recombinant human endostatin (rh-endostatin and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. RESULTS: Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. CONCLUSIONS: Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells

Anti-tumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo

International Nuclear Information System (INIS)

Mule, J.J.; Shu, S.; Rosenberg, S.A.

1985-01-01

The authors showed previously that adoptive immunotherapy with the combination of LAK cells and recombinant IL 2 (RIL 2) can markedly reduce pulmonary micrometastases from multiple sarcomas established 3 days after the i.v. injection of syngeneic tumor cells in C57BL/6 mice. In this report, they analyzed the factors required for successful therapy. Titration analysis in vivo revealed an inverse relationship between the number of pulmonary metastases remaining after treatment and both the number of LAK cells and the amount of RIL 2 administered. Fresh or unstimulated splenocytes had no anti-tumor effect; a 2- to 3-day incubation of splenocytes in RIL 2 was required. LAK cells generated from allogeneic DBA (H-2d) splenocytes were as effective in vivo as syngeneic, C57BL/6 (H-2b) LAK cells. The anti-metastatic capacity of LAK cells was significantly reduced or eliminated when irradiated with 3000 rad before adoptive transfer. The combined therapy of LAK cells plus RIL 2 was shown to be highly effective in mice immunosuppressed by 500 rad total body irradiation and in treating macrometastases established in the lung 10 days after the i.v. injection of sarcoma cells. Further, reduction of both micrometastases and macrometastases could also be achieved by RIL 2 alone when administered at higher levels than were required with LAK cells. The value of LAK cell transfer and of IL 2 administration for the treatment of tumors established at other sites is currently under investigation

Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis.

Science.gov (United States)

Kim, Seongyeong; Min, Ahrum; Lee, Kyung-Hun; Yang, Yaewon; Kim, Tae-Yong; Lim, Jee Min; Park, So Jung; Nam, Hyun-Jin; Kim, Jung Eun; Song, Sang-Hyun; Han, Sae-Won; Oh, Do-Youn; Kim, Jee Hyun; Kim, Tae-You; Hangauer, David; Lau, Johnson Yiu-Nam; Im, Kyongok; Lee, Dong Soon; Bang, Yung-Jue; Im, Seock-Ah

2017-07-01

KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo . The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate the in vivo effects. KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho-Src and proliferative-signaling molecules were down-regulated in KX-01-sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01-induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01-sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model. KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstrated in vivo using a mouse xenograft model.

IB-11PSEUDO-PROGRESSION (PsdPg) IS A HARBINGER OF A MORE EFFECTIVE ANTI-TUMOR RESPONSE

Science.gov (United States)

Sturla, Lisa; Donahue, John; Machan, Jason; Delamonte, Suzanne; Jeyapalan, Suriya

2014-01-01

BACKGROUND: PsdPg is the increased contrast enhancement, high choline/creatine ratio and increased perfusion observed in the residual tumor bed of high-grade glioma patients after completion of temozolomide/radiation. It resolves within 3-6 months and incidence ranges from 10 - 31%. Though correlated with longer patient survival, its pathological basis is unclear. We used a cytokine/chemokine focused approach to compare the tumor microenvironment in pre- and post-treatment tumor tissue from patients with PsdPg to patients with true progression (TP). METHODS: We obtained pre-treatment formalin fixed paraffin embedded (FFPE) tissue from 35 GBM patients and post-treatment FFPE tissue from five patients with PsdPg and TP. A quantitative PCR array and custom Quantigene 2.0 multiplex was used to quantify gene expression corresponding to major cytokines/chemokines. An 18-gene signature was used to determine the macrophage polarization score (cumulative M2-associated cytokine expression - cumulative M1-associated cytokine expression). Immunohistochemistry (IHC) was used to confirm significantly different targets at the protein level. RESULTS: IHC revealed 7-fold higher B-cell infiltration in TP patients as compared to patients with PsdPg (p = 0.003). Macrophage and T-cell infiltration were not significantly different between the two groups. Nevertheless, the cytokines associated with macrophage polarization indicated pro-tumorigenic (M2) polarization in TP patients while PsdPg patients exhibited classical anti-tumorigenic (M1) polarization. TP patients had a 10-fold higher M2 score (p = 0.03) compared to PsdPg patients. The M1 score of tissue from PsdPg patients post-treatment was 25-fold higher than their pre-treatment tissue (p = 0.01). Analysis of a 7-gene signature associated with natural killer (NK) cell recruitment and activation showed a 8-fold higher expression in pre-treatment tissue from PsdPg patients compared to TP patients (p = 0.009) suggesting that NK cells

A Single Domain–Based Anti-Her2 Antibody Has Potent Antitumor Activities

Directory of Open Access Journals (Sweden)

Xiaoqiong Wu

2018-04-01

Full Text Available Human epidermal growth factor receptor 2 (HER2 is overexpressed in approximately 20% to 30% of breast cancers and various other types of cancers, which plays a vital role in the cancer progression. Monoclonal antibodies targeting Her2 are now used in the clinic to treat Her2 overexpression cancer patients. However, relapse or resistance is frequent with the current therapies. To generate a new treatment avenue against Her2, we immunized and selected a specific anti-Her2 single domain antibody C3 for further studies. The C3-Fc antibody drove antibody-dependent cell-mediated cytotoxicity against Her2-positive tumor cells in vitro and resulted in potent antitumor growth in vivo. These data suggest that the C3-Fc antibody may provide an alternative avenue for Her2-positive cancer therapy.

A Novel Synthesis of Fused Uracils: Indenopyrimidopyridazines, Pyrimidopyridazines, and Pyrazolopyrimidines for Antimicrobial and Antitumor Evalution

Directory of Open Access Journals (Sweden)

Samar El-Kalyoubi

2016-12-01

Full Text Available A variety of different compounds of fused uracils were prepared simply by the heating of 6-hydrazinyl-1-methyl-, 6-hydrazinyl-1-propyl-, or 6-hydrazinyl-1,3-dipropyluracil under reflux with ninhydrin, isatin, benzylidene malononitrile, benzylylidene ethyl cyanoacetate, benzil, and phenacyl bromide derivatives. The newly synthesized compounds were completely screened for antimicrobial and antitumor activity.

Antitumor effects of radioiodinated antisense oligonucleotide mediated by VIP receptor

International Nuclear Information System (INIS)

Ou Xiaohong; Tan Tianzhi; Li Yunchun; Kuang Anren

2004-01-01

Purpose: we had constructed a targeting delivery system based on intestinal peptide (VIP) for antisense oligonucleotide (ASON) transfer into VIP receptor-positive cells in previous study. The aims of present studies are to observe the antitumor effect of VIP-131I-ASON in HT29 human colon adenocarcinoma xenografts. Methods: A 15-met phosphorothioate ASON, which was complementary to the translation start region of the C-myc oncogene mRNA, was labeled with 131I and the labelled compound was linked to the VIP bound covalently 'to a polylysine chain so as to deliver oligonucleotide into tumor cells. Distribution experiments for evaluating the radiolabeled antisense complexe uptake in tumor tissue were performed in BALB/c nude mice bearing with HT29 tumor xenografts. Nude mice beating HT29 tumor xenografts were adminstered VIP-131I-ASON (3.7,7.4 MBq) or 131I-ASON (3.7 MBq), 131I labeled control sense and nosense DNA (3.7 MBq), or saline. Antitumor effects were assessed using endpoints of tumor growth delay. C-myc-encoded protein expression of tumor was measured by immunocytohistochemical staining. Results: Distribution experiment performed with athymic mice bearing human colon tumor xenografts revealed maximal accumulation of conjugated ASON in the tumor tissue 2 h after administration and significantly higher than that in nude mice injected unconjngated ASON [(5.89±1.03)%ID/g and(1.56±0.31)%ID/g, respectively; t=7.7954 P<0.001]. The radioratio of tumor to muscle was peaked 4h after administration. VIP-131I-ASON exhibited strong antitumor effects against HT29 xenografts, decreasing their growth rate 7-fold compare with that in saline-treated mice(tumor growth delay, 25.4±0.89 day). The antitumor effects of unconjugated 131I-ASON were much less profound than VIP-131I-ASON (tumor growth delay, 3.2±1.3 and 25.4±0.89 day, respectively; q=51.4126 P<0.01). Sense, nosense control ON with VIP carder caused no therapeutic effect. There was no progressive weight loss or

Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

Science.gov (United States)

Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

2016-01-01

Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID:26943775

Antitumor activity of docetaxel-loaded polymeric nanoparticles fabricated by Shirasu porous glass membrane-emulsification technique

Directory of Open Access Journals (Sweden)

Yu YN

2013-07-01

residence time, respectively, compared with those of PLGA nanoparticles, and 2.23-, 13.2-, 8.51-fold higher than those of Taxotere, respectively. In vivo real-time distribution of nanoparticles was measured on tumor-bearing mice by near-infrared fluorescence imaging, which demonstrated that the PLA-TPGS nanoparticles achieved much higher concentration and longer retention in tumors than PLGA nanoparticles after intravenous injection. This is consistent with the pharmacokinetic behavior of the nanoparticles. The tumor-inhibitory effect of DTX-loaded nanoparticles was observed in vivo in an H22 tumor-bearing mice model via intravenous administration. This indicated that PLA-TPGS nanoparticles are a feasible drug-delivery formulation with a pilot fabrication technique and have superior pharmacokinetic and anticancer effects compared to the commercially available Taxotere. Keywords: SPG membrane emulsification, nanoparticles, docetaxel, pharmacokinetics, antitumor activity

A new polyacetylene from Vernonia scorpioides (Lam.) Pers. (Asteraceae) and its in vitro antitumoral activity

Energy Technology Data Exchange (ETDEWEB)

Buskuhl, Humberto; Freitas, Rilton A.; Biavatti, Maique W. [Universidade do Vale do Itajai, Itajai, SC (Brazil). Centro de Ciencias da Saude], e-mail: maique@ccs.ufsc.br; Monache, Franco Delle [Universita ' La Sapienza' , Rome (Italy). Dipt. di Chimica e Tecnologia delle Sostanze Biologicamente Attive; Barison, Andersson; Campos, Francinete R. [Universidade Federal do Parana (UFPR), Curitiba, PR (Brazil). Centro Politecnico. Dept. de Quimica; Corilo, Yuri E.; Eberlin, Marcos N. [Universidade Estadual de Campinas (UNICAMP), SP (Brazil). Inst. de Quimica

2009-07-01

The dichloromethane fraction obtained from hydroalcoholic crude extract of leaves and flowers of Vernonia scorpioides (Asteraceae) was investigated, resulting in the isolation and structure elucidation of a new polyacetylene namely 5-octa-2,4,6-triynyl-furan-2(5H)-one. The structure of the isolated compound was determined based on IR, NMR (1D and 2D) and MS spectrometric data. The antitumor potential, including cytotoxicity to tumor cells and genotoxicity, was investigated. The results suggest that apoptotic cell death may have occurred, at least in part, via a caspase-dependent mechanism. (author)

Ursolic acid liposomes with chitosan modification: Promising antitumor drug delivery and efficacy

Energy Technology Data Exchange (ETDEWEB)

Wang, Meili; Zhao, Tingting; Liu, Yanping; Wang, Qianqian; Xing, Shanshan; Li, Lei; Wang, Longgang [Applying Chemistry Key Lab of Hebei Province, Yanshan University, No.438 Hebei Street, Qinhuangdao 066004 (China); Liu, Lanxiang [The First Hospital of Qinhuangdao, No. 258 Cultural Road, Qinhuangdao 066000 (China); Gao, Dawei, E-mail: dwgao@ysu.edu.cn [Applying Chemistry Key Lab of Hebei Province, Yanshan University, No.438 Hebei Street, Qinhuangdao 066004 (China)

2017-02-01

There are tremendous challenges on antitumor and its therapeutic drugs, and preparation of highly efficient nano-vehicles represents one of the novel topics in antitumor pharmaceutical field. Herein, the novel chitosan-coated ursolic acid (UA) liposome (CS-UA-L) was efficiently prepared with highly tumor targeting, drug controlled release and low side-effect. The CS-UA-L was uniformly spherical particles with diameter of ~ 130 nm, and the size was more easily trapped into the tumor tissues. Chitosan modification can make liposomes carrying positive charges, which were inclined to combine with the negative charges on the surface of tumor cells, and then the CS-UA-L could release UA rapidly at pH 5.0 comparing with pH 7.4. Meanwhile, the CS-UA-L exhibited obvious anti-proliferative effect (76.46%) on HeLa cells and significantly antitumor activity (61.26%) in mice bearing U14 cervical cancer. The tumor tissues of CS-UA-L treated mice had enhanced cell apoptosis, extensive necrosis and low cell proliferation activity. These results demonstrated that the multifunctional CS-UA-L allowed a precision treatment for localized tumor, and reducing the total drug dose and side-effect, which hold a great promise in new safe and effective tumor therapy. - Graphical abstract: Schematic diagram representing the principle of synthesis of CS-UA-L and pH-triggered sequential UA release after treatment on tumor bearing mouse. - Highlights: • The novel chitosan-coated ursolic acid liposomes (CS-UA-L) were successfully prepared. • CS-UA-L possessed sensitive pH-response, which could release UA rapidly at pH 5.0 comparing with pH 7.4. • CS-UA-L exhibited obvious anti-proliferative effect (76.46%) on HeLa cells than UA and UA-L. • CS-UA-L suppressed tumor growth more efficiently than those with UA and UA-L in mice bearing U14 cervical cancer. • The CS-UA-L allow for precision treatment of the tumor and potential to reduce the total drug dose and side-effect.

Intratumoral IL-12 and TNF-alpha-loaded microspheres lead to regression of breast cancer and systemic antitumor immunity.

Science.gov (United States)

Sabel, Michael S; Skitzki, Joseph; Stoolman, Lloyd; Egilmez, Nejat K; Mathiowitz, Edith; Bailey, Nicola; Chang, Wen-Jian; Chang, Alfred E

2004-02-01

Local, sustained delivery of cytokines at a tumor can enhance induction of antitumor immunity and may be a feasible neoadjuvant immunotherapy for breast cancer. We evaluated the ability of intratumoral poly-lactic-acid-encapsulated microspheres (PLAM) containing interleukin 12 (IL-12), tumor necrosis factor alpha (TNF-alpha), and granulocyte-macrophage colony stimulating factor (GM-CSF) in a murine model of breast cancer to generate a specific antitumor response. BALB/c mice with established MT-901 tumors underwent resection or treatment with a single intratumoral injection of PLAM containing IL-12, TNF-alpha, or GM-CSF, alone or in combination. Two weeks later, lymph nodes and spleens were harvested, activated with anti-CD3 monoclonal antibodies (mAb) and rhIL-2, and assessed for antitumor reactivity by an interferon gamma (IFNgamma) release assay. Tumor-infiltrating lymphocyte (TIL) analysis was performed on days 2 and 5 after treatment by mechanically processing the tumors to create a single cell suspension, followed by three-color fluorescence-activated cell sorter (FACS) analysis. Intratumoral injection of cytokine-loaded PLAM significantly suppressed tumor growth, with the combination of IL-12 and TNF-alpha leading to increased infiltration by polymorphonuclear cells and CD8+ T-cells in comparison with controls. The induction of tumor-specific reactive T-cells in the nodes and spleens, as measured by IFN-gamma production, was highest with IL-12 and TNF-alpha. This treatment resulted in resistance to tumor rechallenge. A single intratumoral injection of IL-12 and TNF-alpha-loaded PLAM into a breast tumor leads to infiltration by polymorphonuclear cells and CD8+ T-cells with subsequent tumor regression. In addition, this local therapy induces specific antitumor T-cells in the lymph nodes and spleens, resulting in memory immune response.

The anti-tumor effect of bee honey in Ehrlich ascite tumor model of mice is coincided with stimulation of the immune cells.

Science.gov (United States)

Attia, W Y; Gabry, M S; El-Shaikh, K A; Othman, G A

2008-01-01

Honey is thought to exhibit a broad spectrum of therapeutic properties including antibacterial, antifungal, cytostatic and anti-inflammatory activity and has been used for the treatment of gastric ulcers, burns, and for storage of skin grafts. The present study investigated the antitumor effect of bee honey against Ehrlich ascites tumor in mice and the possible mode of antitumor action. Peroral administration of mice with honey (10, 100 or 1000 mg/ 100 g BW) every other day for 4 weeks before intraperitoneal inoculation with Ehrlich ascites tumor (EAT, 1 x 10(6) cells) increased the number bone marrow cells as well as peritoneal macrophages, but not peripheral blood leukocytes nor splenocytes. The phagocytic function of macrophages as well as the T- and B-cell functions were also increased. Honey pre-treatment also recovered the total lipids, total proteins, as well as liver and kidney enzyme activities in EAT-bearing mice. In vitro studies on EAT cells demonstrated inhibitory effect of honey on tumor cell proliferation, viability % of tumor cells as well as the size of solid tumor. The present results indicate that the preventive treatment with honey is considerably effective against EAT in mice both in vivo and in vitro. The antitumor activity of honey may occur through the activation of macrophages, T-cells and B-cells.

SYNTHESIS, CHARACTERIZATION AND ANTITUMOR ACTIVITY OF A Ca (II COORDINATION POLYMER BASED ON 3-AMINO-2-PYRAZINECARBOXYLIC ACID

Directory of Open Access Journals (Sweden)

XI-SHI TAI

2015-10-01

Full Text Available A new Ca(II coordination polymer has been obtained by reaction of Ca(ClO42·H2O with 3-amino-2-pyrazinecarboxylic acid in CH3CH2OH/H2O. It was characterized by IR, 1HNMR, thermal analysis and X-ray single crystal diffraction analysis. X-ray analysis reveals that each Ca(II center is seven-coordination with a N2O5 distorted pentagonal bipyramidal coordination environment. The Ca(II ions are linked through the O atoms of 3-amino-2-pyrazinecarboxylic acid ligands to form 1D chain structure. And then a 3D network structure is constructed by hydrogen bonds and π-π stacking. The antitumor activity of 3-amino-2-pyrazinecarboxylic acid ligand and its Ca(II coordination polymer against human intestinal adenocarcinoma HCT-8 cells, lung adenocarcinoma HCT-116 cells and human lung adenocarcinoma A549 cells line have been investigated.

In vitro enzyme-mimic activity and in vivo therapeutic potential of HSJ-0017, a novel Mn porphyrin-based antioxidant enzyme mimic.

Science.gov (United States)

Li, Bao-qiu; Dong, Xin; Li, Na; Gao, Ji-you; Yuan, Qiang; Fang, Shi-hong; Gong, Xian-chang; Wang, Shu-juan; Wang, Feng-shan

2014-10-01

Manganese (III) 5, 10, 15, 20-tetrakis [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, designated HSJ-0017, is a novel antioxidant enzyme mimic. The aim of the present study was to investigate the enzyme-mimic activity and the therapeutic potential of HSJ-0017 in free radical-related diseases. Superoxide dismutase (SOD) mimic activity was measured by the nitroblue tetrazolium chloride monohydrate reduction assay. Catalase (CAT) mimic activity was measured based on the decomposition of hydrogen peroxide. The antitumor, radioprotective and chemoprotective effects of HSJ-0017 were evaluated in H22 or S180 tumor-bearing Kunming mice. The anti-inflammatory and hepatoprotective effects were, respectively, evaluated in histamine-induced edema model and CCl4-induced hepatic damage model in Wistar rats. HSJ-0017 over a concentration range of 0.001-10 µmol/L significantly inhibited the generation of superoxide anion. Significant hydrogen peroxide scavenging activity was observed when the concentration of HSJ-0017 was higher than 0.01 µmol/L. HSJ-0017 at a dose of 3.0 mg/kg exhibited significant antitumor effect on S180 tumor xenografts, whereas no significant antitumor effect was observed in H22 tumor xenografts. HSJ-0017 at a dose of 3.0 mg/kg enhanced the antitumor effects of radiotherapy and chemotherapy, and reduced their toxicity. However, HSJ-0017 counteracted the antitumor effects of radiotherapy when administered simultaneously with radiotherapy. HSJ-0017 showed significant anti-inflammatory and hepatoprotective effects. Our results demonstrate that HSJ-0017 exhibits antioxidant, antitumor, anti-inflammatory, radioprotective, chemoprotective, and hepatoprotective effects. It is a potent dual SOD/CAT mimic. © 2014 by the Society for Experimental Biology and Medicine.