Science.gov

Sample records for additive antitumor effects

  1. Additive Anti-Tumor Effects of Lovastatin and Everolimus In Vitro through Simultaneous Inhibition of Signaling Pathways

    PubMed Central

    Nölting, Svenja; Maurer, Julian; Spöttl, Gerald; Aristizabal Prada, Elke Tatjana; Reuther, Clemens; Young, Karen; Korbonits, Márta; Göke, Burkhard; Grossman, Ashley; Auernhammer, Christoph J.

    2015-01-01

    Background The mTORC1-inhibitor everolimus shows limited efficacy in treating patients with gastro-entero-pancreatic or pulmonary neuroendocrine tumors (NETs), and poor outcome in patients with malignant pheochromocytoma or hepatic carcinoma. We speculated that any effect may be enhanced by antogonising other signaling pathways. Methods Therefore, we tested the effect of lovastatin—known to inhibit both ERK and AKT signaling—and everolimus, separately and in combination, on cell viability and signaling pathways in human midgut (GOT), pancreatic (BON1), and pulmonary (H727) NET, hepatocellular carcinoma (HepG2, Huh7), and mouse pheochromocytoma (MPC, MTT) cell lines. Results Lovastatin and everolimus separately significantly reduced cell viability in H727, HepG2, Huh7, MPC and MTT cells at clinically relevant doses (P ≤ 0.05). However, high doses of lovastatin were necessary to affect GOT or BON1 cell viability. Clinically relevant doses of both drugs showed additive anti-tumor effects in H727, HepG2, Huh7, MPC and MTT cells (P ≤ 0.05), but not in BON1 or GOT cells. In all cell lines investigated, lovastatin inhibited EGFR and AKT signaling. Subsequently, combination treatment more strongly inhibited EGFR and AKT signaling than everolimus alone, or at least attenuated everolimus-induced EGFR or AKT activation. Vice versa, everolimus constantly decreased pp70S6K and combination treatment more strongly decreased pp70S6K than lovastatin alone, or attenuated lovastatin-induced p70S6K activation: in BON1 cells lovastatin-induced EGFR inhibition was least pronounced, possibly explaining the low efficacy and consequent absent additive effect. Conclusion In summary, clinically relevant doses of lovastatin and everolimus were effective separately and showed additive effects in 5 out of 7 cell lines. Our findings emphasize the importance of targeting several interacting signaling pathways simultaneously when attempting to attenuate tumor growth. However, the variable

  2. The Eltrombopag antitumor effect on hepatocellular carcinoma.

    PubMed

    Kurokawa, Tomohiro; Murata, Soichiro; Zheng, Yun-Wen; Iwasaki, Kenichi; Kohno, Keisuke; Fukunaga, Kiyoshi; Ohkohchi, Nobuhiro

    2015-11-01

    Currently, sorafenib is the only available chemotherapeutic agent for advanced hepatocellular carcinoma (HCC), but it cannot be used in patients with liver cirrhosis (LC) or thrombocytopenia. In these cases, sorafenib is likely effective if given in combination with treatments that increase the number of platelets, such as thrombopoietin (TPO) receptor agonists. Increasing the platelet count via TPO treatment resulted in reduction of LC. Eltrombopag (EP), a TPO receptor agonist, has been reported to have antitumor effects against certain cancers, despite their lack of TPO receptor expression. We hypothesized that EP may possess antitumor activity against HCC in addition to its ability to suppress hepatic fibrosis by increasing the platelet count. In the present study, the antitumor activity of EP was examined by assessing the inhibition of cell proliferation and then ascertaining the ability of iron supplementation to reverse these effects in HepG2, Hep3B and Huh7 cells. In addition, a cell cycle assay was performed using flow cytometry, and signal transduction was evaluated by analyzing cell cycle-related protein expression. The results of EP were compared with those of the most common iron chelator, deferoxamine (DFO). The combined effect of EP and sorafenib was also assessed. The results revealed that EP exerts antitumor activity in HCC that is mediated by the modulation of intracellular iron content. EP suppressed the expression of the cell cycle-related protein cyclin D1 and elicited cell cycle arrest in the G0/G1 phase. The activity of EP was comparable to that of DFO in HCC, and EP did not compete with sorafenib at low concentrations. In conclusion, our findings suggest that EP is a good candidate chemotherapeutic agent for the treatment of HCC in patients with LC and thrombocytopenia. PMID:26397763

  3. The Eltrombopag antitumor effect on hepatocellular carcinoma

    PubMed Central

    KUROKAWA, TOMOHIRO; MURATA, SOICHIRO; ZHENG, YUN-WEN; IWASAKI, KENICHI; KOHNO, KEISUKE; FUKUNAGA, KIYOSHI; OHKOHCHI, NOBUHIRO

    2015-01-01

    Currently, sorafenib is the only available chemotherapeutic agent for advanced hepatocellular carcinoma (HCC), but it cannot be used in patients with liver cirrhosis (LC) or thrombocytopenia. In these cases, sorafenib is likely effective if given in combination with treatments that increase the number of platelets, such as thrombopoietin (TPO) receptor agonists. Increasing the platelet count via TPO treatment resulted in reduction of LC. Eltrombopag (EP), a TPO receptor agonist, has been reported to have antitumor effects against certain cancers, despite their lack of TPO receptor expression. We hypothesized that EP may possess antitumor activity against HCC in addition to its ability to suppress hepatic fibrosis by increasing the platelet count. In the present study, the antitumor activity of EP was examined by assessing the inhibition of cell proliferation and then ascertaining the ability of iron supplementation to reverse these effects in HepG2, Hep3B and Huh7 cells. In addition, a cell cycle assay was performed using flow cytometry, and signal transduction was evaluated by analyzing cell cycle-related protein expression. The results of EP were compared with those of the most common iron chelator, deferoxamine (DFO). The combined effect of EP and sorafenib was also assessed. The results revealed that EP exerts antitumor activity in HCC that is mediated by the modulation of intracellular iron content. EP suppressed the expression of the cell cycle-related protein cyclin D1 and elicited cell cycle arrest in the G0/G1 phase. The activity of EP was comparable to that of DFO in HCC, and EP did not compete with sorafenib at low concentrations. In conclusion, our findings suggest that EP is a good candidate chemotherapeutic agent for the treatment of HCC in patients with LC and thrombocytopenia. PMID:26397763

  4. Antitumor effects of electrochemical treatment

    PubMed Central

    González, Maraelys Morales; Zamora, Lisset Ortíz; Cabrales, Luis Enrique Bergues; Sierra González, Gustavo Victoriano; de Oliveira, Luciana Oliveira; Zanella, Rodrigo; Buzaid, Antonio Carlos; Parise, Orlando; Brito, Luciana Macedo; Teixeira, Cesar Augusto Antunes; Gomes, Marina das Neves; Moreno, Gleyce; Feo da Veiga, Venicio; Telló, Marcos; Holandino, Carla

    2013-01-01

    Electrochemical treatment is an alternative modality for tumor treatment based on the application of a low intensity direct electric current to the tumor tissue through two or more platinum electrodes placed within the tumor zone or in the surrounding areas. This treatment is noted for its great effectiveness, minimal invasiveness and local effect. Several studies have been conducted worldwide to evaluate the antitumoral effect of this therapy. In all these studies a variety of biochemical and physiological responses of tumors to the applied treatment have been obtained. By this reason, researchers have suggested various mechanisms to explain how direct electric current destroys tumor cells. Although, it is generally accepted this treatment induces electrolysis, electroosmosis and electroporation in tumoral tissues. However, action mechanism of this alternative modality on the tumor tissue is not well understood. Although the principle of Electrochemical treatment is simple, a standardized method is not yet available. The mechanism by which Electrochemical treatment affects tumor growth and survival may represent more complex process. The present work analyzes the latest and most important research done on the electrochemical treatment of tumors. We conclude with our point of view about the destruction mechanism features of this alternative therapy. Also, we suggest some mechanisms and strategies from the thermodynamic point of view for this therapy. In the area of Electrochemical treatment of cancer this tool has been exploited very little and much work remains to be done. Electrochemical treatment constitutes a good therapeutic option for patients that have failed the conventional oncology methods. PMID:23592904

  5. PPARγ-Independent Antitumor Effects of Thiazolidinediones

    PubMed Central

    Wei, Shuo; Yang, Jian; Lee, Su-Lin; Kulp, Samuel K.; Chen, Ching-Shih

    2009-01-01

    The thiazolidinedione (TZD) family of PPARγ agonists, especially troglitazone and ciglitazone, induce cell cycle arrest, differentiation, and apoptosis in cancer cells. Mounting evidence indicates that TZDs interfere with multiple signaling mechanisms independently of PPARγactivation, which affect many aspects of cellular functions governing cell cycle progression and survival of cancer cells. Here, we review the “off-target” mechanisms that underlie the antitumor effects of TZDs with emphasis on three key pathways, namely, inhibition of Bcl-2/Bcl-xL function, proteasomal degradation of cell cycle- and apoptosis-regulatory proteins, and transcriptional repression of androgen receptor (AR) through Sp1 degradation. Relative to tumor cells, nonmalignant cells are resistant to these PPARγ-independent antitumor effects, which underscores the translational potential of these agents. Furthermore, dissociation of these antitumor effects from their PPARγ agonist activity provides a rationale for using TZDs as scaffolds for lead optimization to develop a novel class of antitumor agents with a unique mode of mechanism. PMID:18790559

  6. Antitumor effect of Bothrops jararaca venom.

    PubMed Central

    da Silva, Reinaldo J; da Silva, Márcia G; Vilela, Lízia C; Fecchio, Denise

    2002-01-01

    Many experimental studies have been carried out using snake venoms for the treatment of animal tumors, with controversial results. While some authors have reported an antitumor effect of treatment with specific snake venom fractions, others have reported no effects after this treatment. The aim of this study was to evaluate the effect of Bothrops jararaca venom (BjV) on Ehrlich ascites tumor (EAT) cells in vivo and in vitro. In the in vivo study, Swiss mice were inoculated with EAT cells by the intraperitoneal (i.p.) route and treated with BjV venom (0.4 mg/kg, i.p.), on the 1st, 4th, 7th, 10th, and 13th days. Mice were evaluated for total and differential cells number on the 2nd, 5th, 8th, 11th and 14th days. The survival time was also evaluated after 60 days of tumor growth. In the in vitro study, EAT and normal peritoneal cells were cultivated in the presence of different BjV concentrations (2.5, 5.0, 10.0, 20.0, 40.0, and 80 microg) and viability was verified after 3, 6, 12 and 24 h of cultivation. Results were analyzed statistically by the Kruskal-Wallis and Tukey tests at the 5% level of significance. It was observed that in vivo treatment with BjV induced tumor growth inhibition, increased animal survival time, decreased mortality, increased the influx of polymorphonuclear leukocytes on the early stages of tumor growth, and did not affect the mononuclear cells number. In vitro treatment with BjV produced a dose-dependent toxic effect on EAT and peritoneal cells, with higher effects against peritoneal cells. Taken together, our results demonstrate that BjV has an important antitumor effect. This is the first report showing this in vivo effect for this venom. PMID:12061431

  7. Antitumor effect of traditional Chinese herbal medicines against lung cancer.

    PubMed

    Chen, Yuezhou; Zhu, Jianping; Zhang, Wenpeng

    2014-10-01

    Traditional Chinese herbal medicine (TCHM) is used widely alone or in combination with chemotherapy to treat lung cancer in China. Meta-analysis of clinical trials of TCHM against lung cancer suggested the potential, but not confirmed therapeutic effect. To gain detailed insight into the antilung cancer effects of TCHM, we searched for preclinical studies of TCHM against lung cancer published from 1995 to 2012 and systematically analyzed published articles focusing on the antitumor effect of individual TCHM in lung cancer cell lines or animal models. Among 93 herbal components isolated from 73 Chinese herbs, we found 10 herbal compounds that showed the strongest cytotoxicity in lung cancer cell lines through apoptosis or cell cycle arrest, and agents isolated from seven Chinese herbs that inhibited the primary tumor growth more than 35% in A549 xenografted mice models. In addition, three herbal components suppressed lung cancer cell migration in vitro at the concentration without cytotoxicity. Polyphyllin I, tanshinone IIA, isochaihulactone, 25-OCH3-PPD, and andrographolide were the five TCHM compounds that showed strong antilung cancer effects both in cells and in animal models, and studies of their analogs showed their structure-activity relationships. This review summarizes and analyzes contemporary studies on the antitumor effect of individual TCHM against lung cancer and animal models, providing perspectives to better understand the TCHM effect in lung cancer treatment and develop new antilung cancer drugs from TCHM. PMID:24892722

  8. Photodynamic effect on specific antitumor immune activity

    NASA Astrophysics Data System (ADS)

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

    1995-03-01

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

  9. Immune Regulation and Antitumor Effect of TIM-1

    PubMed Central

    Du, Peng; Xiong, Ruihua; Li, Xiaodong; Jiang, Jingting

    2016-01-01

    T cells play an important role in antitumor immunity, and the T cell immunoglobulin domain and the mucin domain protein-1 (TIM-1) on its surface, as a costimulatory molecule, has a strong regulatory effect on T cells. TIM-1 can regulate and enhance type 1 immune response of tumor association. Therefore, TIM-1 costimulatory pathways may be a promising therapeutic target in future tumor immunotherapy. This review describes the immune regulation and antitumor effect of TIM-1. PMID:27413764

  10. Intratumoral Immunocytokine Treatment Results in Enhanced Antitumor Effects

    PubMed Central

    Johnson, Erik E.; Lum, Hillary D.; Rakhmilevich, Alexander L.; Schmidt, Brian E.; Furlong, Meghan; Buhtoiarov, Ilia N.; Hank, Jacquelyn A.; Raubitschek, Andrew; Colcher, David; Reisfeld, Ralph A.; Gillies, Stephen D.; Sondel, Paul M.

    2008-01-01

    Immunocytokines (IC), consisting of tumor-specific monoclonal antibodies fused to the immunostimulatory cytokine interleukin 2 (IL2), exert significant antitumor effects in several murine tumor models. We investigated whether intratumoral (IT) administration of IC provided enhanced antitumor effects against subcutaneous tumors. Three unique ICs (huKS-IL2, hu14.18-IL2, and GcT84.66-IL2) were administered systemically or IT to evaluate their antitumor effects against tumors expressing the appropriate IC-targeted tumor antigens. The effect of IT injection of the primary tumor on a distant tumor was also evaluated. Here, we show that IT injection of IC resulted in enhanced antitumor effects against B16-KSA melanoma, NXS2 neuroblastoma, and human M21 melanoma xenografts when compared to intravenous (IV) IC injection. Resolution of both primary and distant subcutaneous tumors, and a tumor-specific memory response were demonstrated following IT treatment in immunocompetent mice bearing NXS2 tumors. The IT effect of huKS-IL2 IC was antigen-specific, enhanced compared to IL2 alone, and dose-dependent. Hu14.18-IL2 also showed greater IT effects than IL2 alone. The antitumor effect of IT IC did not always require T cells since IT IC induced antitumor effects against tumors in both SCID and nude mice. Localization studies using radiolabeled 111In-GcT84.66-IL2 IC confirmed that IT injection resulted in a higher concentration of IC at the tumor site than IV administration. In conclusion, we suggest that IT IC is more effective than IV administration against palpable tumors. Further testing is required to determine how to potentially incorporate IT administration of IC into an antitumor regimen that optimizes local and systemic anticancer therapy. PMID:18438664

  11. Antitumor effect of metformin in esophageal cancer: in vitro study.

    PubMed

    Kobayashi, Mitsuyoshi; Kato, Kiyohito; Iwama, Hisakazu; Fujihara, Shintaro; Nishiyama, Noriko; Mimura, Shima; Toyota, Yuka; Nomura, Takako; Nomura, Kei; Tani, Joji; Miyoshi, Hisaaki; Kobara, Hideki; Mori, Hirohito; Murao, Koji; Masaki, Tsutomu

    2013-02-01

    Recent studies suggest that metformin, which is a member of the biguanide family and commonly used as an oral anti-hyperglycemic agent, may reduce cancer risk and improve prognosis of numerous types of cancer. However, the mechanisms underlying the antitumor effect of metformin on esophageal cancer remain unknown. The goal of the present study was to evaluate the effects of metformin on the proliferation of human ESCC in vitro, and to study changes in the expression profile of microRNAs (miRNAs), since miRNAs have previously been associated with the antitumor effects of metformin in other human cancers. The human ESCC cell lines T.T, KYSE30 and KYSE70 were used to study the effects of metformin on human ESCC in vitro. In addition, we used miRNA array tips to explore the differences between miRNAs in KYSE30 cells with and without metformin treatment. Metformin inhibited the proliferation of T.T, KYSE30 and KYSE70 cells in vitro. Metformin blocked the cell cycle in G0/G1 in vitro. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, as well as decreases in cyclin-dependent kinase (Cdk)4, Cdk6 and phosphorylated retinoblastoma protein (Rb). In addition, the expression of miRNAs was markedly altered with the treatment of metformin in vitro. Metformin inhibited the growth of three ESCC cell lines, and this inhibition may have involved reductions in cyclin D1, Cdk4 and Cdk6. PMID:23229592

  12. Antioxidant and antitumor effects of ferula sinkiangensis K. M. Shen

    PubMed Central

    Zhang, Haiying; Lu, Jun; Zhou, Longlong; Jiang, Lin; Zhou, Mingxin

    2015-01-01

    Objective: This study is to investigate the antioxidant and antitumor effects of the extract fractions of the Ferula sinkiangensis K. M. Shen. Methods: Four different fractions of the Ferula sinkiangensis K. M. Shen were obtained by the extraction with petroleum ether, ethyl acetate, n-butanol, and methanol, respectively, which were used to treat the HCT116, Caco-2, HepG2, and MFC cells. Free radical scavenging effects of the ferula fractions were deteced with the DPPH assay. Effects of the ferula fractions on the peroliferatoin of the tumor cells were assessed with the SRB assay. Apoptosis was detected with flow cytometry. Results: The DPPH assay showed that the petroleum ether fraction hardly showed any antioxidant activity, while the ethyl acetate, n-butanol, and methanol fractions exhibited free radical-scavenging capacities, in a dose dependent manner. The SRB assay showed that, the proliferation of the tumor cells could be inhibited by the ferula fractions, in a dose dependent manner. However, differential effects were observed for the different fractions in different model cells. Particularly, the ethyl acetate fraction exerted the most efficient inhibiting effects on the tumor cell proliferation. In addition, the flow cytometry showed that, all the ferula fractions significantly enhanced the apoptotic process in the tumor cells, with differential enhancing capacities in different model cells. Conclusion: Extract fractions of the Ferula sinkiangensis K. M. Shen could exert antioxidant, proliferation-inhibiting, and apoptosis-enhancing effects in tumor cells. Particularly, the ethyl acetate fraction exhibits the most potent antioxidant and antitumor effects. PMID:26885009

  13. Spirulina platensis Lacks Antitumor Effect against Solid Ehrlich Carcinoma in Female Mice

    PubMed Central

    Barakat, Waleed; Elshazly, Shimaa M.; Mahmoud, Amr A. A.

    2015-01-01

    Spirulina is a blue-green alga used as a dietary supplement. It has been shown to possess anti-inflammatory, antioxidant, and hepatoprotective properties. This study was designed to evaluate the antitumor effect of spirulina (200 and 800 mg/kg) against a murine model of solid Ehrlich carcinoma compared to a standard chemotherapeutic drug, 5-fluorouracil (20 mg/kg). Untreated mice developed a palpable solid tumor after 13 days. Unlike fluorouracil, spirulina at the investigated two dose levels failed to exert any protective effect. In addition, spirulina did not potentiate the antitumor effect of fluorouracil when they were administered concurrently. Interestingly, their combined administration resulted in a dose-dependent increase in mortality. The present study demonstrates that spirulina lacks antitumor effect against this model of solid Ehrlich carcinoma and increased mortality when combined with fluorouracil. However, the implicated mechanism is still elusive. PMID:26366170

  14. Spirulina platensis Lacks Antitumor Effect against Solid Ehrlich Carcinoma in Female Mice.

    PubMed

    Barakat, Waleed; Elshazly, Shimaa M; Mahmoud, Amr A A

    2015-01-01

    Spirulina is a blue-green alga used as a dietary supplement. It has been shown to possess anti-inflammatory, antioxidant, and hepatoprotective properties. This study was designed to evaluate the antitumor effect of spirulina (200 and 800 mg/kg) against a murine model of solid Ehrlich carcinoma compared to a standard chemotherapeutic drug, 5-fluorouracil (20 mg/kg). Untreated mice developed a palpable solid tumor after 13 days. Unlike fluorouracil, spirulina at the investigated two dose levels failed to exert any protective effect. In addition, spirulina did not potentiate the antitumor effect of fluorouracil when they were administered concurrently. Interestingly, their combined administration resulted in a dose-dependent increase in mortality. The present study demonstrates that spirulina lacks antitumor effect against this model of solid Ehrlich carcinoma and increased mortality when combined with fluorouracil. However, the implicated mechanism is still elusive. PMID:26366170

  15. Antitumor effect of arabinogalactan and platinum complex.

    PubMed

    Starkov, A K; Zamay, T N; Savchenko, A A; Ingevatkin, E V; Titova, N M; Kolovskaya, O S; Luzan, N A; Silkin, P P; Kuznetsova, S A

    2016-03-01

    The article presents the results of investigation of antitumor properties of platinum-arabinogalactan complex. We showed the ability of the complex to inhibit the growth of Ehrlich ascites tumor cells. It is found that the distribution of the platinum-arabinogalactan complex is not specific only for tumor cells in mice. The complex was found in all tissues and organs examined (ascites cells, embryonic cells, kidney, and liver). The mechanism of action of the arabinogalactan-platinum complex may be similar to cisplatin as the complex is able to accumulate in tumor cells. PMID:27193706

  16. Combined Treatment of Herbal Mixture Extract H9 with Trastuzumab Enhances Anti-tumor Growth Effect.

    PubMed

    Lee, Sunyi; Han, Sora; Jeong, Ae Lee; Park, Jeong Su; Jung, Seung Hyun; Choi, Kang-Duk; Yang, Young

    2015-07-01

    Extracts from Asian medicinal herbs are known to be successful therapeutic agents against cancer. In this study, the effects of three types of herbal extracts on anti-tumor growth were examined. Among the three types of herbal extracts, H9 showed stronger anti-tumor growth effects than H5 and H11 in vivo. To find the molecular mechanism by which H9 inhibited the proliferation of breast cancer cell lines, the levels of apoptotic markers were examined. Proapoptotic markers, including cleaved PARP and cleaved caspases 3 and 9, were increased, whereas the anti-apoptotic marker Bcl-2 was decreased by H9 treatment. Next, the combined effect of H9 with the chemotherapeutic drugs doxorubicin/cyclophosphamide (AC) on tumor growth was examined using 4T1-tumor-bearing mice. The combined treatment of H9 with AC did not show additive or synergetic anti-tumor growth effects. However, when tumor-bearing mice were co-treated with H9 and the targeted anti-tumor drug trastuzumab, a delay in tumor growth was observed. The combined treatment of H9 and trastuzumab caused an increase of natural killer (NK) cells and a decrease of myeloid-derived suppressor cells (MDSC). Taken together, H9 induces the apoptotic death of tumor cells while increasing anti-tumor immune activity through the enhancement of NK activity and diminishment of MDSC. PMID:25791851

  17. Doxycycline potentiates antitumor effect of cyclophosphamide in mice

    SciTech Connect

    Chhipa, Rishi Raj; Singh, Sandeep; Surve, Sachin V.; Vijayakumar, Maleppillil Vavachan; Bhat, Manoj Kumar . E-mail: manojkbhat@nccs.res.in

    2005-02-01

    Cyclophosphamide (CPA) is a widely used chemotherapeutic drug in neoplasias. It is a DNA and protein alkylating agent that has a broad spectrum of activity against variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the high-dose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining well-tolerated antibiotic doxycycline (DOX) with CPA and understanding the mechanism of cell killing. Interestingly, we found that DOX significantly enhances the tumor regression activity of CPA on xenograft mice model bearing MCF-7 cells. DOX also potentiates MCF-7 cell killing by CPA in vitro. In presence of DOX (3 {mu}g/ml), the IC{sub 50} value of CPA decreased significantly from 10 to 2.5 mM. Additional analyses indicate that the tumor suppressor p53 and p53-regulated proapoptotic Bax were upregulated in vivo and in vitro following CPA treatment in combination with DOX, suggesting that upregulation of p53 may contribute to the enhancement of antitumor effect of CPA by DOX. Furthermore, downregulation of antiapoptotic Bcl-2 was observed in animals treated with CPA and CPA plus DOX when compared to untreated or DOX-treated groups. Our results raise the possibility that this combination chemotherapeutic regimen may lead to additional improvements in treatment of breast cancer.

  18. Histone deacetylase inhibitory effect of Brazilian propolis and its association with the antitumor effect in Neuro2a cells

    PubMed Central

    Ishiai, Shinobu; Tahara, Wataru; Yamamoto, Etsuko; Yamamoto, Rindai; Nagai, Kaoru

    2014-01-01

    Propolis is a resinous product produced by honey bees and is known to have antitumor functions. On the other hand, histone deacetylase (Hdac) inhibitors have recently attracted attention for their antitumor effects. In this study, we examined whether Brazilian green propolis has an Hdac inhibitory activity and its contribution on antitumor effects. By in vitro Hdac activity assay, Brazilian propolis extract (BPE) significantly inhibited the enzyme activity. Actually, BPE treatment increased the intracellular histone acetylation in Neuro2a cells. Regarding antitumor effect in Neuro2a cells, BPE treatment significantly decreased cell viability. An Hdac activator theophylline significantly attenuated the effect. Then, we analyzed whether the decreasing effect on cell number was caused by cell death or growth retardation. By live/dead cell staining, BPE treatment significantly increased the dead cell number. By cell cycle analysis, BPE treatment retarded cell cycle at the M-phase. Both of these cellular effects were suppressed by addition of theophylline. These data indicate that BPE induced both cell death and growth retardation via Hdac inhibitory activity. We demonstrated that Brazilian propolis bears regulatory functions on histone acetylation via Hdac inhibition, and the effect contributes antitumor functions. Our data suggest that intake of Brazilian propolis shows preventing effects against cancer. PMID:25473514

  19. [Research progress on anti-tumor effect of Huaier].

    PubMed

    Yang, Ai-lin; Hu, Zhong-dong; Tu, Peng-fei

    2015-12-01

    Huaier (Trametes robiniophila) has been widely used as an adjuvant drug for cancer treatment in China. The anti-cancer effect of Huaier extract has been confirmed in liver cancer, lung cancer, breast cancer, ovarian cancer, gastric cancer, and so on. The main mechanisms by which Huaier exerts an anti-neoplastic effect include inhibition of the growth and proliferation of cancer cells, induction of apoptosis of cancer cells, suppression of angiogenesis, inhibition of the invasion and migration of cancer cells, regulation of oncogenes and tumor suppressor genes expression, improving immunity, and reversal of drug resistance in cancer cells. In order to provide references for further study and clinical application on anti-tumor effect of Huaier, the latest research progress on anti-tumor effect of Huaier in recent years is summarized in this paper. PMID:27245026

  20. Metronomic docetaxel in PRINT® nanoparticles and EZH2 silencing have synergistic antitumor effect in ovarian cancer

    PubMed Central

    Gharpure, Kshipra M.; Chu, Kevin S.; Bowerman, Charles; Miyake, Takahito; Pradeep, Sunila; Mangala, Selanere L.; Han, Hee-Dong; Rupaimoole, Rajesha; Armaiz-Pena, Guillermo N.; Rahhal, Tojan B.; Wu, Sherry Y.; Luft, J. Christopher; Napier, Mary E; Lopez-Berestein, Gabriel; DeSimone, Joseph M; Sood, Anil K.

    2014-01-01

    The purpose of this study was to investigate the antitumor effects of a combination of metronomic doses of a novel delivery vehicle, PLGA-PRINT nanoparticles containing docetaxel, and anti-angiogenic mEZH2 siRNA incorporated into chitosan nanoparticles. In vivo dose-finding studies and therapeutic experiments were conducted in well-established orthotopic mouse models of epithelial ovarian cancer. Antitumor effects were determined on the basis of reduction in mean tumor weight and number of metastatic tumor nodules in the animals. The tumor tissues from these in vivo studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase 3), and microvessel density (CD31). The lowest dose of metronomic regimen (0.5 mg/kg) resulted in significant reduction in tumor growth. The combination of PLGA-PRINT-docetaxel and CH-mEZH2 siRNA showed significant antitumor effects in the HeyA8 and SKOV3ip1 tumor models (p<0.05). Individual as well as combination therapies showed significant anti-angiogenic, anti-proliferative, and pro-apoptotic effects, and combination therapy had additive effects. Metronomic delivery of PLGA-PRINT-docetaxel combined with CH-mEZH2 siRNA has significant antitumor activity in preclinical models of ovarian cancer. PMID:24755199

  1. The antitumor effect of magnetic nanodisks and DNA aptamer conjugates.

    PubMed

    Kim, P D; Zamay, S S; Zamay, T N; Prokopenko, V S; Kolovskaya, O S; Zamay, G S; Princ, V Ya; Seleznev, V A; Komonov, A I; Spivak, E A; Rudenko, R Yu; Dubinina, A V; Komarov, A V; Denisenko, V V; Komarova, M A; Sokolov, A E; Narodov, A A; Zjivaev, V P; Zamay, A S

    2016-01-01

    Here we describe a method of forming large arrays (up to 10(9) pieces) of free magnetic Ni-nanodisks 50 nm thick coated on both sides with layers of 5 nm thick Au. The antitumor effect of the magnetic nickel gold-coated nanodisks and DNA aptamer conjugates was evaluated in vivo and in vitro. Under the influence of rotating magnetic field, the studied nanodisks can cause the death of Ehrlich ascites carcinoma cells. PMID:27025491

  2. Anti-tumor effects and cellular mechanisms of resveratrol.

    PubMed

    Han, Guohua; Xia, Jufeng; Gao, Jianjun; Inagaki, Yoshinori; Tang, Wei; Kokudo, Norihiro

    2015-02-01

    Resveratrol (3, 5, 4'-trihydroxystilbene) is a phytoalexin contained in a variety of plants, such as grapes, berries and especially in the dried roots of Polygonum cuspidatum Sieb. et Zucc. It has been shown to exhibit anti-oxidative and anti-inflammation activity, and to reverse the effects of aging. Its ability to suppress cell proliferation, induce apoptosis and suppress the metastasis and invasion in a number of cell lines has prompted a large interest from people for its use as an anti-tumor component. In this review, evidence of resveratrol's anti-tumor effects and molecular mechanisms are recapitulated. First, we present the anti-apoptosis, anti-invasion/metastasis and anti-inflammation effect of resveratrol; second, the main signaling pathways involved in these activities are described and summarized with the studies of different tumors involved. Resveratrol not only induces apoptosis of tumor cells through intrinsic/extrinsic pathways and cell cycle arrest, but also inhibits the invasion and metastasis abilities of tumors via modulating collagen degradation-related molecular targets. Altogether, the present findings suggest the anti-tumor potential of resveratrol against various types of cancers. PMID:25788047

  3. Antitumor effects of the benzophenanthridine alkaloid sanguinarine: Evidence and perspectives

    PubMed Central

    Gaziano, Roberta; Moroni, Gabriella; Buè, Cristina; Miele, Martino Tony; Sinibaldi-Vallebona, Paola; Pica, Francesca

    2016-01-01

    Historically, natural products have represented a significant source of anticancer agents, with plant-derived drugs becoming increasingly explored. In particular, sanguinarine is a benzophenanthridine alkaloid obtained from the root of Sanguinaria canadensis, and from other poppy Fumaria species, with recognized anti-microbial, anti-oxidant and anti-inflammatory properties. Recently, increasing evidence that sanguinarine exibits anticancer potential through its capability of inducing apoptosis and/or antiproliferative effects on tumor cells, has been proved. Moreover, its antitumor seems to be due not only to its pro-apoptotic and inhibitory effects on tumor growth, but also to its antiangiogenic and anti-invasive properties. Although the precise mechanisms underlying the antitumor activity of this compound remain not fully understood, in this review we will focus on the most recent findings about the cellular and molecular pathways affected by sanguinarine, together with the rationale of its potential application in clinic. The complex of data currently available suggest the potential application of sanguinarine as an adjuvant in the therapy of cancer, but further pre-clinical studies are needed before such an antitumor strategy can be effectively translated in the clinical practice. PMID:26798435

  4. Antitumor effects of the benzophenanthridine alkaloid sanguinarine: Evidence and perspectives.

    PubMed

    Gaziano, Roberta; Moroni, Gabriella; Buè, Cristina; Miele, Martino Tony; Sinibaldi-Vallebona, Paola; Pica, Francesca

    2016-01-15

    Historically, natural products have represented a significant source of anticancer agents, with plant-derived drugs becoming increasingly explored. In particular, sanguinarine is a benzophenanthridine alkaloid obtained from the root of Sanguinaria canadensis, and from other poppy Fumaria species, with recognized anti-microbial, anti-oxidant and anti-inflammatory properties. Recently, increasing evidence that sanguinarine exibits anticancer potential through its capability of inducing apoptosis and/or antiproliferative effects on tumor cells, has been proved. Moreover, its antitumor seems to be due not only to its pro-apoptotic and inhibitory effects on tumor growth, but also to its antiangiogenic and anti-invasive properties. Although the precise mechanisms underlying the antitumor activity of this compound remain not fully understood, in this review we will focus on the most recent findings about the cellular and molecular pathways affected by sanguinarine, together with the rationale of its potential application in clinic. The complex of data currently available suggest the potential application of sanguinarine as an adjuvant in the therapy of cancer, but further pre-clinical studies are needed before such an antitumor strategy can be effectively translated in the clinical practice. PMID:26798435

  5. Anti-tumor effects of an engineered 'killer' transfer RNA

    SciTech Connect

    Zhou, Dong-hui; Lee, Jiyoung; Frankenberger, Casey; Geslain, Renaud; Rosner, Marsha; Pan, Tao

    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.

  6. Inhibition of rhotekin exhibits antitumor effects in lung cancer cells

    PubMed Central

    ZHANG, WEIZHEN; LIANG, ZHENYU; LI, JING

    2016-01-01

    Lung cancer is the leading cause for cancer-related death, however, the pathogenesis mechanism is poorly understood. Although the rhotekin (RTKN) gene has been reported to encode an effector for the Rho protein that has critical roles in regulating cell growth, the role of RTKN in lung cancer has not been investigated. In clinical lung cancer patient tumor samples, we identified that the RTKN gene expression level was significantly higher in tumor tissues compared to that of the adjacent normal tissues. To investigate the molecular mechanisms of RTKN in lung cancer, we established RTKN stable knock-down A549 and SPC-A-1 lung adenocarcinoma cell lines using lentiviral transfection of RTKN shRNA and evaluated the antitumor effects. The results showed that RTKN knock-down inhibited lung adenocarcinoma cell viability, induced S phase arrest and increased cell apoptosis. In addition, RTKN knock-down inhibited lung cancer cell invasion and adhesion. Further analysis showed that the S phase promoting factors cyclindependent kinase (CDK)1 and CDK2 levels were decreased in RTKN knock-down cells, and that the DNA replication initiation complex proteins Minichromosome maintenance protein complex (MCM)2 and MCM6 were decreased as well in RTKN knock-down cells. These results indicated that the RTKN protein was associated with lung cancer in clinic samples and exerted anticancer activity in lung adenocarcinoma cells through inhibiting cell cycle progression and the DNA replication machinery. These findings suggest that RTKN inhibition may be a novel therapeutic strategy for lung adenocarcinoma. PMID:26935528

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

    PubMed

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

    1977-06-01

    An almost purified antitumor polysaccharide fraction (SFPP) was obtained by fractional precipitation with ethanol from hot-water extract of Sargassum fulvellum. The fraction showed remarkable tumor-inhibiting effect against sarcoma-180 implanted subcutaneously in mice. The results of chemical and physical analyses suggested that the active substance may be either a sulphated peptidoglycuronoglycan or a sulphated glycuronoglycan. PMID:916293

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed

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

    2016-01-01

    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. PMID:26907515

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

    PubMed Central

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

    2016-01-01

    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. PMID:26907515

  11. Lectin of Abelmoschus esculentus (okra) promotes selective antitumor effects in human breast cancer cells.

    PubMed

    Monte, Leonardo G; Santi-Gadelha, Tatiane; Reis, Larissa B; Braganhol, Elizandra; Prietsch, Rafael F; Dellagostin, Odir A; E Lacerda, Rodrigo Rodrigues; Gadelha, Carlos A A; Conceição, Fabricio R; Pinto, Luciano S

    2014-03-01

    The anti-tumor effects of a newly-discovered lectin, isolated from okra, Abelmoschus esculentus (AEL), were investigated in human breast cancer (MCF7) and skin fibroblast (CCD-1059 sk) cells. AEL induced significant cell growth inhibition (63 %) in MCF7 cells. The expression of pro-apoptotic caspase-3, caspase-9, and p21 genes was increased in MCF7 cells treated with AEL, compared to those treated with controls. In addition, AEL treatment increased the Bax/Bcl-2 ratio in MCF7 cells. Flow cytometry also indicated that cell death (72 %) predominantly occurred through apoptosis. Thus, AEL in its native form promotes selective antitumor effects in human breast cancer cells and may represent a potential therapeutic to combat human breast cancer. PMID:24129958

  12. Anti-tumor effects of an engineered "killer" transfer RNA.

    PubMed

    Zhou, Dong-hui; Lee, Jiyoung; Frankenberger, Casey; Geslain, Renaud; Rosner, Marsha; Pan, Tao

    2012-10-12

    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. PMID:22989754

  13. Features of the Antitumor Effect of Vaccinia Virus Lister Strain

    PubMed Central

    Zonov, Evgeniy; Kochneva, Galina; Yunusova, Anastasiya; Grazhdantseva, Antonina; Richter, Vladimir; Ryabchikova, Elena

    2016-01-01

    Oncolytic abilities of vaccinia virus (VACV) served as a basis for the development of various recombinants for treating cancer; however, “natural” oncolytic properties of the virus are not examined in detail. Our study was conducted to know how the genetically unmodified L-IVP strain of VACV produces its antitumor effect. Human A431 carcinoma xenografts in nude mice and murine Ehrlich carcinoma in C57Bl mice were used as targets for VACV, which was injected intratumorally. A set of virological methods, immunohistochemistry, light and electron microscopy was used in the study. We found that in mice bearing A431 carcinoma, the L-IVP strain was observed in visceral organs within two weeks, but rapidly disappeared from the blood. The L-IVP strain caused decrease of sizes in both tumors, however, in different ways. Direct cell destruction by replicating virus plays a main role in regression of A431 carcinoma xenografts, while in Ehrlich carcinoma, which poorly supported VACV replication, the virus induced decrease of mitoses by pushing tumor cells into S-phase of cell cycle. Our study showed that genetically unmodified VACV possesses at least two mechanisms of antitumor effect: direct destruction of tumor cells and suppression of mitoses in tumor cells. PMID:26771631

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

    NASA Astrophysics Data System (ADS)

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

    2016-07-01

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

  15. Features of the Antitumor Effect of Vaccinia Virus Lister Strain.

    PubMed

    Zonov, Evgeniy; Kochneva, Galina; Yunusova, Anastasiya; Grazhdantseva, Antonina; Richter, Vladimir; Ryabchikova, Elena

    2016-01-01

    Oncolytic abilities of vaccinia virus (VACV) served as a basis for the development of various recombinants for treating cancer; however, "natural" oncolytic properties of the virus are not examined in detail. Our study was conducted to know how the genetically unmodified L-IVP strain of VACV produces its antitumor effect. Human A431 carcinoma xenografts in nude mice and murine Ehrlich carcinoma in C57Bl mice were used as targets for VACV, which was injected intratumorally. A set of virological methods, immunohistochemistry, light and electron microscopy was used in the study. We found that in mice bearing A431 carcinoma, the L-IVP strain was observed in visceral organs within two weeks, but rapidly disappeared from the blood. The L-IVP strain caused decrease of sizes in both tumors, however, in different ways. Direct cell destruction by replicating virus plays a main role in regression of A431 carcinoma xenografts, while in Ehrlich carcinoma, which poorly supported VACV replication, the virus induced decrease of mitoses by pushing tumor cells into S-phase of cell cycle. Our study showed that genetically unmodified VACV possesses at least two mechanisms of antitumor effect: direct destruction of tumor cells and suppression of mitoses in tumor cells. PMID:26771631

  16. Differential Fc-receptor engagement drives an anti-tumor vaccinal effect

    PubMed Central

    DiLillo, David J.; Ravetch, Jeffrey V.

    2015-01-01

    Summary Passively-administered anti-tumor mAbs rapidly kill tumor targets via FcγR-mediated cytotoxicity (ADCC), a short-term process. However, anti-tumor mAb treatment can also induce a vaccinal effect, in which mAb-mediated tumor death induces a long-term anti-tumor cellular immune response. To determine how such responses are generated, we utilized a murine model of an anti-tumor vaccinal effect against a model neoantigen. We demonstrate that FcγR expression by CD11c+ antigen-presenting cells is required to generate anti-tumor T cell responses upon ADCC-mediated tumor clearance. Using FcγR-humanized mice, we demonstrate that anti-tumor huIgG1 must engage hFcγRIIIA on macrophages to mediate ADCC, but also engage hFcγRIIA, the sole hFcγR expressed by human DCs, to generate a potent vaccinal effect. Thus, while next-generation anti-tumor antibodies with enhanced binding to only hFcγRIIIA are now in clinical use, ideal anti-tumor antibodies must be optimized for both cytotoxic effects as well as hFcγRIIA engagement on DCs to stimulate long-term anti-tumor cellular immunity. PMID:25976835

  17. Anti-Tumor Effects From Dendritic Cell-Based Cancer Immunotherapy Using Liposomal Bubbles and Ultrasound

    NASA Astrophysics Data System (ADS)

    Oda, Yusuke; Suzuki, Ryo; Hirata, Keiichi; Nomura, Tetsuya; Utoguchi, Naoki; Maruyama, Kazuo

    2011-09-01

    Dendritic cell (DC)-based cancer immunotherapy has the potential to be a minimally invasive therapy that could prevent cancer metastasis and recurrence. Recently, in order to induce effective anti-tumor immunity, we developed a novel antigen delivery system for DCs by the combination of ultrasound (US) and liposomal bubbles (Bubble Liposomes: BLs) with entrapped perfluoropropane gas. In this study, we investigated the induction of antigen specific immune responses in vivo and the anti-tumor effect caused by immunization of DCs treated with BLs and US. For the immunization of DCs which had delivered antigen, using BLs and US, the mice induced antigen specific cytotoxic T lymphocytes (CTLs) were found to be the main effector cells in DC-based cancer immunotherapy. In addition, immunization with DCs that had been pulsed with antigen using BLs and US completely suppressed tumor growth Therefore, immunization of DCs with this antigen delivery system has promise for the efficient induction of anti-tumor immune responses.

  18. Celecoxib exerts antitumor effects in canine mammary tumor cells via COX‑2‑independent mechanisms.

    PubMed

    Tamura, Dai; Saito, Teruyoshi; Murata, Kanae; Kawashima, Masafumi; Asano, Ryuji

    2015-03-01

    Celecoxib plays antitumor roles via multiple mechanisms in a variety of human cancers. The aim of this study was to clarify the mechanism of action of celecoxib in canine mammary tumors. We examined the antitumor effects of celecoxib in AZACB canine mammary tumor cells expressing low levels of cyclooxygenase‑2 (COX‑2) to minimize the effect of COX‑2 on its activity. Our data revealed that celecoxib inhibited cell proliferation mainly via COX‑2‑independent mechanisms. Specifically, celecoxib decreased the proportion of cells in S phase and increased G2/M arrest, which was associated with increased expression of the cyclin‑dependent kinase inhibitors (CDKIs) p21 and p27. In addition, treatment with celecoxib downregulated COX‑2 expression, and induced apoptosis via both the intrinsic and extrinsic pathways. These findings suggest that celecoxib might be a useful agent for the treatment of canine mammary tumors, regardless of COX‑2 expression. In the future, it might be possible to use a combination of celecoxib and other antitumor agents to treat canine mammary tumors. PMID:25571853

  19. Antiangiogenic and Antitumor Effects of Trypanosoma cruzi Calreticulin

    PubMed Central

    López, Nandy C.; Valck, Carolina; Ramírez, Galia; Rodríguez, Margarita; Ribeiro, Carolina; Orellana, Juana; Maldonado, Ismael; Albini, Adriana; Anacona, Daniel; Lemus, David; Aguilar, Lorena; Schwaeble, Wilhelm; Ferreira, Arturo

    2010-01-01

    Background In Latin America, 18 million people are infected with Trypanosoma cruzi, the agent of Chagas' disease, with the greatest economic burden. Vertebrate calreticulins (CRT) are multifunctional, intra- and extracellular proteins. In the endoplasmic reticulum (ER) they bind calcium and act as chaperones. Since human CRT (HuCRT) is antiangiogenic and suppresses tumor growth, the presence of these functions in the parasite orthologue may have consequences in the host/parasite interaction. Previously, we have cloned and expressed T. cruzi calreticulin (TcCRT) and shown that TcCRT, translocated from the ER to the area of trypomastigote flagellum emergence, promotes infectivity, inactivates the complement system and inhibits angiogenesis in the chorioallantoid chicken egg membrane. Most likely, derived from these properties, TcCRT displays in vivo inhibitory effects against an experimental mammary tumor. Methodology and Principal Findings TcCRT (or its N-terminal vasostatin-like domain, N-TcCRT) a) Abrogates capillary growth in the ex vivo rat aortic ring assay, b) Inhibits capillary morphogenesis in a human umbilical vein endothelial cell (HUVEC) assay, c) Inhibits migration and proliferation of HUVECs and the human endothelial cell line Eahy926. In these assays TcCRT was more effective, in molar terms, than HuCRT: d) In confocal microscopy, live HUVECs and EAhy926 cells, are recognized by FITC-TcCRT, followed by its internalization and accumulation around the host cell nuclei, a phenomenon that is abrogated by Fucoidin, a specific scavenger receptor ligand and, e) Inhibits in vivo the growth of the murine mammary TA3 MTXR tumor cell line. Conclusions/Significance We describe herein antiangiogenic and antitumor properties of a parasite chaperone molecule, specifically TcCRT. Perhaps, by virtue of its capacity to inhibit angiogenesis (and the complement system), TcCRT is anti-inflammatory, thus impairing the antiparasite immune response. The TcCRT antiangiogenic

  20. Anti-tumor effects of pigment epithelium-derived factor (PEDF): implication for cancer therapy. A mini-review.

    PubMed

    Belkacemi, Louiza; Zhang, Shaun Xiaoliu

    2016-01-01

    Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein and a non-inhibitory member of the serine protease inhibitor (serpin) family. It is widely expressed in human fetal and adult tissues but its expression decreases with age and in malignant tissues. The main anti-cancer activities of PEDF derive from its dual effects, either indirectly on the tumor microenvironment (indirect antitumor action) or directly on the tumor itself (direct antitumor influence). The indirect antitumor activities of PEDF were uncovered from the early findings that it stimulates retinoblastoma cell differentiation and that additionally it possesses anti-angiogenic, anti-tumorigenic and anti-metastatic properties. The mechanisms of its direct antitumor effect, however, have not been fully elucidated. This review highlights recent progress in our understanding of the multifunctional activities of PEDF and, in particular, its anti-cancer signaling mechanisms. Additionally, we discuss the possibility of using novel phosphaplatin compounds that can upregulate PEDF expression as a chemotherapy for cancer treatment. PMID:26746675

  1. Enhanced antitumor effect of curcumin liposomes with local hyperthermia in the LL/2 model.

    PubMed

    Tang, Jian-Cai; Shi, Hua-Shan; Wan, Li-Qiang; Wang, Yong-Sheng; Wei, Yu-Quan

    2013-01-01

    Curcumin previously was proven to inhibit angiogenesis and display potent antitumor activity in vivo and in vitro. In the present study, we investigated whether a combination curcumin with hyperthermia would have a synergistic antitumor effect in the LL/2 model. The results indicated that combination therapy significantly inhibited cell proliferation of MS-1 and LL/2 in vitro. LL/2 experiment model also demonstrated that the combination therapy inhibited tumor growth and prolonged the life span in vivo. Furthermore, combination therapy reduced angiogenesis and increased tumor apoptosis. Our findings suggest that the combination therapy exerted synergistic antitumor effects, providing a new perspective fpr clinical tumor therapy. PMID:23725132

  2. Young Barley Indicates Antitumor Effects in Experimental Breast Cancer In Vivo and In Vitro.

    PubMed

    Kubatka, Peter; Kello, Martin; Kajo, Karol; Kruzliak, Peter; Výbohová, Desanka; Šmejkal, Karel; Maršík, Petr; Zulli, Anthony; Gönciová, Gabriela; Mojžiš, Ján; Kapinová, Andrea; Murin, Radovan; Péč, Martin; Adamkov, Marián; Przygodzki, Ronald M

    2016-01-01

    The effect of dietary administered young barley containing a mixture of phytochemicals to female rats for the prevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis was evaluated. After carcinogen administration (14 wk), mammary tumors were removed and prepared for histopathological and immunohistochemical analysis. Moreover, in vitro evaluation of possible mechanisms in MCF-7 breast cancer cell line was performed. Barley (0.3%) demonstrated mild antitumor effect in mammary carcinogenesis, yet 3% barley did not further improve this effect. Immunohistochemical analysis of rat tumor cells in treated groups showed significant increase in caspase-3 expression and significant reduction in Ki67 expression. In addition, 3% barley significantly decreased dityrosine levels versus control. Barley in higher dose significantly decreased serum low-density lipoprotein-cholesterol in rats. In vitro studies showed that barley significantly decreased survival of MCF-7 cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and significantly decreased 5-bromo-20-deoxyuridine incorporation versus control. Barley prevented cell cycle progression and extended incubation with barley showed significant increase in the percentage of annexin V/propidium iodide-positive MCF-7 cells. Our results propose an antitumor effect for the mixture of phytochemicals present in young barley in a breast cancer model. PMID:27042893

  3. Antitumor and immunostimulating effects of Anoectochilus formosanus Hayata.

    PubMed

    Tseng, C-C; Shang, H-F; Wang, L-F; Su, B; Hsu, C-C; Kao, H-Y; Cheng, K-T

    2006-05-01

    The water extract of Anoectochilus formosanus Hayata showed a potent tumor inhibitory activity in BALB/c mice after subcutaneous transplantation of CT-26 murine colon cancer cells. The tumor-inhibition ratios of mice pre-administered with A. formosanus for 2 days before tumor transplantation, and treated further for 12 consecutive days, were 55.4% and 58.9% at the oral dose of 50 and 10 mg/mouse per day, respectively. Even for the tumor-bearing mice, after oral administration of the water extract of A. formosanus for 12 consecutive days, the tumor inhibition ratios were still 23.8% and 40.5% at doses of 50 and 10 mg/mouse, respectively. Because the low-concentration water extract of A. formosanus does not show direct cytotoxicity in CT-26 tumor cells, we observed further that oral administration of the water extract of A. formosanus may activate murine immune responses, such as stimulating the proliferation of lymphoid tissues and activating the phagocytosis of peritoneal macrophages against Staphylococcus aureus. This study suggests that the antitumor activity of A. formosanus may be associated with its potent immunostimulating effect. It is worth further analyzing the immunomodulating component purified from A. formosanus, and evaluating its potential value for the treatment of human cancers. PMID:16635745

  4. Immunological mechanisms of the antitumor effects of supplemental oxygenation

    PubMed Central

    Hatfield, Stephen M.; Kjaergaard, Jorgen; Lukashev, Dmitriy; Schreiber, Taylor H.; Belikoff, Bryan; Abbott, Robert; Sethumadhavan, Shalini; Philbrook, Phaethon; Ko, Kami; Cannici, Ryan; Thayer, Molly; Rodig, Scott; Kutok, Jeffrey L.; Jackson, Edwin K.; Karger, Barry; Podack, Eckhard R.; Ohta, Akio; Sitkovsky, Michail V.

    2015-01-01

    Antitumor T cells either avoid or are inhibited in hypoxic and extracellular adenosine-rich tumor microenvironments (TMEs) by A2A adenosine receptors. This may limit further advances in cancer immunotherapy. There is a need for readily available and safe treatments that weaken the hypoxia–A2-adenosinergic immunosuppression in the TME. Recently, we reported that respiratory hyperoxia decreases intratumoral hypoxia and concentrations of extracellular adenosine. We show that it also reverses the hypoxia-adenosinergic immunosuppression in the TME. This, in turn, stimulates (i) enhanced intratumoral infiltration and reduced inhibition of endogenously developed or adoptively transfered tumor-reactive CD8 T cells, (ii) increased proinflammatory cytokines and decreased immunosuppressive molecules, such as transforming growth factor–β (TGF-β), (iii) weakened immunosuppression by regulatory T cells, and (iv) improved lung tumor regression and long-term survival in mice. Respiratory hyperoxia also promoted the regression of spontaneous metastasis from orthotopically grown breast tumors. These effects are entirely T cell– and natural killer cell–dependent, thereby justifying the testing of supplemental oxygen as an immunological coadjuvant to combine with existing immunotherapies for cancer. PMID:25739764

  5. Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immunotherapy

    PubMed Central

    Sckisel, Gail D.; Mirsoian, Annie; Bouchlaka, Myriam N.; Tietze, Julia K.; Chen, Mingyi; Blazar, Bruce R.

    2016-01-01

    We have demonstrated that immunostimulatory therapies such as interleukin-2 (IL-2) and anti-CD40 (αCD40) can be combined to deliver synergistic anti-tumor effects. While this strategy has shown success, efficacy varies depending on a number of factors including tumor type and severe toxicities can be seen. We sought to determine whether blockade of negative regulators such as cytotoxic T lymphocyte antigen-4 (CTLA-4) could simultaneously prolong CD8+ T cell responses and augment T cell anti-tumor effects. We devised a regimen in which anti-CTLA-4 was administered late so as to delay contraction and minimize toxicities. This late administration both enhanced and prolonged CD8 T cell activation without the need for additional IL-2. The quality of the T cell response was improved with increased frequency of effector/effector memory phenotype cells along with improved lytic ability and bystander expansion. This enhanced CD8 response translated to improved anti-tumor responses both at the primary and metastatic sites. Importantly, toxicities were not exacerbated with combination. This study provides a platform for rational design of immunotherapy combinations to maximize anti-tumor immunity while minimizing toxicities. PMID:26423422

  6. Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

    PubMed Central

    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

  7. Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer.

    PubMed

    Xiang, Meixian; Su, Hanwen; Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

    2016-04-01

    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

  8. The antitumor effect of locoregional magnetic cobalt ferrite in dog mammary adenocarcinoma

    NASA Astrophysics Data System (ADS)

    Şincai, Mariana; Gângǎ, Diana; Bica, Doina; Vékás, Ladislau

    2001-01-01

    The endocytosis of nanosized magnetic particles by tumor cells led to numerous tests to establish the use of this phenomenon in antitumor therapy. The direct antitumor effect of a biocompatible cobalt-ferrite-based magnetic fluid directly inoculated in bitch mammary tumors was studied. A direct correlation between tumor cell lysis and cobalt ferrite was established in tumors. Massive endocytosis of magnetic particles was observed 1 h after the contact of magnetic fluid with tumor cells.

  9. [Progress of study on antitumor effects of antibody dependent cell mediated cytotoxicity--review].

    PubMed

    Qu, Yu-Hua; Li, Yang

    2010-10-01

    In recent years, as increasing of monoclonal antibody application in clinic, the antitumor effect of antibody dependent cell-mediated cytotoxicity (ADCC) get increasing attention. The natural killer (NK) cells are the most important effector cells mediating specific antitumor of ADCC; the phagocytes, T-cells and granulocytes have the definite effect on antitumor of ADCC. ADCC is confirmed as the important mechanism and means for clinically treating the cancers with monoclonal antibodies. The IgG antibody firstly combines with target cells (tumor cells) through antigen-binding sites, and then FcγR on effector cells identifies its Fc fragment and mediates ADCC. Today many kinds of monoclonal antibodies have been put into clinical application such as rituximab and other new anti-CD20 monoclonal antibodies including trastuzumab, erbitux, cetuximab, edrecolomab, nimotuzumab, gemtuzumab ozogamicin and so on, which all can mediate ADCC. The antitumor effects of ADCC mediated by monoclonal antibody can be influenced by IgG Fc receptor gene polymorphism, tumor cell antigen, serum antibody levels, cytokines and drugs etc. As to peripheral blood mononuclear cells, ADCC efficacies of FcγRIIIa-158V/V and FcγRIIa-131H/H are higher than that of other genotypes, while increasing the level of tumor antigen and decreasing the level of serum antibody or adding some cytokines (IL-2, IL-21, IL-15, etc) may elevate the ADCC effect mediated by monoclonal antibodies. Avoiding use of certain drugs (dexamethasone, TNF antagonist) or appropriately using of ondansetron and clemastine also can enhance the anti-tumor effect of ADCC mediated by monoclonal antibodies. In short, ADCC is very important in clinical application for anti-tumor treatment, but its efficacy may be impacted by multiple factors.In this article, the killing mechanisms of ADCC, the clinical use of monoclonal antibodies with antitumor effect of ADCC, the factors influencing anti-tumor efficacy of ADCC, and the antitumor

  10. Antitumor effects of traditional Chinese medicine targeting the cellular apoptotic pathway

    PubMed Central

    Xu, Huanli; Zhao, Xin; Liu, Xiaohui; Xu, Pingxiang; Zhang, Keming; Lin, Xiukun

    2015-01-01

    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. PMID:26056434

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

    NASA Astrophysics Data System (ADS)

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

    2015-09-01

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

  12. Increased anti-tumor effects using IL2 with anti-TGFβ reveals competition between mouse NK and CD8 T cells

    PubMed Central

    Alvarez, Maite; Bouchlaka, Myriam N.; Sckisel, Gail D.; Sungur, Can M.; Chen, Mingyi; Murphy, William J.

    2014-01-01

    Due to increasing interest in the removal of immunosuppressive pathways in cancer, the combination of IL2 with antibodies to neutralize TGFβ, a potent immunosuppressive cytokine, was assessed. Combination immunotherapy resulted in significantly greater anti-tumor effects. These were correlated with significant increases in the numbers and functionality of NK cells, NK progenitors and activated CD8 T cells resulting in the observed anti-tumor effects. Combination immunotherapy was also accompanied with lesser toxicities than IL2 therapy alone. Additionally, we observed a dual competition between NK and activated CD8 T cells such that after immunotherapy, the depletion of either effector population resulted in the increased total expansion of the other population and compensatory anti-tumor effects. This study demonstrates the efficacy of this combination immunotherapeutic regimen as a promising cancer therapy and illustrates the existence of potent competitive regulatory pathways between NK and CD8 T cells in response to systemic activation. PMID:25000978

  13. Oligoesculin fraction induces anti-tumor effects and promotes immune responses on B16-F10 mice melanoma.

    PubMed

    Mokdad Bzeouich, Imen; Mustapha, Nadia; Sassi, Aicha; Ghedira, Kamel; Ghoul, Mohamed; Chebil, Latifa; Luis, José; Chekir-Ghedira, Leila

    2016-08-01

    Laccase was used to enzymatically polymerize esculin. Oligoesculin fraction was obtained after ultrafiltration through a 5-kDa membrane. Several studies have been carried out to prove the effectiveness of natural substances such as immunomodulators to promote the anti-cancer activity in situ. The purpose of our report was to explore whether the anti-tumor potential of the oligoesculin fraction in vitro and in vivo is linked to its immunological mechanisms in melanoma-bearing mice. We revealed that oligoesculin fraction reduced B16-F10 proliferation and migration in vitro in a dose-related manner. Moreover, melanin synthesis and tyrosinase activity were inhibited in these melanoma cells in a concentration-dependent way. The anti-tumor potential of oligoesculin fraction was also assessed in vivo. Our results showed that intraperitoneal administration of oligoesculin fraction, at 50 mg/kg body weight (b.w.) for 21 days, reduced tumor size and weight with percentages of inhibition of 94 and 87 %, respectively. Oligoesculin fraction was effective in promoting lysosomal activity and nitric oxide (NO) production by peritoneal macrophages in tumor-implanted mice. In addition, the activities of natural killer (NK), cytotoxic T lymphocytes, and macrophages were significantly enhanced by oligoesculin fraction. These findings suggested that this polymer with its anti-tumor and immunomodulatory properties could be used for the treatment of melanoma. PMID:26960691

  14. In vitro antitumor effects of two novel oligostilbenes, cis- and trans-suffruticosol D, isolated from Paeonia suffruticosa seeds.

    PubMed

    Almosnid, Nadin Marwan; Gao, Ying; He, Chunnian; Park, Hyo Sim; Altman, Elliot

    2016-02-01

    Naturally derived stilbenes have been shown to elicit cytotoxic, anti-steroidal, anti-mutagenic, anti-oxidative, anti-inflammatory, and antitumor bioactivities. Previous phytochemical studies revealed that the seeds of Paeonia suffruticosa are rich in natural stilbenes. In this study the antitumor effects and mechanism of action of the oligostilbene isomers, cis- and trans-suffruticosol D, isolated from the seeds of P. suffruticosa were examined. cis- and trans-suffruticosol D exhibited remarkable cytotoxicity against the human cancer cell lines A549 (lung), BT20 (breast), MCF-7 (breast), and U2OS (osteosarcoma), but showed significantly less toxicity to the normal human cell lines HMEC (breast) and HPL1A (lung). We also demonstrated that cis- and trans-suffruticosol D exerted their antitumor effects by provoking oxidative stress, stimulating apoptosis, decreasing the mitochondrial membrane potential, inhibiting cell motility, and blocking the NF-κB pathway in human lung cancer cells. In addition, we evaluated their respective bioefficacy and found that trans-suffruticosol D is more potent than cis-suffruticosol D. Collectively, our results suggest that cis- and trans-suffruticosol D could be promising chemotherapeutic agents against cancer. PMID:26647827

  15. Potassium increases the antitumor effects of ascorbic acid in breast cancer cell lines in vitro

    PubMed Central

    FRAJESE, GIOVANNI VANNI; BENVENUTO, MONICA; FANTINI, MASSIMO; AMBROSIN, ELENA; SACCHETTI, PAMELA; MASUELLI, LAURA; GIGANTI, MARIA GABRIELLA; MODESTI, ANDREA; BEI, ROBERTO

    2016-01-01

    Ascorbic acid (A) has been demonstrated to exhibit anti-cancer activity in association with chemotherapeutic agents. Potassium (K) is a regulator of cellular proliferation. In the present study, the biological effects of A and K bicarbonate, alone or in combination (A+K), on breast cancer cell lines were evaluated. The survival of cancer cells was determined by sulforhodamine B cell proliferation assay, while analysis of the cell cycle distribution was conducted via fluorescence-activated cell sorting. In addition, the expression of signaling proteins was analyzed upon treatment. The results indicated that there was a heterogeneous response of the different cell lines to A and K, and the best effects were achieved by A+K and A treatment. The interaction between A+K indicated an additive or synergistic effect. In addition, A+K increased the percentage of cells in the sub-G1 phase of the cell cycle, and was the most effective treatment in activating the degradation of poly(adenosine diphosphate-ribose) polymerase-1. In the breast cancer cell line MCF-7, A+K induced the appearance of the 18 kDa isoform of B-cell lymphoma-2-associated X protein (Bax), which is a more potent inducer of apoptosis than the full-length Bax-p21. The effects of A and K on the phosphorylation of extracellular signal-regulated kinase (ERK)1 and ERK2 were heterogeneous. In addition, treatment with K, A and A+K inhibited the expression of nuclear factor-κB. Overall, the results of the present study indicated that K potentiated the anti-tumoral effects of A in breast cancer cells in vitro. PMID:27313770

  16. Proteomic analysis of anti-tumor effects by tetrandrine treatment in HepG2 cells.

    PubMed

    Cheng, Zhixiang; Wang, Keming; Wei, Jia; Lu, Xiang; Liu, Baorui

    2010-11-01

    Tetrandrine (TET), a bis-benzylisoquinoline alkaloid isolated from the root of Hang-Fang-Chi (Stephenia tetrandra S Moore), exhibits broad pharmacological effects, including anti-tumor activity. Recently, the beneficial effects of TET on cytotoxicity towards tumor cells, radiosensitization, circumventing multidrug resistance, normal tissue radioprotection, and antiangiogenesis have been examined extensively. To explore the potential molecular mechanism of the anti-tumor effect of TET, we applied proteomic tools to profile the proteins in HepG2 cells subjected to TET treatment. The levels of 39 proteins in cells exposed to TET (IC₅₀=5±0.6 μg/ml) for 48 h were observed to undergo significant alterations. Six proteins were identified by matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) using peptide fingerprinting from 10 protein spots (density difference >1.5-fold between the control and TET-treated group). Among them, 5 proteins were downregulated (proteasome activator complex subunit 3, 40S ribosomal protein S12, phosphoglycerate mutase 1, destrin, transaldolase) and 1 protein was upregulated (guanylate kinase 1) by TET treatment in HepG2 cells as determined by spot volume (P<0.05). Most of the identified proteins were associated with tumor growth, migration, and anti-tumor drug resistance. These data will be helpful in elucidating the molecular mechanism of TET's anti-tumor effect in HepG2 cells. PMID:20554191

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

    PubMed

    Miyashita, Michiko; Sadzuka, Yasuyuki

    2013-03-01

    As malignant neoplasm is a major public health problem, there is a need for the development of a novel modulator that enhances antitumor activity and reduces adverse reactions to antitumor agents. In this study, the effects of some volatile oil components in Humulus lupulus on doxorubicin (DOX) permeability in tumor cells and DOX-induced antitumor activity were examined. In vitro, DOX levels in tumor cells by combined linalool as its component significantly increased in the DOX influx system, and the increased effect by linalool on DOX cytotoxicity was shown. In vivo, the combination of DOX with linalool significantly decreased tumor weight compared with that of DOX alone treated group. The promotion of DOX influx level by combined linalool did not depend on energy, whereas it was suppressed by the absence of Na(+). This promoting effect was suppressed by the presence of S-(4-nitrobenzyl)-6-thioinosine and inhibited dependently on phlorizin concentration. It is considered that linalool promoted DOX influx in tumor cells because of its action on DOX transport through concentrative Na(+)-dependent nucleoside transporter 3, which increased DOX concentration in tumor cells and thus enhanced the antitumor activity of DOX. Therefore, linalool as a food component is anticipated to be an effective DOX modulator. PMID:23220514

  18. Antitumor Effects of EGFR Antisense Guanidine-Based Peptide Nucleic Acids in Cancer Models

    PubMed Central

    Thomas, Sufi M.; Sahu, Bichismita; Rapireddy, Srinivas; Bahal, Raman; Wheeler, Sarah E.; Procopio, Eva M.; Kim, Joseph; Joyce, Sonali C.; Contrucci, Sarah; Wang, Yun; Chiosea, Simion I.; Lathrop, Kira L.; Watkins, Simon; Grandis, Jennifer R.; Armitage, Bruce A.; Ly, Danith H.

    2013-01-01

    Peptide nucleic acids have emerged over the past two decades as a promising class of nucleic acid mimics because of their strong binding affinity and sequence selectivity toward DNA and RNA, and resistance to enzymatic degradation by proteases and nucleases. While they have been shown to be effective in regulation of gene expression in vitro, and to a small extent in vivo, their full potential for molecular therapy has not yet been fully realized due to poor cellular uptake. Herein, we report the development of cell-permeable, guanidine-based peptide nucleic acids targeting the epidermal growth factor receptor (EGFR) in preclinical models as therapeutic modality for head and neck squamous cell carcinoma (HNSCC) and nonsmall cell lung cancer (NSCLC). A GPNA oligomer, 16 nucleotides in length, designed to bind to EGFR gene transcript elicited potent antisense effects in HNSCC and NSCLC cells in preclinical models. When administered intraperitoneally in mice, EGFRAS-GPNA was taken-up by several tissues including the xenograft tumor. Systemic administration of EGFRAS-GPNA induced antitumor effects in HNSCC xenografts, with similar efficacies as the FDA-approved EGFR inhibitors: cetuximab and erlotinib. In addition to targeting wild-type EGFR, EGFRAS-GPNA is effective against the constitutively active EGFR vIII mutant implicated in cetuximab resistance. Our data reveals that GPNA is just as effective as a molecular platform for treating cetuximab resistant cells, demonstrating its utility in the treatment of cancer. PMID:23113581

  19. Antitumor effects of celecoxib in COX-2 expressing and non-expressing canine melanoma cell lines

    PubMed Central

    Seo, Kyoung-won; Coh, Ye-rin; Rebhun, Robert B.; Ahn, Jin-ok; Han, Sei-Myung; Lee, Hee-woo; Youn, Hwa-Young

    2016-01-01

    Cyclooxygenase-2 (COX-2) is a potential target for chemoprevention and cancer therapy. Celecoxib, a selective COX-2 inhibitor, inhibits cell growth of various types of human cancer including malignant melanoma. In dogs, oral malignant melanoma represents the most common oral tumor and is often a fatal disease. Therefore, there is a desperate need to develop additional therapeutic strategies. The purpose of this study was to investigate the anticancer effects of celecoxib on canine malignant melanoma cell lines that express varying levels of COX-2. Celecoxib induced a significant anti-proliferative effect in both LMeC and CMeC-1 cells. In the CMeC cells, treatment of 50 µM celecoxib caused an increase in cells in the G0/G1 and a decreased proportion of cells in G-2 phase. In the LMeC cells, 50 µM of celecoxib led to an increase in the percentage of cells in the sub-G1 phase and a significant activation of caspase-3 when compared to CMeC-1 cells. In conclusion, these results demonstrate that celecoxib exhibits antitumor effects on canine melanoma LMeC and CMeC-1 cells by induction of G1-S cell cycle arrest and apoptosis. Our data suggest that celecoxib might be effective as a chemotherapeutic agent against canine malignant melanoma. PMID:24656746

  20. Evaluation of antitumor effects of folate-conjugated methyl-β-cyclodextrin in melanoma.

    PubMed

    Motoyama, Keiichi; Onodera, Risako; Tanaka, Nao; Kameyama, Kazuhisa; Higashi, Taishi; Kariya, Ryusho; Okada, Seiji; Arima, Hidetoshi

    2015-01-01

    Melanoma is a life-threatening disorder and its incidence is increasing gradually. Despite the numerous treatment approaches, conventional systemic chemotherapy has not reduced the mortality rate among melanoma patients, probably due to the induction of toxicity to normal tissues. Recently, we have developed folate-conjugated methyl-β-cyclodextrin (FA-M-β-CyD) and clarified its potential as a new antitumor agent involved in autophagic cell death. However, it remains uncertain whether FA-M-β-CyD exerts anticancer effects against melanomas. Therefore, in this study, we investigated the effects of FA-M-β-CyD on the folate receptor-α (FR-α)-expressing melanoma cell-selective cytotoxic effect. FA-M-β-CyD showed cytotoxic effects in Ihara cells, a human melanoma cell line expressing FR-α. In sharp contrast to methyl-β-cyclodextrin, FA-M-β-CyD entered Ihara cells [FR-α(+)] through FR-α-mediated endocytosis. Additionally, FA-M-β-CyD elicited the formation of autophagosomes in Ihara cells. Notably, FA-M-β-CyD suppressed melanoma growth in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double deficient mice bearing Ihara cells. Therefore, these results suggest that FA-M-β-CyD could be utilized as a potent anticancer agent for melanoma chemotherapy by regulating autophagy. PMID:25757918

  1. Comparative study of antitumor effects of bromelain and papain in human cholangiocarcinoma cell lines.

    PubMed

    Müller, Alena; Barat, Samarpita; Chen, Xi; Bui, Khac Cuong; Bozko, Przemyslaw; Malek, Nisar P; Plentz, Ruben R

    2016-05-01

    Cholangiocarcinoma (CC) worldwide is the most common biliary malignancy with poor prognostic value and new systemic treatments are desirable. Plant extracts like bromelain and papain, which are cysteine proteases from the fruit pineapple and papaya, are known to have antitumor activities. Therefore, in this study for the first time we investigated the anticancer effect of bromelain and papain in intra- and extrahepatic human CC cell lines. The effect of bromelain and papain on human CC cell growth, migration, invasion and epithelial plasticity was analyzed using cell proliferation, wound healing, invasion and apoptosis assay, as well as western blotting. Bromelain and papain lead to a decrease in the proliferation, invasion and migration of CC cells. Both plant extracts inhibited NFκB/AMPK signalling as well as their downstream signalling proteins such as p-AKT, p-ERK, p-Stat3. Additionally, MMP9 and other epithelial-mesenchymal-transition markers were partially found to be downregulated. Apoptosis was induced after bromelain and papain treatment. Interestingly, bromelain showed an overall more effective inhibition of CC as compared to papain. siRNA mediated silencing of NFκB on CC cells indicated that bromelain and papain have cytotoxic effects on human CC cell lines and bromelain and partially papain in comparison impair tumor growth by NFκB/AMPK signalling. Especially bromelain can evolve as promising, potential therapeutic option that might open new insights for the treatment of human CC. PMID:26935541

  2. Effect of Paclitaxel on Antitumor Activity of Cyclophosphamide: Study on Two Transplanted Tumors in Mice.

    PubMed

    Kaledin, V I; Nikolin, V P; Popova, N A; Pyshnaya, I A; Bogdanova, L A; Morozkova, T S

    2015-11-01

    Antitumor effect of paclitaxel used as the monotherapy or in combination with cyclophosphamide was studied on CBA/LacSto mice with transplanted LS and RLS tumors characterized by high (LS) and low (RLS) sensitivity to cyclophosphamide. The therapeutic effects of cyclophosphamide and paclitaxel were summed in animals with drug-resistant RLS tumor, while combined use of these drugs in LS tumor highly sensitive to the apoptogenic effect of cyclophosphamide was no more effective than cyclophosphamide alone. PMID:26597686

  3. Pegfilgrastim Enhances the Antitumor Effect of Therapeutic Monoclonal Antibodies.

    PubMed

    Cornet, Sébastien; Mathé, Doriane; Chettab, Kamel; Evesque, Anne; Matera, Eva-Laure; Trédan, Olivier; Dumontet, Charles

    2016-06-01

    Therapeutic mAbs exert antitumor activity through various mechanisms, including apoptotic signalization, complement-dependent cytotoxicity, and antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis (ADCP). G-CSF and GM-CSF have been reported to increase the activity of antibodies in preclinical models and in clinical trials. To determine the potential role of pegfilgrastim as an enhancer of anticancer antibodies, we performed a comparative study of filgrastim and pegfilgrastim. We found that pegfilgrastim was significantly more potent than filgrastim in murine xenograft models treated with mAbs. This was observed with rituximab in CD20(+) models and with trastuzumab in HER2(+) models. Stimulation with pegfilgrastim was associated with significant enhancement of leukocyte content in spleen as well as mobilization of activated monocytes/granulocytes from the spleen to the tumor bed. These results suggest that pegfilgrastim could constitute a potent adjuvant for immunotherapy with mAbs possessing ADCC/ADCP properties. Mol Cancer Ther; 15(6); 1238-47. ©2016 AACR. PMID:26988998

  4. The Safety and Anti-Tumor Effects of Ozonated Water in Vivo

    PubMed Central

    Kuroda, Kohei; Azuma, Kazuo; Mori, Takuro; Kawamoto, Kinya; Murahata, Yusuke; Tsuka, Takeshi; Osaki, Tomohiro; Ito, Norihiko; Imagawa, Tomohiro; Itoh, Fumio; Okamoto, Yoshiharu

    2015-01-01

    Ozonated water is easier to handle than ozone gas. However, there have been no previous reports on the biological effects of ozonated water. We conducted a study on the safety of ozonated water and its anti-tumor effects using a tumor-bearing mouse model and normal controls. Local administration of ozonated water (208 mM) was not associated with any detrimental effects in normal tissues. On the other hand, local administration of ozonated water (20.8, 41.6, 104, or 208 mM) directly into the tumor tissue induced necrosis and inhibited proliferation of tumor cells. There was no significant difference in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL)-positive cells following administration of ozonated water. The size of the necrotic areas was dependent on the concentration of ozonated water. These results indicate that ozonated water does not affect normal tissue and damages only the tumor tissue by selectively inducing necrosis. There is a possibility that it exerts through the production of reaction oxygen species (ROS). In addition, the induction of necrosis rather than apoptosis is very useful in tumor immunity. Based on these results, we believe that administration of ozonated water is a safe and potentially simple adjunct or alternative to existing antineoplastic treatments. PMID:26506343

  5. Antitumor effect of vandetanib through EGFR inhibition in head and neck squamous cell carcinoma

    PubMed Central

    Klein, Jonah D.; Christopoulos, Apostolos; Ahn, Sun M.; Gooding, William E.; Grandis, Jennifer R.; Kim, Seungwon

    2013-01-01

    Background The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) have been implicated as therapeutic targets for head and neck squamous cell carcinoma (HNSCC). Vandetanib is a small-molecule tyrosine kinase inhibitor (TKI) with dual specificity for EGFR and VEGFR. Here we characterize the phenotypic and biochemical effects of vandetanib on various HNSCC cell lines. Methods In vitro models were used for studying tumor cell viability, invasion, and signaling as well as in vivo xenograft models. Results Treatment with vandetanib reduced viability, invasion, and tumor growth of HNSCC cell lines. Phosphorylation levels of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) were reduced in vandetanib-treated HNSCC cells. Additionally, vandetanib abrogates EGF-induced STAT3 activity and STAT3 target gene expression. Conclusions We demonstrated that vandetanib inhibits the growth of head and neck cancer cell lines. The antitumor effects of vandetanib appear to be exerted via the EGFR inhibitory effect of the compound. PMID:22307735

  6. Combinatorial Antitumor Effect of Rapamycin and β-Elemene in Follicular Thyroid Cancer Cells

    PubMed Central

    Zhou, Jun; He, Li-Li; Ding, Xiao-Fei; Yuan, Qiu-Qi; Zhang, Jian-Xin; Liu, Shuang-Chun; Chen, Guang

    2016-01-01

    Background. mTOR signaling would be a promising target for thyroid cancer therapy. However, in clinical trials, objective response rate with mTOR inhibitor monotherapy in most cancer types was modest. A new focus on development of combinatorial strategies with rapalogs is increasing. Objective. Investigating the combinatorial antitumor effect of rapamycin and β-elemene in follicular thyroid cancer cells. Methods. MTT assay was used to determine the FTC-133 cell proliferation after culturing with rapamycin and/or β-elemene. To analyze their combinatorial effect, immunoblotting was performed to analyze the activation status of AKT. Moreover, β-elemene attenuated rapamycin-induced immunosuppression was tested in mice. Results. Combination of rapamycin and β-elemene exerted significant synergistic antiproliferative effects in FTC-133 cell lines in vitro, based on inhibiting the AKT feedback activation induced by rapamycin. In vivo, the β-elemene could attenuate rapamycin-induced immunosuppression via reversing imbalance of Treg/Th17, with the underlying mechanism needed to be declared. Conclusions. We demonstrate that the novel combination of mTOR inhibitor with β-elemene synergistically attenuates tumor cell growth in follicular thyroid cancer, which requires additional preclinical validation. PMID:27274989

  7. The in vitro sustained release profile and antitumor effect of etoposide-layered double hydroxide nanohybrids.

    PubMed

    Qin, Lili; Wang, Mei; Zhu, Rongrong; You, Songhui; Zhou, Ping; Wang, Shilong

    2013-01-01

    Magnesium-aluminum layered double hydroxides intercalated with antitumor drug etoposide (VP16) were prepared for the first time using a two-step procedure. The X-ray powder diffraction data suggested the intercalation of VP16 into layers with the increased basal spacing from 0.84-1.18 nm was successful. Then, it was characterized by X-ray powder diffraction, Fourier transform infrared spectroscopy, thermogravimetry and differential thermal analysis, and transmission electron microscopy. The prepared nanoparticles, VP16-LDH, showed an average diameter of 62.5 nm with a zeta potential of 20.5 mV. Evaluation of the buffering effect of VP16-LDH indicated that the nanohybrids were ideal for administration of the drugs that treat human stomach irritation. The loading amount of intercalated VP16 was 21.94% and possessed a profile of sustained release. The mechanism of VP16-LDH release in the phosphate buffered saline solution at pH 7.4 is likely controlled by the diffusion of VP16 anions from inside to the surface of LDH particles. The in vitro cytotoxicity and antitumor assays indicated that VP16-LDH hybrids were less toxic to GES-1 cells while exhibiting better antitumor efficacy on MKN45 and SGC-7901 cells. These results imply that VP16-LDH is a potential antitumor drug for a broad range of gastric cancer therapeutic applications. PMID:23737669

  8. The in vitro sustained release profile and antitumor effect of etoposide-layered double hydroxide nanohybrids

    PubMed Central

    Qin, Lili; Wang, Mei; Zhu, Rongrong; You, Songhui; Zhou, Ping; Wang, Shilong

    2013-01-01

    Magnesium-aluminum layered double hydroxides intercalated with antitumor drug etoposide (VP16) were prepared for the first time using a two-step procedure. The X-ray powder diffraction data suggested the intercalation of VP16 into layers with the increased basal spacing from 0.84–1.18 nm was successful. Then, it was characterized by X-ray powder diffraction, Fourier transform infrared spectroscopy, thermogravimetry and differential thermal analysis, and transmission electron microscopy. The prepared nanoparticles, VP16-LDH, showed an average diameter of 62.5 nm with a zeta potential of 20.5 mV. Evaluation of the buffering effect of VP16-LDH indicated that the nanohybrids were ideal for administration of the drugs that treat human stomach irritation. The loading amount of intercalated VP16 was 21.94% and possessed a profile of sustained release. The mechanism of VP16-LDH release in the phosphate buffered saline solution at pH 7.4 is likely controlled by the diffusion of VP16 anions from inside to the surface of LDH particles. The in vitro cytotoxicity and antitumor assays indicated that VP16-LDH hybrids were less toxic to GES-1 cells while exhibiting better antitumor efficacy on MKN45 and SGC-7901 cells. These results imply that VP16-LDH is a potential antitumor drug for a broad range of gastric cancer therapeutic applications. PMID:23737669

  9. Antitumor effect of a polysaccharide isolated from Phellinus pullus as an immunostimulant

    PubMed Central

    YANG, WEIHUA; ZHANG, HENGLAN; JI, MINGYU; PEI, FENGYAN; WANG, YUNSHAN

    2016-01-01

    The antitumor function of fungal polysaccharides is a popular area of interest in the research field due to their high efficiency and low side effects. The main mechanism of fungal polysaccharides is immune enhancement. The polysaccharose (APS-3) was extracted from the fruit body of Phellinus pullus. The proliferation inhibition to mouse sarcoma 180 (S180) tumor cells was studied by the MTT method. Mice models of transplanted S180 tumor were established and treated with APS-3 to verify the antitumor activity in vivo. Natural killer (NK) and lymphokine-activated killer (LAK) cytotoxicities of the mice were evaluated by the lactate dehydrogenase method. APS-3 can significantly inhibit the proliferation of the S180 cells. Cells could be completely inhibited by 1.6 mg/ml APS-3 after 24 h treatment. After 18 days of treatment, the antitumor rate of the high-dose group was 85.47%. Histopathology detection showed that for the APS-3-treated mice, the tumor cells dissolved, and exhibited a large range of structureless necrotic areas. NK and LAK cytotoxicities of the APS-3 treated mice increased by 61.85 and 56.16%, respectively, compared with the normal control mice. APS-3 can be used as an antitumor agent by way of immune enhancement. PMID:26998276

  10. Aromatase inhibitors and their antitumor effects in model systems.

    PubMed

    Brodie, A; Lu, Q; Liu, Y; Long, B

    1999-06-01

    The potential of aromatase (estrogen synthetase) within the breast to provide a significant source of estrogen mediating tumor proliferation is suggested by studies reporting 4- to 6-fold higher estrogen levels in tumors than in plasma of postmenopausal patients with breast cancer. Recent studies in our laboratory have identified aromatase and its mRNA in tumor epithelial cells using immunocytochemistry and in situ hybridization. In addition, significant aromatase activity, which was stimulated 7-fold by dexamethasone, was measured in metastatic cells isolated from a breast cancer patient. Increase in proliferation, as measured by proliferating cell nuclear antigen immunostaining in tumor sections and by thymidine incorporation into DNA in response to testosterone, was observed in histocultures of breast cancer samples. This latter effect could be inhibited by 4-hydroxyandrostenedione. These results imply that intratumoral aromatase has functional significance and may be an important target for successful inhibitor treatment of breast cancer patients. To investigate treatment strategies with aromatase inhibitors and antiestrogens, we developed an intratumoral aromatase model to simulate the hormone responsive postmenopausal breast cancer patient. Tumors of estrogen receptor positive human breast carcinoma cells (MCF-7) transfected with the human aromatase gene are grown in ovariectomized nude mice. These cells synthesize sufficient estrogen to stimulate tumor formation. We have utilized this model to investigate the effects on tumor growth of the antiestrogens, tamoxifen and ICI 182780, and the aromatase inhibitors, letrozole and anastrozole (arimidex), alone and in combination. Both the aromatase inhibitors and the antiestrogens were effective in suppressing tumor growth. However, letrozole was significantly more effective than the antiestrogens. When the aromatase inhibitors were combined with the antiestrogen, tamoxifen, tumor growth was suppressed to about the

  11. Water-soluble extract of Saxifraga stolonifera has anti-tumor effects on Lewis lung carcinoma-bearing mice.

    PubMed

    Liu, Dong; Yang, Ping; Zhang, Yu-Qing

    2016-10-01

    Saxifraga stolonifera is an evergreen and herbaceous plant well known in Korea, Japan and western China, which has great potential applications in gardening and pharmacology. The aim of this study is to evaluate the anti-tumor effects of S. stolonifera extraction on lung tumors of Lewis mice. By the measurement of MS/MS, we found that there were four main bioactive components in methanol extract of S. stolonifera, including gallic acid, norbergenin, protocatechuic acid and bergenin, and the results of quantitative analysis showed that the contents of gallic acid, protocatechuic acid and bergenin in methanol extract of S. stolonifera were 5.150, 1.492, 24.559mg/g, respectively. Animal experiment showed that the mean tumor weight of Lewis lung carcinoma-bearing mice treated with water-soluble extract of S. stolonifera was obviously smaller than model group (cis-DDP), and its inhibition rate was 49.2%. In addition, histopathological evaluation and immunohistochemical assay confirmed the anti-tumor effects of S. stolonifera. Investigation of four haematological parameters revealed that the Lewis mice fed with S. stolonifera showed good resilience in the level of leukocyte, haemoglobin, blood platelets and red blood cell compared with the model group. In addition, RT-PCR suggested that the relative expression of pro-apoptosis gene p53, Sox and Bax was enhanced, while the relative expression of anti-apoptosis gene Bcl2 was diminished in comparison with model group. These results suggested that water-soluble extract of S. stolonifera has anti-tumor effects on Lewis lung tumors. PMID:27575479

  12. A COX-2 inhibitor enhances the antitumor effects of chemotherapy and radiotherapy for esophageal squamous cell carcinoma.

    PubMed

    Yusup, Gulbostan; Akutsu, Yasunori; Mutallip, Muradil; Qin, Wei; Hu, Xin; Komatsu-Akimoto, Aki; Hoshino, Isamu; Hanari, Naoyuki; Mori, Mikito; Akanuma, Naoki; Isozaki, Yuka; Matsubara, Hisahiro

    2014-04-01

    Cyclooxygenase-2 (COX-2) is a key enzyme of prostaglandin (PG) synthesis that has been demonstrated to be overexpressed in several types of cancers. The function of COX-2 in tumor progression has been recently elucidated. In tumors in which COX-2 is overexpressed, the antitumor effects are suppressed. We examined the effects of celecoxib, a COX-2 inhibitor, in enhancing the antitumor effects of chemotherapy and radiotherapy for esophageal squamous cell carcinoma (ESCC) by reducing the COX-2 activity. We used the human esophageal squamous cell lines TE2 and T.Tn treated with celecoxib and 5-FU/radiation, after which cell viability assays were performed. Changes in the expressions of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) mRNA and PGE2 were also measured. In addition, apoptotic changes, and the invasion and migration activity in both the celecoxib and 5-FU treated cells were evaluated. The experiments showed that T.Tn and TE2 proliferation was strongly inhibited by the combination of 5-FU/radiation and the COX-2 inhibitor. Inhibiting the COX-2 activity induced a reduction in PGE2 levels in TE2/T.Tn cells. Following treatment with the COX-2 inhibitor and 5-FU, the OPRT expression was upregulated and the DPD expression was downregulated in the resistant cells. In addition, the combination treatment with the COX-2 inhibitor and 5-FU markedly inhibited both the cell invasion and migration activity. Therefore, COX-2 inhibitors can be useful enhancers of antitumor drugs and radiotherapy for ESCC. PMID:24535229

  13. Study on fluorouracil-chitosan nanoparticle preparation and its antitumor effect.

    PubMed

    Chen, Gaimin; Gong, Rudong

    2016-05-01

    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, (1)H 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 prospects for development. PMID

  14. Antitumor effect of metformin on cholangiocarcinoma: In vitro and in vivo studies.

    PubMed

    Fujimori, Takayuki; Kato, Kiyohito; Fujihara, Shintaro; Iwama, Hisakazu; Yamashita, Takuma; Kobayashi, Kiyoyuki; Kamada, Hideki; Morishita, Asahiro; Kobara, Hideki; Mori, Hirohito; Okano, Keiichi; Suzuki, Yasuyuki; Masaki, Tsutomu

    2015-12-01

    Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC). Treatment with the anti-diabetic drug metformin has been associated with reduced cancer incidence in patients with type 2 diabetes. Thus, the present study evaluated the effects of metformin on human CCA cell proliferation in vitro and in vivo and identified the microRNAs associated with its antitumor effects. Metformin inhibited the proliferation of the CCA cell lines HuCCT-1 and TFK-1 and blocked the G0 to G1 cell cycle transition, accompanied by AMP kinase pathway activation. Metformin treatment also led to marked decreases in cyclin D1 and cyclin-dependent kinase (Cdk) 4 protein levels and retinoblastoma protein phosphorylation. However, this drug did not affect p27kip protein expression. In addition, it reduced the phosphorylation of Axl, EphA10, ALK and PYK, as well as tumor proliferation in athymic nude mice with xenograft tumors. Furthermore, it markedly altered microRNA expression. These findings suggest that metformin may have clinical use in the treatment of CCA. PMID:26398221

  15. The effect of taurine, a novel biochemical modulator, on the antitumor activity of doxorubicin.

    PubMed

    Sadzuka, Yasuyuki; Matsuura, Makoto; Sonobe, Takashi

    2009-09-01

    Taurine is contained in seafood and has been studied extensively on life-style related diseases. Theanine increased the effects of the doxorubicin (DOX) as an antitumor agent in some tumors and enhanced the DOX level in tumor cells. It is expected that the advanced effect of food uptake in cancer chemotherapy may be effective from the viewpoint of quality of life (QOL) improvement, although this approach has not been investigated in detail. In this study, the effect of taurine as a functional amino acid was examined. Taurine did not change the DOX influx into M5076 cells, whereas it significantly inhibited DOX efflux, which maintained the DOX level in tumor cells. Furthermore, experiments with taurine decreased tumor weight by 40%, compared to the DOX-alone group and significantly increased its antitumor effect. Moreover, as taurine did not increase DOX concentration in normal tissue, it is suggested that it increased the antitumor effect without enhancing DOX-induced adverse effects. DOX efflux is inhibited by beta-alanine as a taurine transporter inhibitor, therefore, enhancement of the DOX level by taurine was suggested to act via taurine transport. Namely, it was clarified that taurine was useful as a modulator to enhance the therapeutic index of cancer patients and improve QOL. PMID:19721236

  16. Mcam Silencing With RNA Interference Using Magnetofection has Antitumor Effect in Murine Melanoma

    PubMed Central

    Prosen, Lara; Markelc, Bostjan; Dolinsek, Tanja; Music, Branka; Cemazar, Maja; Sersa, Gregor

    2014-01-01

    The melanoma cell adhesion molecule (MCAM) is involved in melanoma development and its progression, including invasiveness, metastatic potential and angiogenesis. Therefore, MCAM represents a potential target for gene therapy of melanoma, whose expression could be hindered with posttranscriptional specific gene silencing with RNA interference technology. In this study, we constructed a plasmid DNA encoding short hairpin RNA against MCAM (pMCAM) to explore the antitumor and antiangiogenic effects. The experiments were performed in vitro on murine melanoma and endothelial cells, as well as in vivo on melanoma tumors in mice. The antiproliferative, antimigratory, antiangiogenic and antitumor effects were examined after gene therapy with pMCAM. Gene delivery was performed by magnetofection, and its efficacy compared to gene electrotransfer. Gene therapy with pMCAM has proved to be an effective approach in reducing the proliferation and migration of melanoma cells, as well as having antiangiogenic effect in endothelial cells and antitumor effect on melanoma tumors. Magnetofection as a developing nonviral gene delivery system was effective in the transfection of melanoma cells and tumors with pMCAM, but less efficient than gene electrotransfer in in vivo tumor gene therapy due to the lack of antiangiogenic effect after silencing Mcam by magnetofection. PMID:25350580

  17. Antitumor effect of 5-fluorouracil is enhanced by rosemary extract in both drug sensitive and resistant colon cancer cells.

    PubMed

    González-Vallinas, Margarita; Molina, Susana; Vicente, Gonzalo; de la Cueva, Ana; Vargas, Teodoro; Santoyo, Susana; García-Risco, Mónica R; Fornari, Tiziana; Reglero, Guillermo; Ramírez de Molina, Ana

    2013-06-01

    5-Fluorouracil (5-FU) is the most used chemotherapeutic agent in colorectal cancer. However, resistance to this drug is relatively frequent, and new strategies to overcome it are urgently needed. The aim of this work was to determine the antitumor properties of a supercritical fluid rosemary extract (SFRE), alone and in combination with 5-FU, as a potential adjuvant therapy useful for colon cancer patients. This extract has been recognized as a healthy component by the European Food Safety Authority (EFSA). The effects of SFRE both alone and in combination with 5-FU were evaluated in different human colon cancer cells in terms of cell viability, cytotoxicity, and cell transformation. Additionally, colon cancer cells resistant to 5-FU were used to assay the effects of SFRE on drug resistance. Finally, qRT-PCR was performed to ascertain the mechanism by which SFRE potentiates the effect of 5-FU. Our results show that SFRE displays dose-dependent antitumor activities and exerts a synergistic effect in combination with 5-FU on colon cancer cells. Furthermore, SFRE sensitizes 5-FU-resistant cells to the therapeutic activity of this drug, constituting a beneficial agent against both 5-FU sensitive and resistant tumor cells. Gene expression analysis indicates that the enhancement of the effect of 5-FU by SFRE might be explained by the downregulation of TYMS and TK1, enzymes related to 5-FU resistance. PMID:23557932

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

    PubMed Central

    ZHENG, RUINIAN; YOU, ZHIJIAN; JIA, JUN; LIN, SHUNHUAN; HAN, SHUAI; LIU, AIXUE; LONG, HUIDONG; WANG, SENMING

    2016-01-01

    At present, the therapeutic treatment strategies for patients with hepatocellular carcinoma (HCC) remain unsatisfactory, and novel methods are urgently required to treat this disease. Members of the B cell lymphoma (Bcl)-2 family are anti-apoptotic proteins, which are commonly expressed at high levels in certain HCC tissues and positively correlate with the treatment resistance of patients with HCC. ABT-737, an inhibitor of Bcl-2 anti-apoptotic proteins, has been demonstrated to exhibit potent antitumor effects in several types of tumor, including HCC. However, treatment with ABT-737 alone also activates certain pro-survival signaling pathways, which attenuate the antitumor validity of ABT-737. Curcumin, which is obtained from Curcuma longa, is also an antitumor potentiator in multiple types of cancer. In the present study, the synergistic effect of curcumin and ABT-737 on HCC cells was investigated for the first time, to the best of our knowledge. It was found that curcumin markedly enhanced the antitumor effects of ABT-737 on HepG2 cells, which was partially dependent on the induction of apoptosis, according to western blot analysis and flow cytometric apoptosis analysis. In addition, the sustained activation of the ROS-ASK1-c-Jun N-terminal kinase pathway may be an important mediator of the synergistic effect of curcumin and ABT-737. Collectively, these results indicated that the combination of curcumin and ABT-737 can efficaciously induce the death of HCC cells, and may offer a potential treatment strategy for patients with HCC. PMID:26707143

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

    PubMed Central

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

    2015-01-01

    We identified a novel Akt signaling mechanism that mediates fucoidan-induced suppression of human colon cancer cell (HT29) proliferation and anticancer effects. Fucoidan treatment significantly inhibited growth, induced G1-phase-associated upregulation of p21WAF1 expression, and suppressed cyclin and cyclin-dependent kinase expression in HT29 colon cancer cells. Additionally, fucoidan treatment activated the Akt signaling pathway, which was inhibited by treatment with an Akt inhibitor. The inhibition of Akt activation reversed the fucoidan-induced decrease in cell proliferation, the induction of G1-phase-associated p21WAF1 expression, and the reduction in cell cycle regulatory protein expression. Intraperitoneal injection of fucoidan reduced tumor volume; this enhanced antitumor efficacy was associated with induction of apoptosis and decreased angiogenesis. These data suggest that the activation of Akt signaling is involved in the growth inhibition of colon cancer cells treated with fucoidan. Thus, fucoidan may serve as a potential therapeutic agent for colon cancer. PMID:25995820

  20. Antitumor effects of calgranulin B internalized in human colon cancer cells

    PubMed Central

    Yoo, Byong Chul; Ku, Ja-Lok; Shin, Young-Kyoung; Cho, Jae Youl; Kim, Minjae; Kwon, Myung-Hee; Goh, Sung Ho; Chang, Hee Jin; Oh, Jae Hwan

    2016-01-01

    Calgranulin B is a small, calcium-binding protein expressed in neutrophils that is secreted into the tumor microenvironment in cancer cases. We previously showed that calgranulin B levels are increased in the stools of colorectal cancer patients. In patient tumor tissues, calgranulin B protein levels correlated with the presence of stromal inflammatory cells surrounding tumor cells, and calgranulin B promoter methylation was observed in both paired human tissues and colon cancer cell lines. Cell lines did not express calgranulin B, but in vitro studies showed that colon cancer cells internalized extracellular calgranulin B, while other types of cancer cells did not. Calgranulin B internalization led to reduced cell proliferation and increased apoptotic cell death. AKT and ERK signals were also increased after calgranulin B treatment, as were p53, β-catenin, E-cadherin and cleaved caspase-3 levels. Additionally, a human protein microarray identified aurora A kinase as a calgranulin B binding partner, and binding inhibited aurora A kinase activity in a dose-dependent manner. Our findings demonstrate the antitumor effects of calgranulin B in the inflammatory microenvironment and suggest that calgranulin B could be potentially efficacious in the treatment of colon cancer. PMID:26933915

  1. Antitumor effect and biological pathways of a recombinant adeno-associated virus as a human renal cell carcinoma suppressor.

    PubMed

    Chen, Jie; Ruan, Xiyun; Wang, Shaomei; Zhang, Bin; Liu, Bo; Sun, Zeqiang; Liu, Qingyong

    2014-11-01

    The aims of this work are to study the antitumor effect of the adeno-associated virus on the xenografted tumors of chick embryo chorioallantoic membrane and predict potential genes and biological pathways which are associated with renal cell carcinoma. The adeno-associated virus NT4-TAT-6 × His-VHLbeta was constructed and identified. Then, chick embryos with xenografted tumor were divided into three groups and respectively inoculated with rAAV/NT4-TAT-6 × His-VHLbeta (group A), empty virus (group B), and phosphate-buffered saline (group C, the control subject). Antitumor effect in each group was investigated by means of immunofluorescence observation. Genes interacted with von Hippel-Lindau were screened by Search Tool for the Retrieval of Interacting Genes/Proteins database, while pathway analysis were performed based on Kyoto Encyclopedia of Genes and Genomes. The growth of xenografted tumors inoculated with recombinant adeno-associated virus was slower than the control subjects. The tumor volumes of group A showed significant difference compared with group B and group C (P < 0.05). Growth of xenografted tumors which administered with the recombinant adeno-associated virus was inhibited. Among the protein-protein interaction network, TCEB2, HIF1A, TCEB1, CUL2, RBX1, and PHF17 were hub genes which might be involved in the development of renal cell carcinoma. The most significant signaling pathway was renal cell carcinoma. In this paper, we constructed and identified the recombinant adeno-associated virus NT4-TAT-6 × His-VHLbeta and studied the antitumor effect of the adeno-associated virus on xenografted tumors of chicken embryo chorioallantoic membrane. In addition, genes in the protein-protein interaction network which are associated with renal cell carcinoma were revealed and the biological pathway of renal cell carcinoma was identified. Our results provide a gene-therapeutic agent for the treatment of human renal cell carcinoma. PMID:25091575

  2. Synergistic anti-tumor effects of zoledronic acid and radiotherapy against metastatic hepatocellular carcinoma.

    PubMed

    Morii, Kazuhiko; Aoyama, Yuhki; Nakamura, Shinichiro; Okushin, Hiroaki

    2015-01-01

    A 72-year-old man with advanced hepatocellular carcinoma and decompensated hepatitis C virus-related cirrhosis suffered from a metastatic femoral fracture. After undergoing radiotherapy, he was only treated with supportive care, except for the administration of zoledronic acid (ZA). Thereafter, the initially elevated serum α-fetoprotein and des-gamma carboxyprothrombin levels declined to within the normal ranges. Hepatic and metastatic adrenal tumors, distant from the radiation field, exhibited a surprising regression. ZA is known to inhibit the activity of osteoclasts, bone-residential macrophages, and has been reported to have a direct anti-tumor effect. ZA may adjust the immunological milieu in tumor microenvironments by inhibiting the tumor-associated macrophages. Because radiotherapy can enhance the presentation of tumor-associated antigens, ZA and radiotherapy may exert synergistic anti-tumor effects. PMID:26466697

  3. Adenovirus with p16 gene exerts antitumor effect on laryngeal carcinoma Hep2 cells.

    PubMed

    Yang, Zhengang; Hu, Jingxia; Li, Dajun; Pan, Xinliang

    2016-08-01

    Laryngeal cancer is an uncommon form of cancer. The tumor suppressor P16, known to be mutated or deleted in various types of human tumor, including laryngeal carcinoma, is involved in the formation and development of laryngeal carcinoma. It has been previously reported that the inactivation or loss of P16 is associated with the acquisition of malignant characteristics. The current study hypothesized that restoring wild‑type P16 activity into P16‑null malignant Hep2 cells may exert an antitumor effect. A recombinant adenovirus carrying the P16 gene (Ad‑P16) was used to infect and express high levels of P16 protein in P16‑null Hep2 cells. Cell proliferation and invasion assays and polymerase chain reaction were performed to evaluate the effects of the P16 gene on cell proliferation and the antitumor effect on Hep2 cells. The results demonstrated that the Hep2 cells infected with Ad‑P16 exhibited significantly reduced cell proliferation, invasion and tumor volume compared with untreated or control adenovirus cells. Furthermore, the expression of laryngeal carcinoma‑associated genes, EGFR, survivin and cyclin D1, were measured in Ad‑P16‑infected cells and were significantly reduced compared with control groups. The results of the current study demonstrate that restoring wild‑type P16 activity into P16-null Hep2 cells exerts an antitumor effect. PMID:27277704

  4. Valproic Acid Enhances the Anti-tumor Effect of (-)-gossypol to Burkitt Lymphoma Namalwa Cells.

    PubMed

    Gong, Yi; Ni, Zhen Hong; Zhang, Xi; Chen, Xing Hua; Zou, Zhong Min

    2015-10-01

    Burkitt lymphoma is a highly aggressive B-cell neoplasm. New therapeutic methods are needed to overcome the adverse effect of intensive chemotherapy regimens. Valproic acid and (-)-gossypol are two kinds of chemical compounds used as new anti-tumor drugs in recent years. To investigate the anti-tumor effect of valproic acid and (-)-gossypol, Burkitt lymphoma Namalwa cells were cultured and treated with valproic acid and (-)-gossypol at different concentrations. The proliferation of Namalwa cells was dramatically suppressed after the combination treatment with 2 mmol/L valproic acid and 5 μmol/L (-)-gossypol. The combined treatment also enhanced intrinsic apoptosis by down-regulating anti-apoptotic protein Mcl-1. Moreover, the autophagy flux significantly increased in Namalwa cells after combined treatment. However, the enhanced autophagy showed little effect on cell survival with present regimen. The results confirmed that combination of valproic acid and (-)-gossypol had synergistic anti-tumor effect to Burkitt lymphoma Namalwa cells. The related mechanisms might include the down-regulation of anti-apoptotic protein Mcl-1 and avianized pro-survival role of autophagy. PMID:26582100

  5. Antitumor Effect of Zhihuang Fuzheng Soft Capsules on Tumor-Bearing Mice

    PubMed Central

    Bao, Yanyan; Pan, Xin; Jin, Yahong; Gao, Yingjie; Cui, Xiaolan

    2016-01-01

    Chinese medicines (CMs) have been shown to have some advantages in preventing and controlling tumors. In this study, we investigated the antitumor effect of ZFSC by establishing a mouse model of HT-1080, A-549, and HCT-8 tumors. The result showed that tumor volumes of HT-1080 tumor-bearing nude mice in ZFSC low, medium, and high dose groups were lower significantly compared to the model group, and the high dose ZFSC showed the best antitumor effect. Tumor volumes of A-549 tumor-bearing nude mice in ZFSC low, medium, and high dose groups were lower significantly compared to the model group and showed a good dose-response relationship. There was no significant effect on human colon cancer, although inhibition trends disappeared in the bar chart. In order to verify the immunomodulatory effect of ZFSC, ELISA was used to analyze serums IL-2, TNF-α, and IFN in spleens. The results showed that ZFSC could enhance the immune function of tumor-bearing mice. ZFSC reduced IFN-γ and TNF-α content in the serum of HT-1080 tumor-bearing mice and inhibit PD1 and PDL1 and suggested that the antitumor mechanism of ZFSC on human fibrosarcoma could be attributed to inhibition of the PDL1/PD1 pathway. PMID:27493673

  6. Inhibition of TGF-β signaling with halofuginone can enhance the antitumor effect of irradiation in Lewis lung cancer

    PubMed Central

    Lin, Runlong; Yi, Shuai; Gong, Linlin; Liu, Weishuai; Wang, Peng; Liu, Ningbo; Zhao, Lujun; Wang, Ping

    2015-01-01

    Purpose It was reported that halofuginone has inhibitory effects on transforming growth factor-beta (TGF-β) signaling pathway. The study was aimed to: 1) evaluate the antitumor effects of halofuginone in combination with radiation therapy; and 2) preliminarily explore the possible mechanisms associated with these effects. Materials and methods Lewis lung cancer (LLC) cell lines and xenograft model mice randomly received ionizing radiation, halofuginone, or combination treatment. The changes associated with antitumor effect of halofuginone, including hepatic and pulmonary metastases and survival, were observed. The migratory and invasive capabilities of LLC cells were investigated by using scratch assay and transwell chamber assay. The expression level of TGF-β and its activation were assessed with enzyme-linked immunosorbent assay, immunohistochemistry, and Western blotting. Chi-square test and survival analysis were performed for statistical analysis. P<0.05 was regarded as statistically significant. Unless otherwise specified, data were expressed as mean ± standard deviation (x¯±s). Results After irradiation, the migratory and invasive capabilities of LLC cells were strengthened, and the TGF-β pathway was activated. The addition of halofuginone can significantly inhibit the migratory and invasive trend induced by irradiation, and the TGF-β pathway was also inhibited. In animal xenograft model, the addition of halofuginone to irradiation inhibited the growth of subcutaneously implanted xenografts, reduced hepatic and pulmonary metastases, and improved survival of the mice. The effect was accompanied by a decrease in TGF-β levels. In addition, halofuginone inhibited type I collagen expression and angiopoiesis. Conclusion Halofuginone treatment not only produces significant radiation-sensitizing effects but also inhibits hepatic and pulmonary metastases. The underlying mechanisms of these phenomena warrant additional studies. PMID:26664138

  7. Relationship of molecular weight to antiviral and antitumor activities and toxic effects of maleic anhydride-divinyl ether (MVE) polyanions.

    PubMed

    Morahan, P S; Barnes, D W; Munson, A E

    1978-11-01

    The molecular weight (MW) and dose dependency of several of the toxic effects and antitumor and antiviral activities of a new series of five maleic anhydride-divinyl ether copolymers (MVE) were established. Each polyanion preparation was relatively homogeneous and exhibited a narrow MW range, from 12,500 (MVE-1) to greater than 52,000 (MVE-5). All of the polyanions were effective as adjuvants to surgery against the metastatic Lewis lung carcinoma, and also exhibited marked antitumor activity against the P815 mastocytoma. MVE-1 retained antitumor activity while losing considerable antiviral activity. This polyanion also exhibited the least toxicity with regard to criteria such as sensitization to the lethal effects of endotoxin, inhibition of reticuloendothelial function, and depression of the microsomal mixed functional oxidase system. The MVE-4 (MW, 32,000) and MVE-5 (MW, 52,600) polyanions exhibited potent antitumor and antiviral activity, but also demonstrated dose-dependent toxic effects. PMID:103618

  8. Preparation and Sonodynamic Antitumor Effect of Protohemin-Conjugated Multiwalled Carbon Nanotubes Functionalized with Carboxylic Group.

    PubMed

    Wang, Chuan-Jin; Li, Wei

    2016-05-01

    Preclinical Research Sonodynamic therapy (SDT) is a cutting edge approach to treating cancer that involves necrosis and/or apoptosis. Multiwalled carbon nanotubes functionalized with carboxylic groups (MWCNTs-COOH) due their physicochemical structure represent a novel drug delivery system in the field of nanomedicine. The purpose of the research reported in this paper was to increase the antitumor potency and reduce the potential side effects of protohemin (Ph), a sonosensitizer for SDT, which was noncovalently encapsulated into MWCNTs-COOH (MWCNTs-Ph). The Ph loading efficiency in MWCNTs-COOH carrier was determined as approximately 68.8% (w/w). The growth inhibition rate of MWCNTs-Ph (Ph: 180 μg/mL) was approximately 95 ± 8.5%, whereas Ph-F (Ph: 180 μg/mL) inhibited 58 ± 4.5% of tumor cell. Ph (Ph: 180 μg/mL) alone had no antitumor effect in HepG-2 cells using ultrasound treatment at 1.0 MHz and 0.5 W/cm(2) for 100 s. Assessment of the antitumor effects of MWCNTs-Ph and Ph-F at day 11 after SDT showed that he tumor inhibition ratio for MWCNTs-Ph (6.18 × 10(-2) g·kg(-1) ·d(-1) ) was 82.8%, twice that of Ph-F (6.18 × 10(-2) g·kg(-1) ·d(-1) ) ay 41.8%. In conclusion, MWCNTs-Ph had increased antitumor efficiency and also decreased potential side effects. Drug Dev Res 77 : 152-158, 2016. © 2016 Wiley Periodicals, Inc. PMID:27029561

  9. In vivo immunological antitumor effect of OK-432-stimulated dendritic cell transfer after radiofrequency ablation.

    PubMed

    Nakagawa, Hidetoshi; Mizukoshi, Eishiro; Iida, Noriho; Terashima, Takeshi; Kitahara, Masaaki; Marukawa, Yohei; Kitamura, Kazuya; Nakamoto, Yasunari; Hiroishi, Kazumasa; Imawari, Michio; Kaneko, Shuichi

    2014-04-01

    Radiofrequency ablation therapy (RFA) is a radical treatment for liver cancers and induces tumor antigen-specific immune responses. In the present study, we examined the antitumor effects of focal OK-432-stimulated dendritic cell (DC) transfer combined with RFA and analyzed the functional mechanisms involved using a murine model. C57BL/6 mice were injected subcutaneously with colon cancer cells (MC38) in their bilateral flanks. After the establishment of tumors, the subcutaneous tumor on one flank was treated using RFA, and then OK-432-stimulated DCs were injected locally. The antitumor effect of the treatment was evaluated by measuring the size of the tumor on the opposite flank, and the immunological responses were assessed using tumor-infiltrating lymphocytes, splenocytes and draining lymph nodes. Tumor growth was strongly inhibited in mice that exhibited efficient DC migration after RFA and OK-432-stimulated DC transfer, as compared to mice treated with RFA alone or treatment involving immature DC transfer. We also demonstrated that the antitumor effect of this treatment depended on both CD8-positive and CD4-positive cells. On the basis of our findings, we believe that combination therapy for metastatic liver cancer consisting of OK-432-stimulated DCs in combination with RFA can proceed to clinical trials, and it is anticipated to be markedly superior to RFA single therapy. PMID:24384836

  10. Antitumor effects of the partially purified polysaccharides from Antrodia camphorata and the mechanism of its action

    SciTech Connect

    Liu, J.-J.; Huang, T.-S.; Hsu, M.-L.; Chen, C.-C.; Lin, W.-S.; Lu, F.-J. . E-mail: fjlu@csmu.edu.tw; Chang, W.-H. . E-mail: whchang@csmu.edu.tw

    2004-12-01

    Antrodia camphorata is a popular folk medicine that has attracted great attention due to its fame for antitumor activity against cancer. However, there is little information available about its action. In the present study, we purified a unique polysaccharide component from A. camphorata mycelia (AC-PS) and found that it has pronounced anti-tumor effects on both in vitro and in vivo model. Our results showed that AC-PS alone did not show any direct cytotoxic effect to human leukemic U937 cells, even at high concentration (200 {mu}g/ml). However, it could inhibit the proliferation of U937 cells via activation of mononuclear cells (MNCs). Treatment of U937 cells with AC-PS-stimulated-MNC-CM could significantly inhibit its proliferation with 55.3% growth inhibition rate. The in vitro antitumor activity was substantiated by the in vivo therapeutical study of AC-PS in sarcoma 180-bearing mice. Intraperitoneal and oral administration of AC-PS, 100 and 200 mg/kg significantly suppressed the tumor growth with the inhibition rate of 69.1% and 58.8%, respectively. In vivo studies also showed that several immunoparameters, such as the spontaneous proliferation of spleen cells, after AC-PS administration, were two-fold higher than in control mice. Furthermore, the cytolytic activity of spleen cells also increased from 9.8 {+-} 1.1% in control mice to 34.2 {+-} 5.5% and 48.2 {+-} 2.5%, after oral and intraperitoneal treatment, respectively. Besides, the mice serum interleukin-12 levels increased significantly by AC-PS treatment. Considering all these results, it is suggested that AC-PS elicit its anti-tumor effect by promoting a Th1-dominant state and killer activities.

  11. Effective antibody therapy induces host protective antitumor immunity that is augmented by TLR4 agonist treatment

    PubMed Central

    Wang, Shangzi; Astsaturov, Igor A.; Bingham, Catherine A.; McCarthy, Kenneth M.; von Mehren, Margaret; Xu, Wei; Alpaugh, R. Katherine; Tang, Yong; Littlefield, Bruce A.; Hawkins, Lynn D.; Ishizaka, Sally T.; Weiner, Louis M.

    2012-01-01

    Toll-like receptors are potent activators of the innate immune system and generate signals leading to the initiation of the adaptive immune response that can be utilized for therapeutic purposes. We tested the hypothesis that combined treatment with a toll-like receptor agonist and an anti-tumor monoclonal antibody is effective and induces host-protective anti-tumor immunity. C57BL/6 human mutated HER2 (hmHER2) transgenic mice that constitutively express kinase-deficient human HER2 under control of the CMV promoter were established. These mice demonstrate immunological tolerance to D5-HER2, a syngeneic human HER2-expressing melanoma cell line. This human HER2 tolerant model offers the potential to serve as a preclinical model to test both antibody therapy and the immunization potential of human HER2 targeted therapeutics. Here we show that E6020, a toll like receptor-4 (TLR4) agonist effectively boosted the antitumor efficacy of the monoclonal antibody trastuzumab in immunodeficient C57BL/6 SCID mice as well as in C57BL/6 hmHER2 transgenic mice. E6020 and trastuzumab co-treatment resulted in significantly greater inhibition of tumor growth than was observed with either agent individually. Furthermore, mice treated with the combination of trastuzumab and the TLR4 agonist were protected against re-challenge with human HER2 transfected tumor cells in hmHER2 transgenic mouse strains. These findings suggest that combined treatment with trastuzumab and a TLR4 agonist not only promotes direct anti-tumor effects but also induces a host-protective human HER2-directed adaptive immune response indicative of a memory response. These data provide an immunological rationale for testing TLR4 agonists in combination with antibody therapy in patients with cancer. PMID:21842208

  12. Anti-tumor effects of genetic vaccines against HPV major oncogenes

    PubMed Central

    Cordeiro, Marcelo Nazário; Paolini, Francesca; Massa, Silvia; Curzio, Gianfranca; Illiano, Elena; Duarte Silva, Anna Jéssica; Franconi, Rosella; Bissa, Massimiliano; Morghen, Carlo De Giuli; de Freitas, Antonio Carlos; Venuti, Aldo

    2014-01-01

    Expression of HPV E5, E6 and E7 oncogenes are likely to overcome the regulation of cell proliferation and to escape immunological control, allowing uncontrolled growth and providing the potential for malignant transformation. Thus, their three oncogenic products may represent ideal target antigens for immunotherapeutic strategies. In previous attempts, we demonstrated that genetic vaccines against recombinant HPV16 E7 antigen were able to affect the tumor growth in a pre-clinical mouse model. To improve this anti-HPV strategy we developed a novel approach in which we explored the effects of E5-based genetic immunization. We designed novel HPV16 E5 genetic vaccines based on two different gene versions: whole E5 gene and E5Multi. The last one is a long multi epitope gene designed as a harmless E5 version. Both E5 genes were codon optimized for mammalian expression. In addition, we demonstrated that HPV 16 E5 oncogene is expressed in C3 mouse cell line making it an elective model for the study of E5 based vaccine. In this mouse model the immunological and biological activity of the E5 vaccines were assessed in parallel with the activity of anti-E7 and anti-E6 vaccines already reported to be effective in an immunotherapeutic setting. These E7 and E6 vaccines were made with mutated oncogenes, the E7GGG mutant that does not bind pRb and the E6F47R mutant that is less effective in inhibiting p53, respectively. Results confirmed the immunological activity of genetic formulations based on attenuated HPV16 oncogenes and showed that E5-based genetic immunization provided notable anti-tumor effects. PMID:25483514

  13. Verification of antitumor effect in vivo using nanosecond pulsed streamer discharge

    NASA Astrophysics Data System (ADS)

    Yonetamari, Kenta; Shirakawa, Yuki; Akiyama, Taketoshi; Mizuno, Kazue; Ono, Ryo

    2015-09-01

    Cancer treatment using plasma has intensively studied these days. In this work, antitumor effect by nanosecond pulsed streamer discharge was investigated. Nanosecond pulsed streamer plasma was used as a plasma source, which can generate stable streamer discharge by using a nanosecond pulsed power supply. The rod electrode of 3 mm diameter is made of copper. Its end is formed into a semispherical shape of 1.5 mm curvature. The electrode is inserted into a quartz tube (inner diameter: 4 mm, thickness: 1 mm) concentrically, so any gas can be introduced. B16F10 cells were selected to perform in vivo antitumor study. These cells were injected under the skin of leg of mice to make cancer tumor. One week later from injections, plasma was applied to the cancer tumor. Mice were randomly assigned into three groups which were one control group and two plasma treatment groups. In the control group, mice were not treated. In the plasma treatment groups, plasma with dry N2 and wet O2 as a working gas were irradiated for 5 consecutive days. Processing time was 10 min and the gap distance between the electrode and tumor was 4 mm. After 5 days plasma treatment, antitumor effect was observed. The result indicates that the streamer discharge has a potential for cancer treatment.

  14. Anti-tumor effects of peptide analogs targeting neuropeptide hormone receptors on mouse pheochromocytoma cells.

    PubMed

    Ziegler, C G; Ullrich, M; Schally, A V; Bergmann, R; Pietzsch, J; Gebauer, L; Gondek, K; Qin, N; Pacak, K; Ehrhart-Bornstein, M; Eisenhofer, G; Bornstein, S R

    2013-05-22

    Pheochromocytoma is a rare but potentially lethal chromaffin cell tumor with currently no effective treatment. Peptide hormone receptors are frequently overexpressed on endocrine tumor cells and can be specifically targeted by various anti-tumor peptide analogs. The present study carried out on mouse pheochromocytoma cells (MPCs) and a more aggressive mouse tumor tissue-derived (MTT) cell line revealed that these cells are characterized by pronounced expression of the somatostatin receptor 2 (sst2), growth hormone-releasing hormone (GHRH) receptor and the luteinizing hormone-releasing hormone (LHRH) receptor. We further demonstrated significant anti-tumor effects mediated by cytotoxic somatostatin analogs, AN-162 and AN-238, by LHRH antagonist, Cetrorelix, by the cytotoxic LHRH analog, AN-152, and by recently developed GHRH antagonist, MIA-602, on MPC and for AN-152 and MIA-602 on MTT cells. Studies of novel anti-tumor compounds on these mouse cell lines serve as an important basis for mouse models of metastatic pheochromocytoma, which we are currently establishing. PMID:23267837

  15. CpG Oligodeoxynucleotide1826 combined with radioresistant cancer cell vaccine confers significant antitumor effects.

    PubMed

    Zhuang, X B; Xing, N; Zhang, Q; Yuan, S J; Chen, W; Qiao, T K

    2015-01-01

    Immunotherapy is a hot issue in cancer research over the years and tumor cell vaccine is one of the increasing number of studies. Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. CpG Oligodeoxynucleotides (CpG ODNs), synthetic oligonucleotides containing a cytosine-phosphate-guanine(CpG) motif, was shown to enhance immune responses to a wide variety of antigens. In this study, we generated the radioresistant Lewis lung cancer cell by repeated X-ray radiation and inactivated it as a whole tumor cell vaccine to enhance the immunogenicity of tumor cell vaccine. Mice were subcutaneously immunized with this inactivated vaccine combined with CpG ODN1826 and then inoculated with autologous Lewis lung cancer (LLC) to estimate the antitumor efficacy. The results showed that the radioresistant tumor cell vaccine combined with CpG ODN1826 could significantly inhibit tumor growth, increased survival of the mice and with 20% of the mice surviving tumor free in vivo compared with the unimmunized mice bearing LLC tumor. A significant increase of apoptosis was also observed in the tumor prophylactically immunized with vaccine of inactivated radioresistant tumor cell plus CpG ODN1826. The potent antitumor effect correlated with higher secretion levels of tumor necrosis factor-alpha(TNF-α) and lower levels of interleukin-10(IL-10) concentration in serum. Furthermore, the results suggested that the antitumor mechanism was probably depended on the decreased level of programmed death ligand-1(PD-L1) which plays an important role in the negative regulation of immune response by the inhibition of tumor antigen-specific T cell activation. These findings clearly demonstrated that the radioresistant tumor cell vaccine combined with CpG ODN1826 as an appropriate adjuvant could induce effective antitumor immunity in vivo. PMID:26458317

  16. Anti-tumor effect and influence of Gekko gecko Linnaeus on the immune system of sarcoma 180-bearing mice.

    PubMed

    You, Qi; Han, Shiyu; Zhang, Yuanlong; Zheng, Jianhua

    2009-01-01

    Gekko gecko Linnaeus (GgL) is an extract used in traditional Chinese medicine. In the present study, we examined the anti-tumor activity of GgL and its effect on the immune system of mice. Sarcoma 180-bearing mice were used as the animal model, and cisplatin was applied as the positive control drug. The mice were randomly divided into six groups, and each group was treated with a different drug or drug concentration. The effects of GgL were evaluated based on its anti-tumor activity and prolongation of the lifespan, the lymphocyte transformation rate and pathological changes observed in the tumors. The results suggest that GgL has anti-tumor activities and up-regulates the immune system in a dose-dependent manner. This study provides original data related to the anti-tumor and immune up-regulating function of GgL. PMID:21475868

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

    PubMed

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

    2016-01-01

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

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

    PubMed

    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. PMID:26152290

  19. Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

    PubMed Central

    Salvati, Erica; Leonetti, Carlo; Rizzo, Angela; Scarsella, Marco; Mottolese, Marcella; Galati, Rossella; Sperduti, Isabella; Stevens, Malcolm F.G.; D’Incalci, Maurizio; Blasco, Maria; Chiorino, Giovanna; Bauwens, Serge; Horard, Béatrice; Gilson, Eric; Stoppacciaro, Antonella; Zupi, Gabriella; Biroccio, Annamaria

    2007-01-01

    Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors γ-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA–binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy. PMID:17932567

  20. Effects of Antitumor Drug Sorafenib on Chick Embryo Development.

    PubMed

    Cheng, Yi-Sen; Wang, Xiao-Yu; Wang, Guang; Li, Yan; Chen, Yue-Lei; Chuai, Man-Li; Lee, Kenneth Ka Ho; Ding, Xiao-Yan; Yang, Xue-Song

    2015-07-01

    Sorafenib has been used as an oral anti-cancer drug because of its ability to inhibit tumor growth. However, the pharmacological effect of sorafenib is still the lack of in vivo experimental evidence. Tumor and embryonic cells share some similar features, so we investigated the effects of sorafenib on the development of gastrulating chick embryos. We found that sorafenib exposure was markedly attributed to the number of embryonic cell in proliferation and apoptosis. We also detected sorafenib significantly interfered with epithelial-mesenchymal transition (EMT). Furthermore, sorafenib treatment impaired the production and migration of neural crest cells. PMID:25810088

  1. Membrane associated antitumor effects of crocine-, ginsenoside- and cannabinoid derivates.

    PubMed

    Molnár, J; Szabó, D; Pusztai, R; Mucsi, I; Berek, L; Ocsovszki, I; Kawata, E; Shoyama, Y

    2000-01-01

    In the present work a systematic study was initiated with crocine, ginsenoside and cannabinoid derivatives on multidrug resistant mouse lymphoma cells, viral tumor antigen expression and some human leukocyte functions. Among saffron derivatives, crocin and picrocrocin, triglucosyl and diglucosyl crocetin were ineffective on the reversal of multidrug resistance of lymphoma cells. Ginsenoside increased drug accumulation and tumor antigen expression at 2.0-20.0 micrograms/mL. Some cannabinoid derivatives such as cannabinol, cannabispirol and cannabidiol increased drug accumulation, while cannabidiolic acid, delta-9-THC and tetrahydro-cannabidiolic acid reduced drug accumulation of the human mdr1-gene transfected mouse lymphoma cells. The reversal of multidrug resistance is the result of the inhibition of the efflux pump function in the tumor cells. Crocetin esters were less potent than crocin itself in the inhibition of EBV early antigen expression. However crocin and diglucosylcrocetin inhibited early tumor antigen expression of adenovirus infected cells, but triglucosylcrocetin was less effective at 0.01-1.0 microgram/mL. The crocin had no antiviral effect [on HSV-2 infected vero cells] up to 25 micrograms/mL concentration. Ginsenosides had a moderate inhibitory effect except ginsenoside Rb1 (was the less effective) on the drug efflux pump. Among the cannabinoid derivatives the cannabinol and cannabispirol increased drug accumulation, while cannabidiolic acid and delta-8-THC, delta-9-THC and tetrahydro-cannabinol reduced drug accumulation in multidrug resistant mouse lymphoma cells. It is interesting that ginsenosides had a chemical structure-dependent immunomodulating effect by enhancing the activity of NK-cells and ADCC activities. PMID:10810367

  2. Antitumoral effect of Ocoxin on acute myeloid leukemia

    PubMed Central

    Díaz-Rodríguez, Elena; Hernández-García, Susana; Sanz, Eduardo; Pandiella, Atanasio

    2016-01-01

    Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy whose incidence is growing in developed countries. In the relapse setting, very limited therapeutic options are available and in most cases only palliative care can be offered to patients. The effect of a composite formulation that contains several antioxidants, Ocoxin Oral solution (OOS), was tested in this condition. When analyzed in vitro, OOS exhibited anti-AML action that was both time and dose dependent. In vivo OOS induced a ralentization of tumor growth that was due to a decrease in cell proliferation. Such effect could, at least partially, be due to an increase in the cell cycle inhibitor p27, although other cell cycle proteins seemed to be altered. Besides, OOS induced an immunomodulatory effect through the induction of IL6. When tested in combination with other therapeutic agents normally used in the treatment of AML patients, OOS demonstrated a higher antiproliferative action, suggesting that it may be used in combination with those standard of care treatments to potentiate their antiproliferative action in the AML clinic. PMID:26756220

  3. Bisphosphonates Inhibit Stellate Cell Activity and Enhance Antitumor Effects of Nanoparticle Albumin Bound-Paclitaxel in Pancreatic Ductal Adenocarcinoma

    PubMed Central

    Gonzalez-Villasana, Vianey; Rodriguez-Aguayo, Cristian; Arumugam, Thiruvengadam; Cruz-Monserrate, Zobeida; Fuentes-Mattei, Enrique; Deng, Defeng; Hwang, Rosa F.; Wang, Huamin; Ivan, Cristina; Garza, Raul Joshua; Cohen, Evan; Gao, Hui; Armaiz-Pena, Guillermo N.; Monroig-Bosque, Paloma del C.; Philip, Bincy; Rashed, Mohammed H.; Aslan, Burcu; Erdogan, Mumin Alper; Gutierrez-Puente, Yolanda; Ozpolat, Bulent; Reuben, James M.; Sood, Anil K.; Logsdon, Craig; Lopez-Berestein, Gabriel

    2014-01-01

    Pancreatic stellate cells (PSCs) have been recognized as the principal cells responsible for the production of fibrosis in PDAC. Recently PSCs have been noted to share characteristics with cells of monocyte-macrophage lineage (MML cells). Thus, we tested whether PSCs could be targeted with the nitrogen-containing bisphosphonates (NBPs) [pamidronate (Pam) or zoledronic acid (ZA)], which are potent MML cell inhibitors. In addition, we tested NBPs treatment combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to enhance antitumor activity. In vitro we observed that PSCs possess α-naphthyl butyrate esterase (ANBE) enzyme activity, a specific marker of MML cells. Moreover NBPs inhibited PSCs proliferation, activation, release of macrophage chemoattractant protein-1 (MCP-1) and type I collagen expression. NBPs also induced PSC apoptosis and cell cycle arrest in the G1 phase. In vivo, NBPs inactivated PSCs; reduced fibrosis; inhibited tumor volume, tumor weight, peritoneal dissemination, angiogenesis, and cell proliferation; and increased apoptosis in an orthotopic murine model of PDAC. These in vivo antitumor effects were enhanced when NBPs were combined with nab-paclitaxel but not gemcitabine (Gem). Our study suggests that targeting PSCs and tumor cells with NBPs in combination with nab-paclitaxel may be a novel therapeutic approach to PDAC. PMID:25193509

  4. Preparation, characterization, and evaluation of antitumor effect of Brucea javanica oil cationic nanoemulsions

    PubMed Central

    Liu, Ting-ting; Mu, Li-Qiu; Dai, Wei; Wang, Chuan-bang; Liu, Xin-Yi; Xiang, Da-Xiong

    2016-01-01

    The purpose of this study was to prepare Brucea javanica oil cationic nanoemulsions (BJO-CN) with BJO as drug as well as oil phase and chitosan as cationic inducer, to explore the practical suitability of using cationic nanoemulsions for oral delivery of mixed oil, and to test its bioavailability and antitumor effect. BJO-CN was prepared by chitosan solution stirring method and then characterized physicochemically. The obtained BJO-CN had a spherical morphology with a positive zeta potential of 18.9 mV and an average particle size of 42.36 nm, showing high colloidal stability. The drug loading of BJO-CN was 91.83 mg·mL−1, determined by high-performance liquid chromatography with precolumn derivatization. Pharmacokinetic studies revealed that, compared with BJO emulsion (BJO-E) (the dosage of BJO-CN and BJO-E was equal to 505 mg·kg−1, calculated by oleic acid), BJO-CN exhibited a significant increase in the area under the plasma drug concentration–time curve over the period of 24 hours and relative bioavailability was 1.6-fold. Furthermore, the antitumor effect of BJO-CN in the orthotopic mouse model of lung cancer was evaluated by recording the median survival time and the weight of lung tissue with tumor, hematoxylin and eosin staining, and immunohistochemical technique. Results of anticancer experiments illustrated that, even though the administrated dosage in the BJO-CN group was half of that in the BJO-E group, BJO-CN exhibited similar antitumor effect to BJO-E. Moreover, BJO-CN had good synergistic effect in combination therapy with vinorelbine. These results suggested that cationic nanoemulsions are an effective and promising delivery system to enhance the oral bioavailability and anticancer effect of BJO. PMID:27330293

  5. Preparation, characterization, and evaluation of antitumor effect of Brucea javanica oil cationic nanoemulsions.

    PubMed

    Liu, Ting-Ting; Mu, Li-Qiu; Dai, Wei; Wang, Chuan-Bang; Liu, Xin-Yi; Xiang, Da-Xiong

    2016-01-01

    The purpose of this study was to prepare Brucea javanica oil cationic nanoemulsions (BJO-CN) with BJO as drug as well as oil phase and chitosan as cationic inducer, to explore the practical suitability of using cationic nanoemulsions for oral delivery of mixed oil, and to test its bioavailability and antitumor effect. BJO-CN was prepared by chitosan solution stirring method and then characterized physicochemically. The obtained BJO-CN had a spherical morphology with a positive zeta potential of 18.9 mV and an average particle size of 42.36 nm, showing high colloidal stability. The drug loading of BJO-CN was 91.83 mg·mL(-1), determined by high-performance liquid chromatography with precolumn derivatization. Pharmacokinetic studies revealed that, compared with BJO emulsion (BJO-E) (the dosage of BJO-CN and BJO-E was equal to 505 mg·kg(-1), calculated by oleic acid), BJO-CN exhibited a significant increase in the area under the plasma drug concentration-time curve over the period of 24 hours and relative bioavailability was 1.6-fold. Furthermore, the antitumor effect of BJO-CN in the orthotopic mouse model of lung cancer was evaluated by recording the median survival time and the weight of lung tissue with tumor, hematoxylin and eosin staining, and immunohistochemical technique. Results of anticancer experiments illustrated that, even though the administrated dosage in the BJO-CN group was half of that in the BJO-E group, BJO-CN exhibited similar antitumor effect to BJO-E. Moreover, BJO-CN had good synergistic effect in combination therapy with vinorelbine. These results suggested that cationic nanoemulsions are an effective and promising delivery system to enhance the oral bioavailability and anticancer effect of BJO. PMID:27330293

  6. Anti-tumor effect of bevacizumab on a xenograft model of feline mammary carcinoma

    PubMed Central

    MICHISHITA, Masaki; OHTSUKA, Aya; NAKAHIRA, Rei; TAJIMA, Tsuyoshi; NAKAGAWA, Takayuki; SASAKI, Nobuo; ARAI, Toshiro; TAKAHASHI, Kimimasa

    2015-01-01

    Feline mammary carcinomas are characterized by rapid progression and metastases. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis, proliferation and metastasis. The present study aimed to investigate the effects of a single drug therapy of bevacizumab on a xenograft model of feline mammary carcinoma expressing VEGF protein. Bevacizumab treatment suppressed tumor growth by inhibiting angiogenesis and enhancing apoptosis; however, it did not affect the tumor proliferation index. Thus, bevacizumab had anti-tumor effects on a xenograft model, and this may be useful for the treatment of feline mammary carcinoma. PMID:26616000

  7. Antitumor effects of energy restriction-mimetic agents: thiazolidinediones.

    PubMed

    Omar, Hany A; Salama, Samir A; Arafa, El-Shaimaa A; Weng, Jing-Ru

    2013-07-01

    Distinct metabolic strategies used by cancer cells to gain growth advantages, such as shifting from oxidative phosphorylation to glycolysis, constitute a basis for their selective targeting as a novel approach for cancer therapy. Thiazolidinediones (TZDs) are ligands for the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and they are clinically used as oral hypoglycemic agents. Accumulating evidence suggests that the ability of TZDs to suppress cancer cell proliferation through the interplay between apoptosis and autophagy was, at least in part, mediated through PPARγ-independent mechanisms. This review highlights recent advances in the pharmacological exploitation of the PPARγ-independent anticancer effects of TZDs to develop novel agents targeting tumor metabolism, including glucose transporter inhibitors and adenosine monophosphate-activated protein kinase, which have translational potential as cancer therapeutic agents. PMID:23612598

  8. Antitumor effect of hepatocyte growth factor on hepatoblastoma.

    PubMed

    Tsunoda, Y; Shibusawa, M; Tsunoda, A; Gomi, A; Yatsuzuka, M; Okamatsu, T

    1998-01-01

    A six month-old girl presented with an abdominal mass, and high serum level of alpha-fetoprotein. She was diagnosed as having a well-differentiated hepatoblastoma by open biopsy. The biopsy specimen was transplanted on a nude mouse, and a xenograft was successfully established. Because the xenograft maintained the characteristics of the original tumor, the effect of hepatocyte growth factor (HGF) on hepatoblastoma xenograft was investigated. Recently HGF was reported to be involved in growth, invasion, and metastasis of tumor cells. Contrary to our expectations, the treatment of hepatoblastoma xenograft with recombinant 20 ng/ml HGF produced a marked inhibition of cell growth and a suppression of producing alpha-fetoprotein. PMID:9891489

  9. Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model.

    PubMed

    Sociali, Giovanna; Raffaghello, Lizzia; Magnone, Mirko; Zamporlini, Federica; Emionite, Laura; Sturla, Laura; Bianchi, Giovanna; Vigliarolo, Tiziana; Nahimana, Aimable; Nencioni, Alessio; Raffaelli, Nadia; Bruzzone, Santina

    2016-01-19

    Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the biosynthesis of intracellular NAD+. NAMPT inhibitors have potent anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we demonstrated that CD73 enables the utilization of extracellular NAD+/nicotinamide mononucleotide (NMN) by converting them to Nicotinamide riboside (NR), which can cross the plasmamembrane and fuel intracellular NAD+ biosynthesis in human cells. These processes are herein confirmed to also occur in a human ovarian carcinoma cell line (OVCAR-3), by means of CD73 or NRK1 specific silencing. Next, we investigated the anti-tumor activity of the simultaneous inhibition of NAMPT (with FK866) and CD73 (with α, β-methylene adenosine 5'-diphosphate, APCP), in an in vivo human ovarian carcinoma model. Interestingly, the combined therapy was found to significantly decrease intratumor NAD+, NMN and ATP levels, compared with single treatments. In addition, the concentration of these nucleotides in ascitic exudates was more remarkably reduced in animals treated with both FK866 and APCP compared with single treatments. Importantly, tumors treated with FK866 in combination with APCP contained a statistically significant lower proportion of Ki67 positive proliferating cells and a higher percentage of necrotic area. Finally, a slight but significant increase in animal survival in response to the combined therapy, compared to the single agents, could be demonstrated. Our results indicate that the pharmacological inhibition of CD73 enzymatic activity could be considered as a means to potentiate the anti-cancer effects of NAMPT inhibitors. PMID:26658104

  10. Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model

    PubMed Central

    Magnone, Mirko; Zamporlini, Federica; Emionite, Laura; Sturla, Laura; Bianchi, Giovanna; Vigliarolo, Tiziana; Nahimana, Aimable; Nencioni, Alessio; Raffaelli, Nadia; Bruzzone, Santina

    2016-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the biosynthesis of intracellular NAD+. NAMPT inhibitors have potent anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we demonstrated that CD73 enables the utilization of extracellular NAD+/nicotinamide mononucleotide (NMN) by converting them to Nicotinamide riboside (NR), which can cross the plasmamembrane and fuel intracellular NAD+ biosynthesis in human cells. These processes are herein confirmed to also occur in a human ovarian carcinoma cell line (OVCAR-3), by means of CD73 or NRK1 specific silencing. Next, we investigated the anti-tumor activity of the simultaneous inhibition of NAMPT (with FK866) and CD73 (with α, β-methylene adenosine 5′-diphosphate, APCP), in an in vivo human ovarian carcinoma model. Interestingly, the combined therapy was found to significantly decrease intratumor NAD+, NMN and ATP levels, compared with single treatments. In addition, the concentration of these nucleotides in ascitic exudates was more remarkably reduced in animals treated with both FK866 and APCP compared with single treatments. Importantly, tumors treated with FK866 in combination with APCP contained a statistically significant lower proportion of Ki67 positive proliferating cells and a higher percentage of necrotic area. Finally, a slight but significant increase in animal survival in response to the combined therapy, compared to the single agents, could be demonstrated. Our results indicate that the pharmacological inhibition of CD73 enzymatic activity could be considered as a means to potentiate the anti-cancer effects of NAMPT inhibitors. PMID:26658104

  11. Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia.

    PubMed

    Chen, Jing; Pise-Masison, Cynthia A; Shih, Joanna H; Morris, John C; Janik, John E; Conlon, Kevin C; Keating, Anne; Waldmann, Thomas A

    2013-03-14

    Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+)CD25(+) lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. This trial was registered at www.clinicaltrials.gov as #NCT00061048. PMID:23321252

  12. Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia

    PubMed Central

    Chen, Jing; Pise-Masison, Cynthia A.; Shih, Joanna H.; Morris, John C.; Janik, John E.; Conlon, Kevin C.; Keating, Anne

    2013-01-01

    Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4+CD25+ lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. This trial was registered at www.clinicaltrials.gov as #NCT00061048. PMID:23321252

  13. PLGA nanofibers improves the antitumoral effect of daunorubicin.

    PubMed

    Guimarães, Pedro P G; Oliveira, Michele F; Gomes, Alinne D M; Gontijo, Sávio M L; Cortés, Maria E; Campos, Paula P; Viana, Celso T R; Andrade, Silvia P; Sinisterra, Rubén D

    2015-12-01

    The objective of this study was to evaluate the in vivo anti-inflammatory angiogenesis activity and in vitro cytotoxicity on normal and cancer cell models of a drug delivery system consisting of poly(lactic-co-glycolic acid) nanofibers loaded with daunorubicin (PLGA-DNR) that were fabricated using an electrospinning process. The PLGA-DNR nanofibers were also characterized by thermogravimetric analysis (TGA), differential thermal analysis (DTA) and differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM) and confocal fluorescence microscopy. In vitro release of DNR from the nanofibers and its corresponding mechanism were also evaluated. Sixty-five percent of the DNR was released in an initial burst over 8h, and by 1224 h, eighty-five percent of the DNR had been released. The Higuchi model yielded the best fit to the DNR release profile over the first 8h, and the corresponding data from 24 to 1224 h could be modeled using zero-order kinetics. The PLGA-DNR nanofibers exhibited a higher cytotoxicity to A431 cells than free DNR but a cytotoxicity similar to free DNR against fibroblast cells. A higher antiangiogenic effect of PLGA nanofibers was observed in the in vivo data when compared to free DNR, and no inflammatory potential was observed for the nanofibers. PMID:26402423

  14. Cord blood T cells mediate enhanced antitumor effects compared with adult peripheral blood T cells.

    PubMed

    Hiwarkar, Prashant; Qasim, Waseem; Ricciardelli, Ida; Gilmour, Kimberly; Quezada, Sergio; Saudemont, Aurore; Amrolia, Persis; Veys, Paul

    2015-12-24

    Unrelated cord blood transplantation (CBT) without in vivo T-cell depletion is increasingly used to treat high-risk hematologic malignancies. Following T-replete CBT, naïve CB T cells undergo rapid peripheral expansion with memory-effector differentiation. Emerging data suggest that unrelated CBT, particularly in the context of HLA mismatch and a T-replete graft, may reduce leukemic relapse. To study the role of CB T cells in mediating graft-versus-tumor responses and dissect the underlying immune mechanisms for this, we compared the ability of HLA-mismatched CB and adult peripheral blood (PB) T cells to eliminate Epstein-Barr virus (EBV)-driven human B-cell lymphoma in a xenogeneic NOD/SCID/IL2rg(null) mouse model. CB T cells mediated enhanced tumor rejection compared with equal numbers of PB T cells, leading to improved survival in the CB group (P < .0003). Comparison of CB T cells that were autologous vs allogeneic to the lymphoma demonstrated that this antitumor effect was mediated by alloreactive rather than EBV-specific T cells. Analysis of tumor-infiltrating lymphocytes demonstrated that CB T cells mediated this enhanced antitumor effect by rapid infiltration of the tumor with CCR7(+)CD8(+) T cells and prompt induction of cytotoxic CD8(+) and CD4(+) T-helper (Th1) T cells in the tumor microenvironment. In contrast, in the PB group, this antilymphoma effect is impaired because of delayed tumoral infiltration of PB T cells and a relative bias toward suppressive Th2 and T-regulatory cells. Our data suggest that, despite being naturally programmed toward tolerance, reconstituting T cells after unrelated T-replete CBT may provide superior Tc1-Th1 antitumor effects against high-risk hematologic malignancies. PMID:26450984

  15. Tetramethylpyrazine (TMP) exerts antitumor effects by inducing apoptosis and autophagy in hepatocellular carcinoma.

    PubMed

    Cao, Jiao; Miao, Qing; Miao, Shan; Bi, Linlin; Zhang, Song; Yang, Qian; Zhou, Xuanxuan; Zhang, Meng; Xie, Yanhua; Zhang, Jin; Wang, Siwang

    2015-05-01

    Hepatocellular carcinoma (HCC) is one of the most common types of liver cancers with high recurrence rate and mortality rate. Recent studies have indicated that tetramethylpyrazine (TMP), a purified chemical extracted from Ligusticum wallichii Franchat (ChuanXiong), possessed antitumor effects on HCC, but detailed mechanism remains unclear. Our study aims at investigating the antitumor effect of TMP on HCC and its underlying mechanism. We found that TMP inhibited cell proliferation of HepG2 cells in a dose-dependent way, and xenograft tumor models also indicated that high concentrations of TMP administration inhibited tumor growth. Next, flow cytometric analysis and transmission electron microscope images showed that TMP enhanced cell apoptosis in HepG2 cells, and western blot results showed that TMP promoted cleavage of caspase-3 and PARP in vitro and in vivo. We also found that TMP caused autophagy in HCC in vitro and in vivo. In order to examine the role of autophagy in TMP-induced apoptosis, 3-methyladenine (3-MA) was used to block the action of autophagy. Our data showed TMP-induced autophagy might be a pro-apoptosis process in HCC. Furthermore, the results of anti-oxidative enzymes and oxidation-sensitive fluorescent probe 2, 7-dichlorofluorescein diacetate (DCFH-DA) indicated that TMP induced ROS generation and inhibition of ROS diminished the anticancer function of TMP. In conclusion, our studies provide new insights into the mechanisms underlying the antitumor effect of TMP and suggest that TMP can be a novel therapeutic regimen for HCC. PMID:25841319

  16. Synergistic antitumor effects of liposomal honokiol combined with cisplatin in colon cancer models.

    PubMed

    Cheng, Niang; Xia, Tian; Han, Ying; He, Qing Jun; Zhao, Rong; Ma, Jun Rong

    2011-09-01

    Honokiol, a novel antitumor agent, may induce apoptosis and inhibit the growth of vascular endothelium in a number of tumor cell lines and xenograft models. It has been proposed that the antitumor effects of chemotherapy may be increased in combination with an antiangiogenesis agent as an anticancer strategy. In the present study, we examined the potential of honokiol to increase the antitumor effect of cisplatin (DDP) when the agent and drug were combined in murine CT26 colon cancer models, and investigated the underlying mechanism. Liposomal honokiol (LH) was prepared, and female BALB/c mice were administered LH at various doses to determine the optimum doses for honokial. Evaluation of cell apoptosis was analyzed using flow cytometry. Honokiol was encapsulated with liposome to improve its water insolubility. In vitro, LH inhibited the proliferation of CT26 cells via apoptosis and significantly enhanced the DPP-induced apoptosis of CT26 cells. In vivo, the systemic administration of LH plus DDP resulted in the inhibition of subcutaneous tumor growth beyond the effects observed with either LH or DDP alone. This growth reduction was associated with elevated levels of apoptosis (TUNEL staining) and reduced endothelial cell density (CD31 staining) compared with either treatment alone. Collectively, these findings indicate that LH may augment the induction of apoptosis in CT26 cells in vitro and in vivo, and this combined treatment has exhibited synergistic suppression in tumor progression according to the synergistic analysis. The present study may be significant to future exploration of the potential application of the combined approach in the treatment of colon cancer. PMID:22866157

  17. The Antitumor Effect of Gekko Sulfated Glycopeptide by Inhibiting bFGF-Induced Lymphangiogenesis

    PubMed Central

    Ding, Xiu-Li; Man, Ya-Nan; Hao, Jian; Zhu, Cui-Hong; Liu, Chang; Yang, Xue

    2016-01-01

    Objective. To study the antilymphangiogenesis effect of Gekko Sulfated Glycopeptide (GSPP) on human lymphatic endothelial cells (hLECs). Methods. MTS was conducted to confirm the antiproliferation effect of GSPP on hLECs; flow cytometry was employed to detect hLECs cycle distribution; the antimigration effect of GSPP on hLECs was investigated by wound healing experiment and transwell experiment; tube formation assay was used to examine its inhibitory effect on the lymphangiogenesis; western blotting was conducted to detect the expression of extracellular signal-regulated kinase1/2 (Erk1/2) and p-Erk1/2 after GSPP and basic fibroblast growth factor (bFGF) treatment. Nude mice models were established to investigate the antitumor effect of GSPP in vivo. Decreased lymphangiogenesis caused by GSPP in vivo was verified by immunohistochemical staining. Results. In vitro, GSPP (10 μg/mL, 100 μg/mL) significantly inhibited bFGF-induced hLECs proliferation, migration, and tube-like structure formation (P < 0.05) and antagonized the phosphorylation activation of Erk1/2 induced by bFGF. In vivo, GSPP treatment (200 mg/kg/d) not only inhibited the growth of colon carcinoma, but also inhibited the tumor lymphangiogenesis. Conclusion. GSPP possesses the antitumor ability by inhibiting bFGF-inducing lymphangiogenesis in vitro and in vivo, which may further inhibit tumor lymphatic metastasis. PMID:27190997

  18. The Antitumor Effect of Gekko Sulfated Glycopeptide by Inhibiting bFGF-Induced Lymphangiogenesis.

    PubMed

    Ding, Xiu-Li; Man, Ya-Nan; Hao, Jian; Zhu, Cui-Hong; Liu, Chang; Yang, Xue; Wu, Xiong-Zhi

    2016-01-01

    Objective. To study the antilymphangiogenesis effect of Gekko Sulfated Glycopeptide (GSPP) on human lymphatic endothelial cells (hLECs). Methods. MTS was conducted to confirm the antiproliferation effect of GSPP on hLECs; flow cytometry was employed to detect hLECs cycle distribution; the antimigration effect of GSPP on hLECs was investigated by wound healing experiment and transwell experiment; tube formation assay was used to examine its inhibitory effect on the lymphangiogenesis; western blotting was conducted to detect the expression of extracellular signal-regulated kinase1/2 (Erk1/2) and p-Erk1/2 after GSPP and basic fibroblast growth factor (bFGF) treatment. Nude mice models were established to investigate the antitumor effect of GSPP in vivo. Decreased lymphangiogenesis caused by GSPP in vivo was verified by immunohistochemical staining. Results. In vitro, GSPP (10 μg/mL, 100 μg/mL) significantly inhibited bFGF-induced hLECs proliferation, migration, and tube-like structure formation (P < 0.05) and antagonized the phosphorylation activation of Erk1/2 induced by bFGF. In vivo, GSPP treatment (200 mg/kg/d) not only inhibited the growth of colon carcinoma, but also inhibited the tumor lymphangiogenesis. Conclusion. GSPP possesses the antitumor ability by inhibiting bFGF-inducing lymphangiogenesis in vitro and in vivo, which may further inhibit tumor lymphatic metastasis. PMID:27190997

  19. Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase

    PubMed Central

    TSUJIMOTO, HIROAKI; TSUKIOKA, SAYAKA; ONO, SATORU; SAKAMOTO, ETSUKO; SAKAMOTO, KAZUKI; TSUTA, KOHJI; NAKAGAWA, FUMIO; SAITO, HITOSHI; UCHIDA, JUNJI; KINIWA, MAMORU; FUKUSHIMA, MASAKAZU

    2010-01-01

    The combination of oral tegafur-uracil (UFT) with leucovorin (LV) is used to treat patients with stage II to III colon cancer based on the results of postoperative randomized studies in which UFT/LV treatment showed an equivalent efficacy to intravenous 5-FU plus LV therapy. However, whether the addition of LV to UFT can elevate the antitumor activity of UFT in colorectal tumors with high expression levels of thymidylate synthase (TS), which affects 5-FU efficacy, remains to be clarified. This study investigated the effect of LV on the antitumor activity of UFT and/or 5-FU prodrugs in low folate diet-fed nude mice using human colorectal cancer xenografts with various expression levels of TS. The addition of LV to UFT resulted in a 55–79% inhibition of tumor growth among 11 types of colorectal tumor xenograft, whereas UFT alone showed 23–67% antitumor activity. Although there was an inverse relationship between the antitumor effect of UFT alone and UFT plus LV and tumoral TS activity, UFT plus LV appeared to have a more potent antitumor effect than UFT alone on colorectal tumors such as Co-3 and KM12C/5-FU with high expression levels of TS. This finding was confirmed by the significant positive correlation between the relative inhibition ratio of UFT/LV to UFT alone and TS levels in tumors. To investigate the reason for the higher efficacy of UFT/LV on colorectal cancer xenografts with high TS activity, intratumoral levels of reduced folates and a ternary complex of TS after oral UFT with or without LV were measured using Co-3 xenografts. Elevated levels of reduced folates and an increased ternary complex of TS in LV-treated tumors were noted. Our results indicate that a combined therapy of UFT with LV may contribute to the treatment of colorectal cancer patients with low and high expression levels of tumoral TS by increased formation of the ternary complex of TS leading to potentiated antitumor efficacy of UFT. PMID:22870097

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

    PubMed Central

    Jing, Siqun; Zhang, Xiaoming

    2015-01-01

    The objective of the present study was to evaluate the antioxidant activity, antitumor effect, and antiaging property of proanthocyanidins from Kunlun Chrysanthemum flowers (PKCF) grown in Xinjiang. In vitro antioxidant experiments results showed that the total antioxidant activity and the scavenging capacity of hydroxyl radicals (•OH) and 1,1-diphenyl-2-picrylhydrazyl (DPPH•) radicals increased in a concentration-dependent manner and were stronger than those of vitamin C. To investigate the antioxidant activity of PKCF in vivo, we used serum, liver, and kidney from mouse for the measurement of superoxide dismutase (SOD), malondialdehyde (MDA), and total antioxidant capacity (T-AOC). Results indicated that PKCF had antioxidative effect in vivo which significantly improved the activity of SOD and T-AOC and decreased MDA content. To investigate the antitumor activity of PKCF, we used H22 cells, HeLa cells, and Eca-109 cells with Vero cells as control. Inhibition ratio and IC50 values were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; PKCF showed great inhibitory activity on H22 cells and HeLa cells. We also used fruit flies as a model for analyzing the anti-aging property of PKCF. Results showed that PKCF has antiaging effect on Drosophila. Results of the present study demonstrated that PKCF could be a promising agent that may find applications in health care, medicine, and cosmetics. PMID:25628774

  1. Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma.

    PubMed

    Canitano, Andrea; Iessi, Elisabetta; Spugnini, Enrico Pierluigi; Federici, Cristina; Fais, Stefano

    2016-07-01

    Multiple Myeloma (MM) is the second most common hematological malignancy and is responsive to a limited number of drugs. Unfortunately, to date, despite the introduction of novel drugs, no relevant increase in survival rates has been obtained. Proton pump inhibitors (PPIs) have been shown to have significant antitumor action as single agents as well as in combination with chemotherapy. This study investigates the potential anti-tumor effectiveness of two PPIs, Lansoprazole and Omeprazole, against human MM cells. We found that Lansoprazole exerts straightforward efficacy against myeloma cells, even at suboptimal concentrations (50 µM), while Omeprazole has limited cytotoxic action. The Lansoprazole anti-MM effect was mostly mediated by a caspase-independent apoptotic-like cytotoxicity, with only a secondary anti-proliferative action. This study provides clear evidence supporting the use of Lansoprazole in the strive against MM with an efficacy proven much higher than current therapeutical approaches and without reported side effects. It is however conceivable that, consistent with the results obtained in other human tumors, Lansoprazole may well be combined with existing anti-myeloma therapies with the aim to improve the low level of efficacy of the current strategies. PMID:27084522

  2. The antitumor effect of bromophenol derivatives in vitro and Leathesia nana extract in vivo

    NASA Astrophysics Data System (ADS)

    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.

  3. [Immunomodulative effects of Chinese herbs in mice treated with anti-tumor agent cyclophosphamide].

    PubMed

    Jin, R; Wan, L L; Mitsuishi, T; Kodama, K; Kurashige, S

    1994-07-01

    Extracts of Chinese herbs were administered with antitumor agent, cyclophosphamide (CY), and their effects on macrophages and lymphocytes were studied. Number of peritoneal macrophages significantly decreased and their chemotactic activity was suppressed by treatment with CY. Blastogenic responsiveness to Concanavalin A and NK cell activity of spleen lymphocytes were suppressed significantly in CY-treated mice. Extracts of Lithospermi radix, Astragali radix and Glycyrrhizae radix showed protective effects on immunosuppressive mice. The number of macrophages, chemotactic activity of macrophages and blastogenic response of lymphocytes were recovered to the same or more than that of normal levels. An extract of Ginseng radix showed protective effects on the number and functions of macrophages by treatment with CY but did not show any effects on the lymphocytic blastogenesis. On the contrary it showed a strong inhibitory effect on the NK cell activity. These results suggest that Chinese herbs could modulate cellular immune response, especially in the activation of macrophages and splenic lymphocytes. PMID:7932098

  4. Antitumor effects of Osthol from Cnidium monnieri: an in vitro and in vivo study.

    PubMed

    Chou, Szu-Yuan; Hsu, Chun-Sen; Wang, Kun-Teng; Wang, Min-Chieh; Wang, Ching-Chiung

    2007-03-01

    Cnidium monnieri (L.) Cusson is a Chinese medicine which is used widely by traditional medicine doctors. Osthol is a major bio-activity compound of the herb. In this study, osthol was isolated from C. monnieri and its in vitro and in vivo antitumor effects studied. The results of the in vitro study showed: that osthol inhibited the growth of HeLa, in a time- and concentration-dependent manner, with IC(50) values of 77.96 and 64.94 microm for 24 and 48 h, respectively; that osthol had lower cytotoxic effects in primary cultured normal cervical fibroblasts; and that increased DNA fragmentation and activated PARP in HeLa after treatment with osthol which could induce apoptosis. The results of the in vivo model showed that the survival days of the P-388 D1 tumor-bearing CDF(1) mice were prolonged (ILS% = 37) after osthol (30 mg/kg) was given once a day for 9 days. Based on these results, it is suggested that osthol could inhibit P-388 D1 cells in vivo and induce apoptosis in HeLa cells in vitro, and that osthol is good lead compound for developing antitumor drugs. However, C. formosanum Yabe of Taiwan's endemic plants contained little osthol, with no imperatorin, and its major components were different from that of C. monnieri. Therefore, it is suggested that C. formosanum also may possess economic worth. PMID:17154232

  5. [Synergistic inhibitory effect of static magnetic field and antitumor drugs on Hepa1-6 cells].

    PubMed

    Xu, Lingling; Guo, Wei; Liu, Ying; Zhang, Xueqing; Yu, Juntao; Wu, Wencai; Zhao, Tiejun

    2015-09-01

    Chemotherapy as a routine method for clinical treatment of cancer has disadvantages such as significant toxicity and strong resistance. In order to improve the efficacy of the drugs and reduce the by-effects, we tried to combine static magnetic field (SMF) with cisplatin or adriamycin. The growth of Hepa1-6 cells treated with the static magnetic field (SMF) combined with cisplatin or adriamycin was significantly inhibited, as detected with MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) test. Combined treatment group cells underwent significant morphological changes as observed by HE (Hematoxylin and eosin) staining under optical microscope. Cell cycle analysis indicated that SMF increased the ratio of cells arrested in G2/M phase caused by cisplatin, and when treated with SMF combined with adriamycin, cells were almost arrested in G1 and G2/M phase. SCGE test showed that SMF can enhance the ability of cisplatin or adriamycin to promote cell DNA damage. Atomic force microscope observation found that the combination of antitumor drugs and magnetic field treatment induced larger and deeper holes on the cell membrane, and surface structure damage is serious. The combination of antitumor drugs and magnetic field technology effectively inhibits the growth of tumor cells, and reduces drug doses. The results implicate this method as potential cancer therapy. PMID:26955714

  6. Antitumor effect of para-toluenesulfonamide against lung cancer xenograft in a mouse model

    PubMed Central

    Gao, Yang; Gao, Yonghua; Guan, Weijie; Huang, Liyan; Xu, Xiaoming; Zhang, Chenting; Chen, Xiuqing; Wu, Yizhuang; Zeng, Guangqiao

    2013-01-01

    Background Conventional chemotherapy and radiation therapy against non-small cell lung cancer (NSCLC) are relatively insensitive and unsatisfactory. Para-toluenesulfonamide (PTS), a unique antitumor drug for local intratumoral injection, shows an efficacy of severely suppressing solid tumor growth with mild side effects in clinical trials. The aim of this study was to investigate the effect of PTS on lung cancer H460 cells in vivo in nude mice and its underlying mechanisms in vitro. Methods A lung cancer model for in vivo experiment was established in BALB/c nude mice using H460 cells to examine the effect of local injection of PTS on tumor suppression. We also assessed the injury to the normal tissue by subcutaneous injection of PTS. In vitro, PTS was diluted into different doses for study on its antitumor mechanisms. We evaluated the necrotic effect of PTS on H460 cells by PI and Hoechst 33342 staining. Cell viability and membrane permeability were also determined by using CCK-8 and LDH assays respectively. All these tests were conducted in comparison with traditional local injection of anhydrous ethanol. Results PTS was shown to significantly inhibit the growth of H460 tumor xenografts in nude mice by inducing necrosis of the tumor histologically. Its effect on tumor growth was significantly stronger than that of anhydrous ethanol. By contrast, the injured normal tissue by PTS injection was less than that by ethanol. In vitro, PTS still demonstrated excellent necrotizing effect on H460 cells when diluted to a lower concentration. Detailed analysis of PTS on H460 cells indicated that PTS had a better effect on attenuating the cell viability and increasing the cell membrane permeability than ethanol at the same level. Conclusions PTS exhibits excellent inhibition effect on the growth of lung cancer by necrotizing tumor in vivo and in vitro, reducing tumor cell viability and augmenting the membrane permeability in vitro, with only mild injury to normal tissue. The

  7. Antitumor effects of tyropeptin-boronic acid derivatives: New proteasome inhibitors

    PubMed Central

    Momose, Isao; Abe, Hikaru; Watanabe, Takumi; Ohba, Shun-ichi; Yamazaki, Kanami; Dan, Shingo; Yamori, Takao; Masuda, Tohru; Nomoto, Akio

    2014-01-01

    The proteasome degrades numerous regulatory proteins that are critical for tumor growth. Thus, proteasome inhibitors are promising antitumor agents. New proteasome inhibitors, such as tyropeptins and tyropeptin-boronic acid derivatives, have a potent inhibitory activity. Here we report the antitumor effects of two new tyropeptin-boronic acid derivatives, AS-06 and AS-29. AS-06 and AS-29 significantly suppress the degradation of the proteasome-sensitive fluorescent proteins in HEK293PS cells, and induce the accumulation of ubiquitinated proteins in human multiple myeloma cells. We show that these derivatives also suppress the degradation of the NF-κB inhibitor IκB-α and the nuclear translocation of NF-κB p65 in multiple myeloma cells, resulting in the inhibition of NF-κB activation. Furthermore, we demonstrate that AS-06 and AS-29 induce apoptosis through the caspase-8 and caspase-9 cascades. In a xenograft mouse model, i.v. administration of tyropeptin-boronic acid derivatives inhibits proteasome in tumors and clearly suppresses tumor growth in mice bearing human multiple myeloma. Our results indicate that tyropeptin-boronic acid derivatives could be lead therapeutic agents against human multiple myeloma. PMID:25251038

  8. Antitumor Effect of a Polypeptide Fraction from Arca subcrenata in Vitro and in Vivo

    PubMed Central

    Hu, Xianjing; Song, Liyan; Huang, Lijiao; Zheng, Qin; Yu, Rongmin

    2012-01-01

    Arca subcrenata Lischke is a marine traditional Chinese medicine. The study investigated the antitumor effects of P2, a polypeptide fraction from A. subcrenata, and its toxicity in vitro and in vivo. The results showed that P2 could inhibit the proliferation of seven tumor cell lines, especially in HeLa and HT-29 cell lines. The IC50 values were 11.43 μg/mL for HeLa and 13.00 μg/mL for HT-29 treated by P2 for 48 h. P2 had little cytotoxicity on normal liver cells (L-02). The maximum tolerated dose (MTD) of P2 on KM mice was 1000 mg/kg by i.p. or i.v. The tumor growth inhibitory ratios of P2 were 26.4%, 41.4% and 46.4% for H-22, and 34.0%, 45.8% and 60.1% for S-180 tumor-bearing mice. The results demonstrated that P2 might be a potential antitumor agent with high efficiency in dose-dependent and time-dependent manners and low toxicity. PMID:23342393

  9. Anti-tumor effect of β-glucan from Lentinus edodes and the underlying mechanism.

    PubMed

    Xu, Hui; Zou, Siwei; Xu, Xiaojuan; Zhang, Lina

    2016-01-01

    β-Glucans are well known for its various bioactivities, but the underlying mechanism has not been fully understood. This study focuses on the anti-tumor effect and the potential mechanism of a branched β-(1, 3)-glucan (LNT) extracted from Lentinus edodes. The in vivo data indicated that LNT showed a profound inhibition ratio of ~75% against S-180 tumor growth, even significantly higher than the positive control of Cytoxan (~54%). Interestingly, LNT sharply promoted immune cells accumulation into tumors accompanied by cell apoptosis and inhibition of cell proliferation during tumor development. Furthermore, LNT not only up-regulated expressions of the tumor suppressor p53, cell cycle arrestin p21 and pro-apoptotic proteins of Bax and caspase 3/9, but also down-regulated PARP1 and anti-apoptotic protein Bcl-2 expressions in tumor tissues. It was first found that LNT initiated p53-dependent signaling pathway to suppress cell proliferation in vitro, and the caspase-dependent pathway to induce cell apoptosis in vivo. The underlying anti-tumor mechanism was proposed that LNT activated immune responses to induce cell apoptosis through caspase 3-dependent signaling pathway and to inhibit cell proliferation possibly via p53-dependent signaling pathway in vivo. Besides, LNT inhibited angiogenesis by suppressing VEGF expression, leading to slow progression of tumors. PMID:27353254

  10. Antitumor and Antimetastatic Effect of Small Immunostimulatory RNA against B16 Melanoma in Mice

    PubMed Central

    Kabilova, Tatyana O.; Sen’kova, Aleksandra V.; Nikolin, Valeriy P.; Popova, Nelly A.; Zenkova, Marina A.; Vlassov, Valentin V.; Chernolovskaya, Elena L.

    2016-01-01

    Small interfering RNAs, depending on their structure, delivery system and sequence, can stimulate innate and adaptive immunity. The aim of this study was to investigate the antitumor and antimetastatic effects of immunostimulatory 19-bp dsRNA with 3’- trinucleotide overhangs (isRNA) on melanoma B16 in C57Bl/6 mice. Recently developed novel cationic liposomes 2X3-DOPE were used for the in vivo delivery of isRNA. Administration of isRNA/2X3-DOPE complexes significantly inhibits melanoma tumor growth and metastasis. Histopathological analysis of spleen cross sections showed hyperplasia of the lymphoid white pulp and formation of large germinal centers after isRNA/2X3-DOPE administration, indicating activation of the immune system. The treatment of melanoma-bearing mice with isRNA/2X3-DOPE decreases the destructive changes in the liver parenchyma. Thus, the developed isRNA displays pronounced immunostimulatory, antitumor and antimetastatic properties against melanoma B16 and may be considered a potential agent in the immunotherapy of melanoma. PMID:26981617

  11. Anti-tumor effect of β-glucan from Lentinus edodes and the underlying mechanism

    PubMed Central

    Xu, Hui; Zou, Siwei; Xu, Xiaojuan; Zhang, Lina

    2016-01-01

    β-Glucans are well known for its various bioactivities, but the underlying mechanism has not been fully understood. This study focuses on the anti-tumor effect and the potential mechanism of a branched β-(1, 3)-glucan (LNT) extracted from Lentinus edodes. The in vivo data indicated that LNT showed a profound inhibition ratio of ~75% against S-180 tumor growth, even significantly higher than the positive control of Cytoxan (~54%). Interestingly, LNT sharply promoted immune cells accumulation into tumors accompanied by cell apoptosis and inhibition of cell proliferation during tumor development. Furthermore, LNT not only up-regulated expressions of the tumor suppressor p53, cell cycle arrestin p21 and pro-apoptotic proteins of Bax and caspase 3/9, but also down-regulated PARP1 and anti-apoptotic protein Bcl-2 expressions in tumor tissues. It was first found that LNT initiated p53-dependent signaling pathway to suppress cell proliferation in vitro, and the caspase-dependent pathway to induce cell apoptosis in vivo. The underlying anti-tumor mechanism was proposed that LNT activated immune responses to induce cell apoptosis through caspase 3-dependent signaling pathway and to inhibit cell proliferation possibly via p53-dependent signaling pathway in vivo. Besides, LNT inhibited angiogenesis by suppressing VEGF expression, leading to slow progression of tumors. PMID:27353254

  12. Eps8 vaccine exerts prophylactic antitumor effects in a murine model: a novel vaccine for breast carcinoma.

    PubMed

    He, Yan-Jie; Zhou, Jing; Zhao, Tong-Feng; Hu, Liang-Shan; Gan, Jing-Ying; Deng, Lan; Li, Yuhua

    2013-08-01

    Cancer vaccines are an effective way to prevent the occurrence of cancer. Epidermal growth factor receptor pathway substrate 8 (Eps8) is a novel tumor-associated antigen, which is overexpressed in the majority of tumor types. In the present study, the Eps8 protein was cloned and characterized, and its feasibility as an antitumor agent in murine breast carcinoma was investigated. The results revealed that the Eps8 protein increased the secretion of interleukin (IL)-12 in the culture supernatant of dendritic cells (DCs). The Eps8 protein‑pulsed DCs induced significant cytotoxic T lymphocyte (CTL) responses, T-cell proliferation and a higher level of interferon (IFN)-γ in the culture supernatant of the splenocytes ex vivo. Additionally, when the mice were immunized with the Eps8 vaccine, this resulted in a regression of 4T1 breast tumors and significantly prolonged survival time in the tumor‑bearing mice compared with that in the phosphate-buffered saline (PBS) control group. The Eps8 vaccine induced higher CTL responses in the splenocytes of mice vaccinated against the 4T1 cells; the ratio of CD4+/CD8+ T cells was increased in the Eps8 group; and the percentage of CD4+CD25+ FoxP3+ regulatory T (Treg) cells in the Eps8 group was significantly lower compared with that of the PBS group. The results suggested that the Eps8 vaccine was able to stimulate antitumor effects against 4T1 breast cancer cells in vitro and in vivo, and it may provide a potential immunotherapeutic agent for the treatment of breast cancer. PMID:23754615

  13. A new sensitizer DVDMS combined with multiple focused ultrasound treatments: an effective antitumor strategy

    NASA Astrophysics Data System (ADS)

    Xiong, Wenli; Wang, Pan; Hu, Jianmin; Jia, Yali; Wu, Lijie; Chen, Xiyang; Liu, Quanhong; Wang, Xiaobing

    2015-12-01

    Sonodynamic therapy (SDT) was developed as a promising noninvasive approach. The present study investigated the antitumor effect of a new sensitizer (sinoporphyrin sodium, referred to as DVDMS) combined with multiple ultrasound treatments on sarcoma 180 both in vitro and in vivo. The combined treatment significantly suppressed cell viability, potentiated apoptosis, and markedly inhibited angiogenesis in vivo. In vivo, the tumor weight inhibition ratio reached 89.82% fifteen days after three sonication treatments plus DVDMS. This effect was stronger than one ultrasound alone (32.56%) and than one round of sonication plus DVDMS (59.33%). DVDMS combined with multiple focused ultrasound treatments initiated tumor tissue destruction, induced cancer cell apoptosis, inhibited tumor angiogenesis, suppressed cancer cell proliferation, and decreased VEGF and PCNA expression levels. Moreover, the treatment did not show obvious signs of side effects or induce a drop in body weight. These results indicated that DVDMS combined with multiple focused ultrasounds may be a promising strategy against solid tumor.

  14. Nitric oxide involvement in the anti-tumor effect of mistletoe (Viscum album L.) extracts Iscador on human macrophages.

    PubMed

    Mossalayi, M Djavad; Alkharrat, Abir; Malvy, Denis

    2006-06-01

    Lectins from different types of mistletoe (Viscum album, VA) have cytotoxic and immunomodulatory properties that may be relevant in the inhibition of tumor growth. The mechanism of this anti-tumoral activity remains unknown, although recent investigations point out the induction of anti-tumoral cytotoxic T cell activation. In this study therapeutically available mistletoe extracts (Iscador) prepared from Quercus (VA-Q), apple (Malus, VA-M) or pine (Pinus, VA-P) were used to investigate their capacity to induce tumor regression through the modulation of another T helper-1 (Th-1)-mediated anti-tumoral activity: the activation of macrophages. Macrophages are essential targets for both pro- or anti-inflammatory drugs and constitute an essential member of the anti-tumoral immune response. Freshly isolated human monocyte-derived macrophages are activated and various VA extracts are directly incorporated to cultures to assay their properties on the inflammatory and/or tumor cytotoxic responses. The data indicate that immunomodulatory activities of VA extracts differ according to their origin. VA-M and VA-P were able to increase anti-tumoral activity of activated human macrophages, with a possible role for nitric oxide in this effect. PMID:16927526

  15. A HLA-A2-restricted CTL epitope induces anti-tumor effects against human lung cancer in mouse xenograft model.

    PubMed

    Sher, Yuh-Pyng; Lin, Su-I; Chen, I-Hua; Liu, Hsin-Yu; Lin, Chen-Yuan; Chiang, I-Ping; Roffler, Steve; Chen, Hsin-Wei; Liu, Shih-Jen

    2016-01-01

    Cancer immunotherapy is attractive for antigen-specific T cell-mediated anti-tumor therapy, especially in induction of cytotoxic T lymphocytes. In this report, we evaluated human CTL epitope-induced anti-tumor effects in human lung cancer xenograft models. The tumor associated antigen L6 (TAL6) is highly expressed in human lung cancer cell lines and tumor specimens as compared to normal lung tissues. TAL6 derived peptides strongly inhibited tumor growth, cancer metastasis and prolonged survival time in HLA-A2 transgenic mice immunized with a formulation of T-helper (Th) peptide, synthetic CpG ODN, and adjuvant Montanide ISA-51 (ISA-51). Adoptive transfer of peptide-induced CTL cells from HLA-A2 transgenic mice into human tumor xenograft SCID mice significantly inhibited tumor growth. Furthermore, combination of CTL-peptide immunotherapy and gemcitabine additively improved the therapeutic effects. This pre-clinical evaluation model provides a useful platform to develop efficient immunotherapeutic drugs to treat lung cancer and demonstrates a promising strategy with benefit of antitumor immune responses worthy of further development in clinical trials. PMID:26621839

  16. Efficient antitumor effect of co-drug-loaded nanoparticles with gelatin hydrogel by local implantation.

    PubMed

    Zhang, Hao; Tian, Yong; Zhu, Zhenshu; Xu, Huae; Li, Xiaolin; Zheng, Donghui; Sun, Weihao

    2016-01-01

    Tetrandrine (Tet) could enhance the antitumor effect of Paclitaxel (Ptx) by increasing intracellular Reactive Oxygen Species (ROS) levels, which leads to the possibility of co-delivery of both drugs for synergistic antitumor effect. In the current study, we reported an efficient, local therapeutic strategy employing effective Tet and Ptx delivery with a nanoparticle-loaded gelatin system. Tet- and Ptx co-loaded mPEG-PCL nanoparticles (P/T-NPs) were encapsulated into the physically cross-linked gelatin hydrogel and then implanted on the tumor site for continuous drug release. The drug-loaded gelatin hydrogel underwent a phase change when the temperature slowly increased. In vitro study showed that Tet/Ptx-loaded PEG-b-PCL nanoparticles encapsulated within a gelatin hydrogel (P/T-NPs-Gelatin) inhibited the growth and invasive ability of BGC-823 cells more effectively than the combination of free drugs or P/T-NPs. In vivo study validated the therapeutic potential of P/T-NPs-Gelatin. P/T-NPs-Gelatin significantly inhibited the activation of p-Akt and the downstream anti-apoptotic Bcl-2 protein and also inducing the activation of pro-apoptotic Bax protein. Moreover, the molecular-modulating effect of P/T-NPs-Gelatin on related proteins varied slightly under the influence of NAC, which was supported by the observations of the tumor volumes and weights. Based on these findings, local implantation of P/T-NPs-Gelatin may be a promising therapeutic strategy for the treatment of gastric cancer. PMID:27226240

  17. Efficient antitumor effect of co-drug-loaded nanoparticles with gelatin hydrogel by local implantation

    PubMed Central

    Zhang, Hao; Tian, Yong; Zhu, Zhenshu; Xu, Huae; Li, Xiaolin; Zheng, Donghui; Sun, Weihao

    2016-01-01

    Tetrandrine (Tet) could enhance the antitumor effect of Paclitaxel (Ptx) by increasing intracellular Reactive Oxygen Species (ROS) levels, which leads to the possibility of co-delivery of both drugs for synergistic antitumor effect. In the current study, we reported an efficient, local therapeutic strategy employing effective Tet and Ptx delivery with a nanoparticle-loaded gelatin system. Tet- and Ptx co-loaded mPEG-PCL nanoparticles (P/T-NPs) were encapsulated into the physically cross-linked gelatin hydrogel and then implanted on the tumor site for continuous drug release. The drug-loaded gelatin hydrogel underwent a phase change when the temperature slowly increased. In vitro study showed that Tet/Ptx-loaded PEG-b-PCL nanoparticles encapsulated within a gelatin hydrogel (P/T-NPs-Gelatin) inhibited the growth and invasive ability of BGC-823 cells more effectively than the combination of free drugs or P/T-NPs. In vivo study validated the therapeutic potential of P/T-NPs-Gelatin. P/T-NPs-Gelatin significantly inhibited the activation of p-Akt and the downstream anti-apoptotic Bcl-2 protein and also inducing the activation of pro-apoptotic Bax protein. Moreover, the molecular-modulating effect of P/T-NPs-Gelatin on related proteins varied slightly under the influence of NAC, which was supported by the observations of the tumor volumes and weights. Based on these findings, local implantation of P/T-NPs-Gelatin may be a promising therapeutic strategy for the treatment of gastric cancer. PMID:27226240

  18. Triterpenoids Amplify Anti-Tumoral Effects of Mistletoe Extracts on Murine B16.F10 Melanoma In Vivo

    PubMed Central

    Strüh, Christian M.; Jäger, Sebastian; Kersten, Astrid; Schempp, Christoph M.; Scheffler, Armin; Martin, Stefan F.

    2013-01-01

    Purpose Mistletoe extracts are often used in complementary cancer therapy although the efficacy of that therapy is controversially discussed. Approved mistletoe extracts contain mainly water soluble compounds of the mistletoe plant, i.e. mistletoe lectins. However, mistletoe also contains water-insoluble triterpenoids (mainly oleanolic acid) that have anti-tumorigenic effects. To overcome their loss in watery extracts we have solubilized mistletoe triterpenoids with cyclodextrins, thus making them available for in vivo cancer experiments. Experimental design B16.F10 subcutaneous melanoma bearing C57BL/6 mice were treated with new mistletoe extracts containing both water soluble compounds and solubilized triterpenoids. Tumor growth and survival was monitored. In addition, histological examinations of the tumor material and tumor surrounding tissue were performed. Results Addition of solubilized triterpenoids increased the anti-tumor effects of the mistletoe extracts, resulting in reduced tumor growth and prolonged survival of the mice. Histological examination of the treated tumors showed mainly tumor necrosis and some apoptotic cells with active caspase-3 and TUNEL staining. A significant decrease of CD31-positive tumor blood vessels was observed after treatment with solubilized triterpenoids and different mistletoe extracts. Conclusion We conclude that the addition of solubilized mistletoe triterpenoids to conventional mistletoe extracts improves the efficacy of mistletoe treatment and may represent a novel treatment option for malignant melanoma. PMID:23614029

  19. Potential anti-tumor effects of FTY720 associated with PP2A activation: a brief review.

    PubMed

    Cristóbal, Ion; Madoz-Gúrpide, Juan; Manso, Rebeca; González-Alonso, Paula; Rojo, Federico; García-Foncillas, Jesús

    2016-06-01

    FTY720 (Fingolimod, Gilenya (†) ) is an FDA-approved immunosuppressant currently used in the treatment of multiple sclerosis. However, a large number of studies over the last few years have shown that FTY720 shows potent antitumor properties that suggest its potential usefulness as a novel anticancer agent. Interestingly, the restoration of protein phosphatase 2A (PP2A) activity mediated by FTY720 could play a key role in its antitumor effects. Taking into account that PP2A inactivation is a common event that determines poor outcome in several tumor types, FTY720 could serve as an alternative therapeutic strategy for cancer patients with such alterations. PMID:26950691

  20. Combining Antiangiogenic Therapy with Adoptive Cell Immunotherapy Exerts Better Antitumor Effects in Non-Small Cell Lung Cancer Models

    PubMed Central

    Shi, Shujing; Wang, Rui; Chen, Yitian; Song, Haizhu; Chen, Longbang; Huang, Guichun

    2013-01-01

    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 therapy against lung

  1. Anti-tumor effect of inhibition of IL-6 signaling in mucoepidermoid carcinoma

    PubMed Central

    Mochizuki, Daiki; Adams, April; Warner, Kristy A.; Zhang, Zhaocheng; Pearson, Alexander T.; Misawa, Kiyoshi; McLean, Scott A.; Wolf, Gregory T.; Nör, Jacques E.

    2015-01-01

    Mucoepidermoid carcinoma (MEC) is the most frequent malignant salivary gland cancer. Response to chemoradiotherapy is modest, and therefore radical surgery remains the standard-of-care. Emerging evidence suggests that Interleukin (IL)-6 signaling correlates with the survival of cancer stem cells and resistance to therapy. Here, we investigated whether inhibition of IL-6 receptor (IL-6R) signaling with tocilizumab (humanized anti-human IL-6R antibody) sensitizes MEC to chemotherapy using human mucoepidermoid carcinoma cell lines (UM-HMC) and correspondent xenograft models. In vitro, we observed that tocilizumab inhibited STAT3 phosphorylation but had no measurable effect in MEC cell viability (UM-HMC-1,-3A,-3B). In contrast, the anti-tumor effect of single agent tocilizumab on MEC xenografts was comparable to paclitaxel or cisplatin. Combination of tocilizumab with cisplatin or paclitaxel enhanced the inhibitory effect of chemotherapy on xenograft growth (P < 0.05), time to failure (P < 0.01), decreased vascular endothelial growth factor (VEGF) expression and tumor microvessel density (P < 0.05) without added systemic toxicities. Notably, tocilizumab decreased the fraction of MEC cancer stem cells (ALDHhighCD44high) in vitro, and prevented paclitaxel-induced increase in the fraction of cancer stem cells in vivo (P < 0.05). Collectively, these findings demonstrate that tocilizumab enhances the anti-tumor effect of conventional chemotherapy in preclinical models of mucoepidermoid carcinoma, and suggest that patients might benefit from combination therapy with an inhibitor of IL-6R signaling and chemotherapeutic agent such as paclitaxel. PMID:26287605

  2. Anti-tumor effect of inhibition of IL-6 signaling in mucoepidermoid carcinoma.

    PubMed

    Mochizuki, Daiki; Adams, April; Warner, Kristy A; Zhang, Zhaocheng; Pearson, Alexander T; Misawa, Kiyoshi; McLean, Scott A; Wolf, Gregory T; Nör, Jacques E

    2015-09-01

    Mucoepidermoid carcinoma (MEC) is the most frequent malignant salivary gland cancer. Response to chemoradiotherapy is modest, and therefore radical surgery remains the standard-of-care. Emerging evidence suggests that Interleukin (IL)-6 signaling correlates with the survival of cancer stem cells and resistance to therapy. Here, we investigated whether inhibition of IL-6 receptor (IL-6R) signaling with tocilizumab (humanized anti-human IL-6R antibody) sensitizes MEC to chemotherapy using human mucoepidermoid carcinoma cell lines (UM-HMC) and correspondent xenograft models. In vitro, we observed that tocilizumab inhibited STAT3 phosphorylation but had no measurable effect in MEC cell viability (UM-HMC-1,-3A,-3B). In contrast, the anti-tumor effect of single agent tocilizumab on MEC xenografts was comparable to paclitaxel or cisplatin. Combination of tocilizumab with cisplatin or paclitaxel enhanced the inhibitory effect of chemotherapy on xenograft growth (P < 0.05), time to failure (P < 0.01), decreased vascular endothelial growth factor (VEGF) expression and tumor microvessel density (P < 0.05) without added systemic toxicities. Notably, tocilizumab decreased the fraction of MEC cancer stem cells (ALDH(high)CD44(high)) in vitro, and prevented paclitaxel-induced increase in the fraction of cancer stem cells in vivo (P < 0.05). Collectively, these findings demonstrate that tocilizumab enhances the anti-tumor effect of conventional chemotherapy in preclinical models of mucoepidermoid carcinoma, and suggest that patients might benefit from combination therapy with an inhibitor of IL-6R signaling and chemotherapeutic agent such as paclitaxel. PMID:26287605

  3. Antitumor effect and toxicity of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles in mice bearing breast cancer

    PubMed Central

    2013-01-01

    Background Magnetic fluids containing superparamagnetic iron oxide nanoparticles represent an attractive platform as nanocarriers in chemotherapy. Recently, we developed a formulation of maghemite nanoparticles coated with rhodium (II) citrate, which resulted in in vitro cytotoxicity enhanced up to 4.6 times when compared to free rhodium (II) citrate formulation on breast carcinoma cells. In this work, we evaluate the antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Methods Mice were evaluated with regard to the treatments’ toxicity through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine; DNA fragmentation and cell cycle of bone marrow cells; and liver, kidney and lung histology. In addition, the antitumor activity of rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate was verified by tumor volume reduction, histology and immunohistochemistry. Results Regarding the treatments’ toxicity, no experimental groups had alterations in levels of serum ALT or creatinine, and this suggestion was corroborated by the histopathologic examination of liver and kidney of mice. Moreover, DNA fragmentation frequency of bone marrow cells was lower than 15% in all experimental groups. On the other hand, the complexes rhodium (II) citrate-functionalized maghemite and free rhodium (II) citrate led to a marked growth inhibition of tumor and decrease in CD31 and Ki-67 staining. Conclusions In summary, we demonstrated that both rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate formulations exhibited antitumor effects against 4T1 metastatic breast cancer cell line following intratumoral administration. This antitumor effect was followed by inhibition of both cell proliferation and microvascularization and by tumor tissue injury characterized as necrosis and fibrosis. Remarkably, this is the first published report

  4. Resveratrol potentiates the in vitro and in vivo anti-tumoral effects of curcumin in head and neck carcinomas

    PubMed Central

    Masuelli, Laura; Stefano, Enrica Di; Fantini, Massimo; Mattera, Rosanna; Benvenuto, Monica; Marzocchella, Laura; Sacchetti, Pamela; Focaccetti, Chiara; Bernardini, Roberta; Tresoldi, Ilaria; Izzi, Valerio; Mattei, Maurizio; Frajese, Giovanni Vanni; Lista, Florigio; Modesti, Andrea; Bei, Roberto

    2014-01-01

    The survival rate of head and neck squamous cell carcinomas (HNSCC) patients has not considerably changed over the last two decades. Polyphenols inhibit the growth of cancer cells. We determined whether the combination of Resveratrol (RES) and Curcumin (CUR) enhanced their in vitro and in vivo antitumor activities on HNSCC cell lines compared to the single compounds. We provide evidence that RES potentiated the apoptotic effect and reduced the IC50 of CUR on HNSCC cell lines. The model of compounds interaction indicated the onset of an additive effect of the two compounds compared to the single treatment after decrease of their concentrations. RES+CUR compared to CUR increased the PARP-1 cleavage, the Bax/Bcl-2 ratio, the inhibition of ERK1 and ERK2 phosphorylation, and the expression of LC3 II simultaneously with the formation of autophagic vacuoles. RES and CUR induced cytoplasmic NF-κB accumulation. RES+CUR administrations were safe in BALB/c mice and reduced the growth of transplanted salivary gland cancer cells (SALTO) more efficiently than CUR. Overall, combinations of CUR and RES was more effective in inhibiting in vivo and in vitro cancer growth than the treatment with CUR. Additional studies will be needed to define the therapeutic potential of these compounds in combination. PMID:25296980

  5. Proteomic Analysis of Anti-Tumor Effects of 11-Dehydrosinulariolide on CAL-27 Cells

    PubMed Central

    Liu, Chih-I; Chen, Cheng-Chi; Chen, Jiing-Chuan; Su, Jui-Hsin; Huang, Han Hsiang; Chen, Jeff Yi-Fu; Wu, Yu-Jen

    2011-01-01

    The anti-tumor effects of 11-dehydrosinulariolide, an active ingredient isolated from soft coral Sinularia leptoclados, on CAL-27 cells were investigated in this study. In the MTT assay for cell proliferation, increasing concentrations of 11-dehydrosinulariolide decreased CAL-27 cell viability. When a concentration of 1.5 μg/mL of 11-dehydrosinulariolide was applied, the CAL-27 cells viability was reduced to a level of 70% of the control sample. The wound healing function decreased as the concentration of 11-dehydrosinulariolide increased. The results in this study indicated that treatment with 11-dehydrosinulariolide for 6 h significantly induced both early and late apoptosis of CAL-27 cells, observed by flow cytometric measurement and microscopic fluorescent observation. A comparative proteomic analysis was conducted to investigate the effects of 11-dehydrosinulariolide on CAL-27 cells at the molecular level by comparison between the protein profiling (revealed on a 2-DE map) of CAL-27 cells treated with 11-dehydrosinulariolide and that of CAL-27 cells without the treatment. A total of 28 differential proteins (12 up-regulated and 16 down-regulated) in CAL-27 cells treated with 11-dehydrosinulariolide have been identified by LC-MS/MS analysis. Some of the differential proteins are associated with cell proliferation, apoptosis, protein synthesis, protein folding, and energy metabolism. The results of this study provided clues for the investigation of biochemical mechanisms of the anti-tumor effects of 11-dehydrosinulariolide on CAL-27 cells and could be valuable information for drug development and progression monitoring of oral squamous cell carcinoma (OSCC). PMID:21822415

  6. Location and Effects of an Antitumoral Catechin on the Structural Properties of Phosphatidylethanolamine Membranes.

    PubMed

    Casado, Francisco; Teruel, José A; Casado, Santiago; Ortiz, Antonio; Rodríguez-López, José N; Aranda, Francisco J

    2016-01-01

    Green tea catechins exhibit high diversity of biological effects including antioncogenic properties, and there is enormous interest in their potential use in the treatment of a number of pathologies. It is recognized that the mechanism underlying the activity of catechins relay in part in processes related to the membrane, and many studies revealed that the ability of catechins to interact with lipids plays a probably necessary role in their mechanism of action. We present in this work the characterization of the interaction between an antitumoral synthetically modified catechin (3-O-(3,4,5-trimethoxybenzoyl)-(-)-catechin, TMCG) and dimiristoylphosphatidyl-ethanolamine (DMPE) membranes using an array of biophysical techniques which include differential scanning calorimetry, X-ray diffraction, infrared spectroscopy, atomic force microscopy, and molecular dynamics simulations. We found that TMCG incorporate into DMPE bilayers perturbing the thermotropic transition from the gel to the fluid state forming enriched domains which separated into different gel phases. TMCG does not influence the overall bilayer assembly of phosphatidylethanolamine systems but it manages to influence the interfacial region of the membrane and slightly decrease the interlamellar repeat distance of the bilayer. TMCG seems to be located in the interior of the phosphatidylethanolamine bilayer with the methoxy groups being in the deepest position and some portion of the molecule interacting with the water interface. We believe that the reported interactions are significant not only from the point of view of the known antitumoral effect of TMCG, but also might contribute to understanding the basic molecular mechanism of the biological effects of the catechins found at the membrane level. PMID:27347914

  7. Evaluation of antitumor effects following tumor necrosis factor-α gene delivery using nanobubbles and ultrasound.

    PubMed

    Horie, Sachiko; Watanabe, Yukiko; Ono, Masao; Mori, Shiro; Kodama, Tetsuya

    2011-11-01

    The antitumor effects of tumor necrosis factor (TNF-α) were evaluated following transfection of TNF-α plasmid DNA into solid mouse tumors using the nanobubbles (NBs) and ultrasound (US) gene delivery system. Murine breast carcinoma (EMT6) cells expressing luciferase (1 × 10(6) cells) were injected intradermally into the flanks of 6-7-week-old male SCID mice on day 0. Ten microliters of TNF-α (5 μg/μL) or TNF-α mock plasmid DNA (5 μg/μL) with/without NBs (15 μL) and saline was injected intratumorally in a total volume of 30 μL, and tumors were exposed to US (frequency, 1 MHz; intensity, 3.0 W/cm(2); duty cycle, 20%; number of pulses, 200; and exposure time, 60 s) on days 2, 4, 7, and 9. Changes in tumor size were measured with an in vivo bioluminescent imaging system and a mechanical caliper. Changes in tumor vessel area were quantified using contrast-enhanced US imaging with Sonazoid and a high frequency US imaging system (40 MHz) and immunohistochemistry (CD31). At the mRNA level, expression of TNF-α, caspase-3, and p53 were quantified using real-time quantitative RT-PCR. At the protein level, expression of caspase-3 and p53 were confirmed by immunohistochemistry. We show that repeated TNF-α gene delivery using NBs and US can lead to the local production of TNF-α. This results in antitumor effects, including activation of p53-dependent apoptosis, decrease in tumor vessel density, and suppression of tumor size. In this study, we showed the effectiveness of using NBs and US for TNF-α gene delivery into tumor cells. PMID:21824220

  8. Antioxidant and Antitumor Activities of the Extracts from Chinese Yam (Dioscorea opposite Thunb.) Flesh and Peel and the Effective Compounds.

    PubMed

    Liu, Yuanxue; Li, Hongfa; Fan, Yaya; Man, Shuli; Liu, Zhen; Gao, Wenyuan; Wang, Tingting

    2016-06-01

    The aims of this study are to investigate the antioxidant and antitumor activities of the water and ethanol extracts isolated from Chinese yam (Dioscorea opposite Thunb.) flesh (CYF) and peel (CYP) and the effective compounds. It was found that all peel portions have a better effect on reactive oxygen (ROS) scavenging assay than meat portions, especially for the water extract of Chinese yam peel (CYP-W). Its IC50 values for hydroxyl radical (OH•) scavenging assay (744.25 ± 3.46 μg/mL) and for 1,1-diphenyl-2-picrylhydrazyl scavenging assay (374.85 ± 6.78 μg/mL) were both lower than that of yam flesh (CYF-W). Furthermore, the antitumor property of yam peel was more effective than that of yam flesh (CYF-W) on mouse models, with tumor inhibition rates were 47.92% and 27.41% for Ehrlich Ascites Tumor (EAC) model and 40.44% and 24.22% for H22 hepatocarcinoma tumor (H22) model. Meanwhile, extracts of peel showed higher allantoin, total flavonoids, and total phenolics contents than extracts of flesh. In conclusion, this study demonstrated that CYP-W exerted better antitumor activity than flesh extracts and the scavenging ROS effects were also significantly higher in the CYP-W in vitro. Moreover, the data indicated that allantoin may play an important role on antioxidative and antitumor capacity in yam peel. PMID:27122252

  9. [Assessment of Antitumor Effect of Submerged Culture of Ophiocordyceps sinensis and Cordyceps militaris].

    PubMed

    Avtonomova, A V; Krasnopolskaya, L M; Shuktueva, M I; Isakova, E B; Bukhman, V M

    2015-01-01

    Ophiocordyceps sinensis and Cordyceps militaris metabolites showed a high potential in the treatment of tumors as well as some other diseases. Antitumor properties of O. sinensis and C. militaris submerged mycelium were investigated. It was found that the O. sinensis dry biomass in a dose of 50 mg/kg administered once a day to the mice with subcutaneously inoculated P388 lympholeucosis lowered the tumor growth by 65% vs. 54% for the C. militaris dry biomass. The water extract of O. sinensis submerged culture however accelerated the growth of the P388 lympholeucosis tumor node in the mice almost two times, compared to the control. A greater caution in using this fungus as a source of biologically active substances is required since unwanted tumor-stimulating effects can arise. PMID:26863737

  10. Regulatory T cell effects in antitumor laser immunotherapy: a mathematical model and analysis

    NASA Astrophysics Data System (ADS)

    Dawkins, Bryan A.; Laverty, Sean M.

    2016-03-01

    Regulatory T cells (Tregs) have tremendous influence on treatment outcomes in patients receiving immunotherapy for cancerous tumors. We present a mathematical model incorporating the primary cellular and molecular components of antitumor laser immunotherapy. We explicitly model developmental classes of dendritic cells (DCs), cytotoxic T cells (CTLs), primary and metastatic tumor cells, and tumor antigen. Regulatory T cells have been shown to kill antigen presenting cells, to influence dendritic cell maturation and migration, to kill activated killer CTLs in the tumor microenvironment, and to influence CTL proliferation. Since Tregs affect explicitly modeled cells, but we do not explicitly model dynamics of Treg themselves, we use model parameters to analyze effects of Treg immunosuppressive activity. We will outline a systematic method for assigning clinical outcomes to model simulations and use this condition to associate simulated patient treatment outcome with Treg activity.

  11. The Wnt/β-catenin signaling pathway is involved in the antitumor effect of fulvestrant on rat prolactinoma MMQ cells.

    PubMed

    Cao, Lei; Gao, Hua; Li, Ping; Gui, Songbai; Zhang, Yazhuo

    2014-06-01

    Although an antiestrogen treatment for estrogen-dependent diseases, such as breast cancers, has been reported, the effect of this endocrine therapy on prolactinomas and its possible mechanism are unclear. This study investigates the antitumor effect of fulvestrant, which is a new estrogen receptor antagonist, on rat prolactinoma MMQ cells and the possible roles of the Wnt/β-catenin signaling pathway that is involved in this antitumor effect. To investigate the antitumor effect of fulvestrant, the effects of exposure to gradient doses of fulvestrant (0, 0.04, 1, 25, and 625 nM) on the proliferation of cells and the secretion of prolactin (PRL) were studied. Then, the expression levels of the Wnt/β-catenin signaling pathway-related proteins β-catenin and Wnt inhibitory factor-1 (WIF-1) were measured to investigate their possible roles in the antitumor effect of fulvestrant. The cells were also treated with decitabine (10 μM) to investigate the epigenetic mechanism of WIF-1 expression. The proliferation of MMQ cells and the secretion of PRL were suppressed by fulvestrant in a dose-dependent manner (up to 57.0 ± 3.9 % and 51.2 ± 4.9 %, respectively). β-Catenin expression was downregulated and was positively correlated with ER-α expression (P<0.01). As a tumor suppressor, WIF-1 expression was upregulated and was negatively correlated with ER-α expression (P<0.01). Furthermore, WIF-1 expression was upregulated via the hypomethylation of the promoter by decitabine, and cellular proliferation was correspondingly suppressed (37.8 ± 4.3 %). Antitumor effect of fulvestrant was partially disrupted by SB 216763 via activation of the Wnt/β-catenin pathway. In conclusion, through the Wnt/β-catenin signaling pathway, fulvestrant can suppress the proliferation of MMQ cells and the secretion of PRL. PMID:24643679

  12. Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer.

    PubMed

    Miyamoto, Ryoichi; Oda, Tatsuya; Hashimoto, Shinji; Kurokawa, Tomohiro; Inagaki, Yuki; Shimomura, Osamu; Ohara, Yusuke; Yamada, Keiichi; Akashi, Yoshimasa; Enomoto, Tsuyoshi; Kishimoto, Mikio; Yanagihara, Hideto; Kita, Eiji; Ohkohchi, Nobuhiro

    2016-04-01

    Even with current promising antitumor antibodies, their antitumor effects on stroma-rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa-2; moderate, BxPC-3; and abundant, Capan-1 and Ope-xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra-abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa-2 model, moderate (1063) in the BxPC-3 model, and negative in the Capan-1 and Ope-xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8-fold (2980, 3015) in the BxPC-3 model, 2.5- or 4.8-fold (1881, 3615) in the Capan-1 model, and 3.2- or 4.2-fold (1469, 1922) in the Ope-xeno model, respectively. Cetuximab was effective in treating even stroma-rich and k-ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia. PMID:26782353

  13. Inhibition of histone deacetylases by trans-cinnamic acid and its antitumor effect against colon cancer xenografts in athymic mice.

    PubMed

    Zhu, Bingyan; Shang, Boyang; Li, Yi; Zhen, Yongsu

    2016-05-01

    Previous studies have shown that trans-cinnamic acid (tCA) has a broad spectrum of biological activities, and exhibits antioxidant, anti-inflammatory and anticancer properties. In addition, tCA and a variety of its analogs have been detected as gut microbe‑derived metabolites exerting various biological effects in the colon. The aim of this study was to assess the antitumor activity of tCA in vitro and in vivo, in particular its therapeutic efficacy against colon cancer xenografts in athymic mice. Furthermore, it aimed to examine the effects of tCA on histone deacetylases (HDACs) and to identify the underlying molecular mechanisms. Using an MTT assay, tCA was observed to inhibit the proliferation of several cancer cell lines, and the half maximal inhibitory concentration (IC50) in HT29 colon carcinoma cells was ~1 mM. Western blot analysis demonstrated that tCA upregulated the expression of acetyl‑H3 and acetyl‑H4 proteins, which was consistent with the effects of the HDAC inhibitor, trichostatin A (TSA). Furthermore, expression of Bcl‑2 (a marker of cell proliferation) was reduced, and apoptosis was induced. Apoptosis was shown by the activation of cleavage of poly ADP ribose polymerase and the increased expression of Bax. Apoptosis was also confirmed using APC Annexin V and SYTOX Green Nucleic Acid Stain. In addition, the tCA‑induced inhibition of the expression of HDAC markers and activation of apoptosis in tumor tissues were further confirmed by immunohistochemistry. Intragastric administration of tCA at doses of 1.0 and 1.5 mmol/kg body weight suppressed the growth of HT29 human colon carcinoma xenografts in athymic mice at well‑tolerated doses. No toxic changes were found in the heart, lung, liver, kidney, colon or bone marrow following histopathological examination. This study indicated that tCA is effective against colon cancer xenograft in nude mice. The antitumor mechanism of tCA was mediated, at least in part, by inhibition of HDACs in

  14. Inhibition of histone deacetylases by trans-cinnamic acid and its antitumor effect against colon cancer xenografts in athymic mice

    PubMed Central

    ZHU, BINGYAN; SHANG, BOYANG; LI, YI; ZHEN, YONGSU

    2016-01-01

    Previous studies have shown that trans-cinnamic acid (tCA) has a broad spectrum of biological activities, and exhibits antioxidant, anti-inflammatory and anticancer properties. In addition, tCA and a variety of its analogs have been detected as gut microbe-derived metabolites exerting various biological effects in the colon. The aim of this study was to assess the antitumor activity of tCA in vitro and in vivo, in particular its therapeutic efficacy against colon cancer xenografts in athymic mice. Furthermore, it aimed to examine the effects of tCA on histone deacetylases (HDACs) and to identify the underlying molecular mechanisms. Using an MTT assay, tCA was observed to inhibit the proliferation of several cancer cell lines, and the half maximal inhibitory concentration (IC50) in HT29 colon carcinoma cells was ~1 mM. Western blot analysis demonstrated that tCA upregulated the expression of acetyl-H3 and acetyl-H4 proteins, which was consistent with the effects of the HDAC inhibitor, trichostatin A (TSA). Furthermore, expression of Bcl-2 (a marker of cell proliferation) was reduced, and apoptosis was induced. Apoptosis was shown by the activation of cleavage of poly ADP ribose polymerase and the increased expression of Bax. Apoptosis was also confirmed using APC Annexin V and SYTOX Green Nucleic Acid Stain. In addition, the tCA-induced inhibition of the expression of HDAC markers and activation of apoptosis in tumor tissues were further confirmed by immunohistochemistry. Intragastric administration of tCA at doses of 1.0 and 1.5 mmol/kg body weight suppressed the growth of HT29 human colon carcinoma xenografts in athymic mice at well-tolerated doses. No toxic changes were found in the heart, lung, liver, kidney, colon or bone marrow following histopathological examination. This study indicated that tCA is effective against colon cancer xenograft in nude mice. The antitumor mechanism of tCA was mediated, at least in part, by inhibition of HDACs in cancer cells. As

  15. Potentiation of platinum antitumor effects in human lung tumor xenografts by the angiogenesis inhibitor squalamine: effects on tumor neovascularization.

    PubMed

    Schiller, J H; Bittner, G

    1999-12-01

    Squalamine is a novel anti-angiogenic aminosterol that is postulated to inhibit neovascularization by selectively inhibiting the sodium-hydrogen antiporter exchanger. To determine how to most effectively use this agent in patients with cancer, we examined the antitumor effects of squalamine with or without cytotoxic agents in human lung cancer xenografts and correlated these observations with the degree of tumor neovascularization. No direct cytotoxic effects of squalamine against tumor cells were observed in vitro with or without cisplatin. Squalamine was effective in inhibiting the establishment of H460 human tumors in BALBc nude mice but was ineffective in inhibiting the growth of H460, CALU-6, or NL20T-A human tumor xenografts when administered i.p. to mice bearing established tumors. However, when combined with cisplatin or carboplatin, squalamine increased tumor growth delay by > or =1.5-fold in the three human lung carcinoma cell lines compared with cisplatin or carboplatin alone. No enhancement of antitumor activity was observed when squalamine was combined with paclitaxel, vinorelbine, gemcitabine, or docetaxel. Repeated cycles of squalamine plus cisplatin administration delayed H460 tumor growth >8.6-fold. Squalamine plus cisplatin reduced CD31 vessel formation by 25% compared with controls, squalamine alone, or cisplatin alone; however, no inhibition in CD31 vessel formation was observed when squalamine was combined with vinorelbine. These data demonstrate that the combination of squalamine and a platinum analog has significant preclinical antitumor activity against human lung cancer that is related to the anti-angiogenic effects of squalamine. PMID:10632372

  16. Chemopreventive effect of a mixture of Chinese Herbs (antitumor B) on chemically induced oral carcinogenesis.

    PubMed

    Wang, Yian; Yao, Ruisheng; Gao, Song; Wen, Weidong; Du, Yinqiu; Szabo, Eva; Hu, Ming; Lubet, Ronald A; You, Ming

    2013-01-01

    In this study, we evaluated chemopreventive efficacy of Antitumor B, a Chinese herbal mixture of six plants (Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus arvensis L., Dictamnus dasycarpus, and Dioscorea bulbifera) on the development of 4-nitroquinoline-1-oxide (4NQO) induced oral squamous cell carcinomas in A/J mice. Antitumor B, delivered through diet, inhibited 4NQO-induced oral cancer development by 59.19%. The reduction of cell proliferation appears to be associated with efficacy of Antitumor B against 4NQO-induced oral cancer in A/J mice. The expression of epidermal growth factor receptor (EGFR) and phosphorylated EGFR (Tyr1173) were down-regulated by Antitumor B. Tissue distribution of Antitumor B was determined using obacunone, matrine, and maackiain as marker chemicals. We found significant amounts of obacunone, matrine, and maackiain in the blood after 1-wk treatment. The concentrations of these three compounds did not increase further at 18  wk, suggesting that plasma concentrations had reached a steady-state level at 1  wk. There was no significant body weight loss and there was no other obvious sign of toxicity in Antitumor B-treated mice. These results suggest that Antitumor B is a promising agent for human oral cancer chemoprevention. PMID:22086836

  17. Microbubbles Enhance the Antitumor Effects of Sinoporphyrin Sodium Mediated Sonodynamic Therapy both In Vitro and In Vivo

    PubMed Central

    Wang, Haiping; Wang, Pan; Li, Li; Zhang, Kun; Wang, Xiaobing; Liu, Quanhong

    2015-01-01

    Objectives: To evaluate the anti-cancer effect of sonodynamic therapy combined with microbubbles both in vitro and in vivo. Methods: Cell viability was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide and guava viacount assays. Annexin V-FITC/PI staining was adopted to analyze cell apoptosis rate. FD500 uptake assay was performed to assess cell membrane permeability changes. Tumor weight, mice weight and the visual image of tumor size were used to reflect the anti-tumor effect of this combined method. Histological change of tumor tissue after different treatments was measured through hematoxylin and eosin (H&E) staining. Results: Microbubbles can significantly enhance the cytotoxicity and necrocytosis rate induced by SDT treatment. Increased cell membrane permeability and more uptake of DVDMS were founded in SDT combined with microbubbles group. For in vivo experiments, SDT with microbubbles can significantly reduce tumor weight and size with pimping difference of mice weight compare with other treatment groups. In addition, microbubbles notably improved tumor tissue destruction caused by ultrasound and SDT treatment. Conclusion: The results suggest that microbubbles can markedly improve the anti-cancer effect of DVDMS mediate sonodynamic therapy both in vitro and in vivo. PMID:26681919

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

    PubMed

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

    2016-04-20

    This study was to investigate the effects of different extraction methods on the yield, chemical structure and antitumor activity of polysaccharides from Cordyceps gunnii (C. gunnii) mycelia. Five extraction methods were used to extract crude polysaccharides (CPS), which include room-temperature water extraction (RWE), hot-water extraction (HWE), microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE) and cellulase-assisted extraction (CAE). Then Sephadex G-100 was used for purification of CPS. As a result, the antitumor activities of CPS and PPS on S180 cells were evaluated. Five CPS and purified polysaccharides (PPS) were obtained. The yield of CPS by microwave-assisted extraction (CPSMAE) was the highest and its anti-tumor activity was the best and its macromolecular polysaccharide (3000-1000kDa) ratio was the largest. The PPS had the same monosaccharide composition, but their obvious difference was in the antitumor activity and the physicochemical characteristics, such as intrinsic viscosity, specific rotation, scanning electron microscopy and circular dichroism spectra. PMID:26876874

  19. The in vitro and in vivo anti-tumor effect of layered double hydroxides nanoparticles as delivery for podophyllotoxin.

    PubMed

    Qin, Lili; Xue, Meng; Wang, Wenrui; Zhu, Rongrong; Wang, Shilong; Sun, Jing; Zhang, Rui; Sun, Xiaoyu

    2010-03-30

    In this research, we intercalated anti-tumor drug podophyllotoxin (PPT) into layered double hydroxides (LDHs) and investigated the in vitro cytotoxicity to tumor cells, the cellular uptake and in vivo anti-tumor inhibition of PPT-LDH. The nanohybrids were prepared by a two-step method with the size of 80-90nm and the zeta potential of 20.3mV. The in vitro cytotoxicity experiment indicated that PPT-LDH nanoparticles show better anti-tumor efficacy than PPT and are more readily taken up by Hela cells. PPT-LDH shows a long-term suppression effect on the tumor growth, and enhances the apoptotic process of tumor cells. The in vivo tests reveal that delivery of PPT via LDH nanoparticles is more efficient, but the mice toxicity of PPT in PPT-LDH hybrids is reduced in comparison with PPT alone. Pharmacokinetics study displays a prolonged circulation time and an increased bioavailability of PPT-LDH than PPT. These observations imply that LDH nanoparticles are the potential carrier of anti-tumor drugs in a range of new therapeutic applications. PMID:20045452

  20. Anti-tumor effects in mice induced by survivin-targeted siRNA delivered through polysaccharide nanoparticles.

    PubMed

    Yang, Feifei; Huang, Wei; Li, Yunfei; Liu, Shan; Jin, Mingji; Wang, Yuli; Jia, Lihua; Gao, Zhonggao

    2013-07-01

    Recently, survivin has been attracting great attention because it plays an important role in inhibiting the apoptosis process of tumor cells. Down-regulating the expression of survivin gene by small interfering RNA (siRNA) offers a promising method for anti-tumor therapy. However, lack of appropriate siRNA delivery vector has significantly hindered the successful application of survivin-targeted siRNA in anti-tumor therapy. The purpose of this study was to use polysaccharide vector TAT-g-CS we synthesized to deliver functional siRNA and evaluate its in vivo anti-tumor activity. TAT-g-CS vector was firstly synthesized and well structurally characterized. MTT assay showed that TAT-g-CS vector exhibited good biocompatibility. TAT-g-CS complexed with siRNA offering nanoparticles with an average particle size of 212.2 nm and a polydispersity index of 0.121, and the zeta potential of the nanoparticles was +18.58 mV. Results from reporter gene assay suggested that luciferase-targeted siRNA when delivered by TAT-g-CS could down-regulate the expression of luciferase gene with 75.3% reduction. Most importantly, we use siRNA(Sur) targeting survivin gene to assess the in vitro and in vivo delivery capacity of TAT-g-CS and its anti-tumor effects. Our results demonstrated that TAT-g-CS/siRNA(Sur) nanoparticles not only strongly inhibited the in vitro proliferation of 4T1-Luc tumor cells via inducing cell apoptosis, but also effectively inhibited the in vivo growth and metastasis of malignant breast tumor, which suggested that TAT-g-CS/siRNA nanoparticle was a highly efficient non-viral system for siRNA delivery, especially for anti-tumor therapy based on siRNA therapeutics. PMID:23632321

  1. Propionibacterium acnes Augments Antitumor, Anti-Angiogenesis and Immunomodulatory Effects of Melatonin on Breast Cancer Implanted in Mice

    PubMed Central

    Talib, Wamidh H.; Saleh, Suhair

    2015-01-01

    Breast cancer is one of the most invasive cancers with high mortality. The immune stimulating Propionibacterium acnes is a Gram positive bacterium that has the ability to cause inflammation and activate Th1-type cytokine immune response. Antitumor response was associated with the inflammation induced by P. acnes, but the antitumor effect of this bacterium was not evaluated in combination with other agents. The aim of this study was to test the antitumor potential of a combination of melatonin and P. acnes against breast cancer implanted in mice. Balb/C mice were transplanted with EMT6/P cell line and in vivo antitumor effect was assessed for P. acnes, melatonin, and a combination of melatonin and P. acnes. Tumor and organs sections were examined using hematoxylin/eosin staining protocol, and TUNEL colorimetric assay was used to detect apoptosis. The expression of vascular endothelial growth factor (VEGF) was measured in tumor sections and serum levels of INF-γ, and IL-4 were measured to evaluate the immune system function. To evaluate the toxicity of our combination, AST and ALT levels were measured in the serum of treated mice. The combination of melatonin and P. acnes has high efficiency in targeting breast cancer in mice. Forty percent of treated mice were completely cured using this combination and the combination inhibited metastasis of cancer cells to other organs. The combination therapy reduced angiogenesis, exhibited no toxicity, induced apoptosis, and stimulates strong Th1-type cytokine antitumor immune response. The combination of melatonin and P. acnes represents a promising option to treat breast cancer. However, carful preclinical and clinical evaluation is needed before considering this combination for human therapy. PMID:25919398

  2. Propionibacterium acnes Augments Antitumor, Anti-Angiogenesis and Immunomodulatory Effects of Melatonin on Breast Cancer Implanted in Mice.

    PubMed

    Talib, Wamidh H; Saleh, Suhair

    2015-01-01

    Breast cancer is one of the most invasive cancers with high mortality. The immune stimulating Propionibacterium acnes is a Gram positive bacterium that has the ability to cause inflammation and activate Th1-type cytokine immune response. Antitumor response was associated with the inflammation induced by P. acnes, but the antitumor effect of this bacterium was not evaluated in combination with other agents. The aim of this study was to test the antitumor potential of a combination of melatonin and P. acnes against breast cancer implanted in mice. Balb/C mice were transplanted with EMT6/P cell line and in vivo antitumor effect was assessed for P. acnes, melatonin, and a combination of melatonin and P. acnes. Tumor and organs sections were examined using hematoxylin/eosin staining protocol, and TUNEL colorimetric assay was used to detect apoptosis. The expression of vascular endothelial growth factor (VEGF) was measured in tumor sections and serum levels of INF-γ, and IL-4 were measured to evaluate the immune system function. To evaluate the toxicity of our combination, AST and ALT levels were measured in the serum of treated mice. The combination of melatonin and P. acnes has high efficiency in targeting breast cancer in mice. Forty percent of treated mice were completely cured using this combination and the combination inhibited metastasis of cancer cells to other organs. The combination therapy reduced angiogenesis, exhibited no toxicity, induced apoptosis, and stimulates strong Th1-type cytokine antitumor immune response. The combination of melatonin and P. acnes represents a promising option to treat breast cancer. However, carful preclinical and clinical evaluation is needed before considering this combination for human therapy. PMID:25919398

  3. TWEAK mediates anti-tumor effect of tumor-infiltrating macrophage

    SciTech Connect

    Kaduka, Yuki; Takeda, Kazuyoshi . E-mail: ktakeda@med.juntendo.ac.jp; Nakayama, Masafumi; Kinoshita, Katsuyuki; Yagita, Hideo; Okumura, Ko

    2005-06-03

    TWEAK induces diverse cellular responses, including pro-inflammatory chemokine production, migration, proliferation, and cell death through the TWEAK receptor, Fn14. In the present study, we examined the effect of TWEAK or Fn14 expression in tumor cells on tumor outgrowth in vivo. Administration of neutralizing anti-TWEAK mAb significantly reduced the frequency of tumor rejection and shortened the survival of mice intraperitoneally inoculated with TWEAK-sensitive Fn14-expressing tumor cells. Moreover, anti-TWEAK mAb treatment promoted the subcutaneous growth of TWEAK-sensitive Fn14-expressing tumor cells, and this promotion was abolished by the inhibition of macrophage infiltration but not NK cell depletion. In contrast, administration of anti-TWEAK mAb had no apparent effect on the growth of TWEAK-resistant tumor cells, even if tumor cells expressed Fn14. On the other hand, TWEAK expression in tumor cells had no significant effect on subcutaneous tumor growth. These results indicate that TWEAK mediates anti-tumor effect of macrophages in vivo.

  4. In vivo antitumor and antimetastatic effects of flavokawain B in 4T1 breast cancer cell-challenged mice

    PubMed Central

    Abu, Nadiah; Mohamed, Nurul Elyani; Yeap, Swee Keong; Lim, Kian Lam; Akhtar, M Nadeem; Zulfadli, Aimi Jamil; Kee, Beh Boon; Abdullah, Mohd Puad; Omar, Abdul Rahman; Alitheen, Noorjahan Banu

    2015-01-01

    Flavokawain B (FKB) is a naturally occurring chalcone that can be isolated through the root extracts of the kava-kava plant (Piper methysticum). It can also be synthesized chemically to increase the yield. This compound is a promising candidate as a biological agent, as it is reported to be involved in a wide range of biological activities. Furthermore, FKB was reported to have antitumorigenic effects in several cancer cell lines in vitro. However, the in vivo antitumor effects of FKB have not been reported on yet. Breast cancer is one of the major causes of cancer-related deaths in the world today. Any potential treatment should not only impede the growth of the tumor, but also modulate the immune system efficiently and inhibit the formation of secondary tumors. As presented in our study, FKB induced apoptosis in 4T1 tumors in vivo, as evidenced by the terminal deoxynucleotidyl transferase dUTP nick end labeling and hematoxylin and eosin staining of the tumor. FKB also regulated the immune system by increasing both helper and cytolytic T-cell and natural killer cell populations. In addition, FKB also enhanced the levels of interleukin 2 and interferon gamma but suppressed interleukin 1B. Apart from that, FKB was also found to inhibit metastasis, as evaluated by clonogenic assay, bone marrow smearing assay, real-time polymerase chain reaction, Western blot, and proteome profiler analysis. All in all, FKB may serve as a promising anticancer agent, especially in treating breast cancer. PMID:25834398

  5. Tumor Microenvironment Remodeling by 4-Methylumbelliferone Boosts the Antitumor Effect of Combined Immunotherapy in Murine Colorectal Carcinoma.

    PubMed

    Malvicini, Mariana; Fiore, Esteban; Ghiaccio, Valentina; Piccioni, Flavia; Rizzo, Miguel; Olmedo Bonadeo, Lucila; García, Mariana; Rodríguez, Marcelo; Bayo, Juan; Peixoto, Estanislao; Atorrasagasti, Catalina; Alaniz, Laura; Aquino, Jorge; Matar, Pablo; Mazzolini, Guillermo

    2015-09-01

    We have previously demonstrated that a low dose of cyclophosphamide (Cy) combined with gene therapy of interleukin-12 (AdIL-12) has a synergistic, although limited, antitumoral effect in mice with colorectal carcinoma. The main mechanism involved in the efficacy of Cy+AdIL-12 was the induction of a specific immune response mediated by cytotoxic T lymphocytes. Our current aims were to evaluate the effects of 4-methylumbelliferone (4Mu), a selective inhibitor of hyaluronan (HA) synthesis, on tumor microenvironment (TME) and to investigate how 4Mu affects the therapeutic efficacy of Cy+AdIL-12. The results showed that 4Mu significantly reduced the amount of tumoral HA leading to a significant decrease in tumor interstitial pressure (TIP). As a consequence, tumor perfusion was improved allowing an increased adenoviral transgene expression. In addition, treatment with 4Mu boosted the number of cytotoxic T lymphocytes that reach the tumor after adoptive transfer resulting in a potent inhibition of tumor growth. Importantly, we observed complete tumor regression in 75% of mice when 4Mu was administrated in combination with Cy+AdIL-12. The triple combination 4Mu+Cy+AdIL-12 also induced a shift toward antiangiogenic factors production in tumor milieu. Our results showed that TME remodeling is an interesting strategy to increase the efficacy of anticancer immunotherapies based on gene and/or cell therapy. PMID:26105158

  6. Anti-tumoral effects of a trypsin inhibitor derived from buckwheat in vitro and in vivo.

    PubMed

    Bai, Chong-Zhi; Feng, Ma-Li; Hao, Xu-Liang; Zhao, Zhi-Juan; Li, Yu-Ying; Wang, Zhuan-Hua

    2015-08-01

    Native buckwheat, a common component of food products and medicine, has been observed to inhibit cancer cell proliferation in vitro. The aim of the present study was to evaluate the in vitro and in vivo anti-tumoral effects of recombinant buckwheat trypsin inhibitor (rBTI) on hepatic cancer cells and the mechanism of apoptosis involved. Apoptosis in the H22 cell line induced by rBTI was identified using MTT assays, DNA electrophoresis, flow cytometry, morphological observation of the nuclei, measurement of cytochrome C and assessment of caspase activation. It was identified that rBTI decreases cell viability by inducing apoptosis, as evidenced by the formation of apoptotic bodies and DNA fragmentation. rBTI-induced apoptosis occurred in association with mitochondrial dysfunction, leading to the release of cytochrome C from the mitochondria to the cytosol, as well as the activation of caspase-3, -8 and -9. In conclusion, the results of the present study suggested that rBTI specifically inhibited the growth of the H22 hepatic carcinoma cell line in vitro and in vivo in a concentration-dependent and time-dependent manner, while there were minimal effects on the 7702 normal liver cell line. In addition, rBTI‑induced apoptosis in H22 cells was, at least in part, mediated by a mitochondrial pathway via caspase-9. PMID:25901645

  7. [NEW MECHANISM OF HYPOGLYCEMIC ACTION OF EMBRYONIC ANTITUMOR MODULATOR MKRTCHYAN BY ACTIVATION OF IT'S MEMBRANOPROTECTIVE EFFECT].

    PubMed

    Aghajanova, E

    2015-12-01

    As a new means of prevention and treatment of diabetes can be considered Embryonic antitumor modulator Mkrtchyan (EATM). According to our data on the STZ model of diabetes in rats EATM revealed hypoglycemic effect. Moreover, EATM prevented the development of oxidative stress. It is shown that EATM having immunomodulatory action, realizes its effect by regulating the Nox (NAPH oxidase) system. Inactivation of Nox, including the pancreas, is one of the factors determining the safety of the organ responsible for the development of diabetes. The release of the Nox is increased ex vivo and in the patients with type 1 and 2 diabetes. Mechanism for enhancing of the Nox isoforms release from erythrocyte membranes and blood serum exosomes in the presence of ferriHb in diabetes may be due to destabilizing of the cell membranes. It is established that the glucose at low concentrations bound to isoforms of Nox at the membrane surface due to increasing their stability, and at high concentrations, on the contrary, it lowers their stability. Thus, we have demonstrated a new mechanism of destabilization of cell membranes in diabetes mellitus. Suppression of the release of the pancreas Nox membrane cells in this pathology by means of EATM is perhaps a new mechanism of stabilization of these membranes, which explains the antidiabetic effect of the preparation. PMID:26719557

  8. Curcumin exerts antitumor effects in retinoblastoma cells by regulating the JNK and p38 MAPK pathways.

    PubMed

    Yu, Xiaoming; Zhong, Jingtao; Yan, Li; Li, Jie; Wang, Hui; Wen, Yan; Zhao, Yu

    2016-09-01

    Curcumin, a naturally occurring polyphenolic compound present in turmeric (Curcuma longa), exerts antitumor effects in various types of malignancy. However, the precise mechanisms responsible for the effects of curcumin on retinoblastoma (RB) cells have not been fully explored. In the present study, the molecular mechanisms by which curcumin exerts its anticancer effects in RB Y79 cells were investigated. The results showed that curcumin reduced cell viability in Y79 cells. Curcumin induced G1 phase arrest through downregulating the expression of cyclin D3 and cyclin-dependent kinase (CDK)2/6 and upregulating the expression of CDK inhibitor proteins p21 and p27. Curcumin-induced apoptosis of Y79 cells occurred through the activation of caspases-9/-3. Moreover, flow cytometric analysis showed that curcumin induced mitochondrial membrane potential (∆Ψm) collapse in Y79 cells. We also found that curcumin induced the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). JNK and p38 MAPK inhibitors significantly suppressed curcumin‑induced activation of caspases-9/-3 and inhibited the apoptosis of Y79 cells. Taken together, our results suggest that curcumin induced the apoptosis of Y79 cells through the activation of JNK and p38 MAPK pathways. These findings provide a novel treatment strategy for human RB. PMID:27432244

  9. Pronounced antitumor effects and tumor radiosensitization of double suicide gene therapy.

    PubMed

    Rogulski, K R; Zhang, K; Kolozsvary, A; Kim, J H; Freytag, S O

    1997-11-01

    The efficacy of HSV-1 thymidine kinase (TK) and Escherichia coli cytosine deaminase (CD) suicide gene therapies as cancer treatments are currently being examined in humans. We demonstrated previously that compared to single suicide gene therapy, greater levels of targeted cytotoxicity and radiosensitization can be achieved in vitro by genetically modifying tumor cells to express CD and HSV-1 TK concomitantly, as a fusion protein. In the present study, the efficacy of the combined double suicide gene therapy/radiotherapy approach was examined in vivo. Nude mice were injected either s.c. or i.m. with 9L gliosarcoma cells expressing an E. coli CD/HSV-1 TK fusion gene. Double suicide gene therapy using 5-fluorocytosine (500 mg/kg) and ganciclovir (30 mg/kg) proved to be markedly better at delaying tumor growth and achieving a tumor cure than single suicide gene therapy, which used 5-fluorocytosine or ganciclovir administered independently. Importantly, double suicide gene therapy was highly effective against large experimental tumors (>2 cm3), reducing tumor volume an average of 99% and producing a 40% tumor cure. Moreover, double suicide gene therapy profoundly potentiated the antitumor effects of radiation. The results indicate that double suicide gene therapy, particularly when coupled with radiotherapy, may represent a highly effective means of eradicating tumors. PMID:9815600

  10. A new sensitizer DVDMS combined with multiple focused ultrasound treatments: an effective antitumor strategy

    PubMed Central

    Xiong, Wenli; Wang, Pan; Hu, Jianmin; Jia, Yali; Wu, Lijie; Chen, Xiyang; Liu, Quanhong; Wang, Xiaobing

    2015-01-01

    Sonodynamic therapy (SDT) was developed as a promising noninvasive approach. The present study investigated the antitumor effect of a new sensitizer (sinoporphyrin sodium, referred to as DVDMS) combined with multiple ultrasound treatments on sarcoma 180 both in vitro and in vivo. The combined treatment significantly suppressed cell viability, potentiated apoptosis, and markedly inhibited angiogenesis in vivo. In vivo, the tumor weight inhibition ratio reached 89.82% fifteen days after three sonication treatments plus DVDMS. This effect was stronger than one ultrasound alone (32.56%) and than one round of sonication plus DVDMS (59.33%). DVDMS combined with multiple focused ultrasound treatments initiated tumor tissue destruction, induced cancer cell apoptosis, inhibited tumor angiogenesis, suppressed cancer cell proliferation, and decreased VEGF and PCNA expression levels. Moreover, the treatment did not show obvious signs of side effects or induce a drop in body weight. These results indicated that DVDMS combined with multiple focused ultrasounds may be a promising strategy against solid tumor. PMID:26631871

  11. The therapeutic effect of death: Newcastle disease virus and its antitumor potential.

    PubMed

    Cuadrado-Castano, Sara; Sanchez-Aparicio, Maria T; García-Sastre, Adolfo; Villar, Enrique

    2015-11-01

    Programmed cell death is essential to survival of multicellular organisms. Previously restricted to apoptosis, the concept of programmed cell death is now extended to other mechanisms, as programmed necrosis or necroptosis, autophagic cell death, pyroptosis and parthanatos, among others. Viruses have evolved to manipulate and take control over the programmed cell death response, and the infected cell attempts to neutralize viral infections displaying different stress signals and defensive pathways before taking the critical decision of self-destruction. Learning from viruses and their interplay with the host may help us to better understand the complexity of the self-defense death response that when altered might cause disorders as important as cancer. In addition, as the fields of immunotherapy and oncolytic viruses advance as promising novel cancer therapies, the programmed cell death response reemerges as a key point for the success of both therapeutic approaches. In this review we summarize the research of the multimodal cell death response induced by Newcastle disease viruses (NDV), considered nowadays a promising viral oncolytic therapeutic, and how the manipulation of the host programmed cell death response can enhance the NDV antitumor capacity. PMID:26221764

  12. Commentary on "Proteasome Inhibitors: A Novel Class of Potent and Effective Antitumor Agents".

    PubMed

    Tew, Kenneth D

    2016-09-01

    The relatively recent clinical success of bortezomib, particularly in multiple myeloma, has established the validity of the proteasome as a viable target for anticancer drug development. This highly cited 1999 Cancer Research article from Adams and colleagues was published during the period when this drug was transitioning from preclinical studies to phase I clinical trial status. Their results detail structure-activity analyses using a series of boronic acid proteasome inhibitors and correlate cytotoxicity with inhibition of proteasome activity. In and of itself, the recognition that interference with proteasome functions represented a novel therapeutic approach likely underlies the popularity of this article. In addition, the provision of in vitro (at that time using the NCI 60 cell line panel) and in vivo antitumor activity, toxicology, and mouse pharmacokinetic and pharmacodynamic data provided a solid basis for establishing the future credentials for bortezomib to gain initial FDA approval in 2003. Cancer Res; 76(17); 4916-7. ©2016 AACRSee related article by Adams et al., Cancer Res 1999;59:2615-22Visit the Cancer Research 75(th) Anniversary timeline. PMID:27587650

  13. Effect of glutathione addition in sparkling wine.

    PubMed

    Webber, Vanessa; Dutra, Sandra Valduga; Spinelli, Fernanda Rodrigues; Marcon, Ângela Rossi; Carnieli, Gilberto João; Vanderlinde, Regina

    2014-09-15

    This study aims to evaluate the effect of the addition of glutathione (GSH) on secondary aromas and on the phenolic compounds of sparkling wine elaborated by traditional method. It was added 10 and 20 mg L(-1) of GSH to must and to base wine. The determination of aroma compounds was performed by gas chromatography. Phenolic compounds and glutathione content were analyzed by high performance liquid chromatography. Sparkling wines with addition of GSH to must showed lower levels of total phenolic compounds and hydroxycinnamic acids. Furthermore, the sparkling wine with addition of GSH to must showed higher levels of 2-phenylethanol, 3-methyl-1-butanol and diethyl succinate, and lower concentrations of ethyl decanoate, octanoic and decanoic acids. The GSH addition to the must show a greater influence on sparkling wine than to base wine, however GSH addition to base wine seems retain higher SO2 free levels. The concentration of GSH added showed no significant difference. PMID:24767072

  14. Pharmacological and Chemical Effects of Cigarette Additives

    PubMed Central

    Rabinoff, Michael; Caskey, Nicholas; Rissling, Anthony; Park, Candice

    2007-01-01

    We investigated tobacco industry documents and other sources for evidence of possible pharmacological and chemical effects of tobacco additives. Our findings indicated that more than 100 of 599 documented cigarette additives have pharmacological actions that camouflage the odor of environmental tobacco smoke emitted from cigarettes, enhance or maintain nicotine delivery, could increase the addictiveness of cigarettes, and mask symptoms and illnesses associated with smoking behaviors. Whether such uses were specifically intended for these agents is unknown. Our results provide a clear rationale for regulatory control of tobacco additives. PMID:17666709

  15. Antitumor effect of manumycin on colorectal cancer cells by increasing the reactive oxygen species production and blocking PI3K-AKT pathway

    PubMed Central

    Zhang, Jingyu; Jiang, Hua; Xie, Li; Hu, Jing; Li, Li; Yang, Mi; Cheng, Lei; Liu, Baorui; Qian, Xiaoping

    2016-01-01

    Manumycin is a natural, well-tolerated microbial metabolite and is regarded as a farnesyltransferase inhibitor. Some data suggest that manumycin inhibits proliferation of diverse cancer cells through various pathways. However, the antitumor effect of manumycin on colorectal cancer (CRC) remains unknown. In the present study, we investigated the antitumor effect of manumycin on CRC in vitro and in vivo. The results of cell viability assay revealed that the proliferation of the CRC cells was significantly inhibited by manumycin. Moreover, cell apoptosis induced by manumycin was also found in a time- and dose-dependent manner. Interestingly, treatment of the CRC cells with manumycin resulted in increased generation of reactive oxygen species. Subsequently, manumycin also decreased the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and AKT, as well as the expression of caspase-9 and poly(ADP-ribose) polymerase (PARP) in a time-dependent manner. In addition, we found that N-acetyl-l-cysteine (NAC) attenuated the effect of manumycin on the PI3K-AKT pathway, and wortmannin reduced the effect of manumycin on caspase-9 and PARP expression. More importantly, the anticancer effect of manumycin was also observed in established tumor xenografts. Taken together, these findings supported the potential application of manumycin against colorectal carcinoma. PMID:27307747

  16. Antitumoral effect of PLK-1-inhibitor BI2536 in combination with cisplatin and docetaxel in squamous cell carcinoma cell lines of the head and neck.

    PubMed

    Wagenblast, Jens; Hirth, Daniel; Eckardt, Anne; Leinung, Martin; Diensthuber, Marc; Stöver, Timo; Hambek, Markus

    2013-03-01

    Inhibition of the polo-like-kinase-1 (PLK-1) has been shown to be effective in several haematological and solid tumor models. In this systemic in vitro study, the antitumor effect of BI2536, a small molecule inhibitor of PLK-1, in combination with cisplatin and docetaxel was examined in nine squamous cell carcinoma cell lines, most of which had a head and neck origin (SCCHN). Dose escalation studies were conducted with nine SCCHN cell lines using BI2536, cisplatin and docetaxel in cell line-specific concentrations. Growth inhibitory and proapoptotic effects were measured quantitatively using cytohistology and a Human Apoptose Array kit. BI2536 in combination with cisplatin and docetaxel showed a markedly higher antiproliferative and apoptotic activity in the SCCHN cell lines investigated (P≤0.008), compared with single agent cisplatin or docetaxel alone. The findings of this study showed that the addition of PLK-1-inhibitor BI2536 to conventional chemotherapeutic drugs led to a statistically higher antiproliferative and apoptotic effect in SCCHN cell lines compared with cisplatin or docetaxel alone. Inaugurating BI2536 in the clinical setting might enhance the antitumoral activity of conventional drugs, possibly leading to less toxic side effects of cancer therapy. PMID:24649162

  17. Could Caffeic Acid Phenethyl Ester Expand the Antitumor Effect of Tamoxifen in Breast Carcinoma?

    PubMed

    Motawi, Tarek K; Abdelazim, Samy A; Darwish, Hebatallah A; Elbaz, Eman M; Shouman, Samia A

    2016-01-01

    Despite tamoxifen (TAM) is beneficial in treating a significant proportion of patients with breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE) is a component of honeybee propolis, with a plethora of important biological actions including anticancer activity. This study aimed to explore the cytotoxicity, the type of drugs interaction as well as the apoptotic and autophagic pathways of the combined treatment of TAM and CAPE in MCF-7 cells. Their antitumor activity and effect on survival of mice bearing Ehrlich tumor were also analyzed. The results showed synergistic cytotoxic effects, manifested by significant activation of apoptotic machinery, along with downregulation of protein levels of Bcl-2 and beclin-1, upon using the combination regimen. However, the ratio between microtubule-associated protein light chain 3-II and -I was not altered. Moreover, a decrease in vascular endothelial growth factor level was detected. Similarly, TAM + CAPE increased the life span of tumor-bearing animals and caused a marked regression in their tumor size and weight compared with those treated with either TAM or CAPE alone. In conclusion, CAPE relatively improved the anticancer activity of TAM in both in vitro and in vivo models via its apoptotic and angiostatic potentials. PMID:27007181

  18. Supercritical fluid extracts of rosemary leaves exhibit potent anti-inflammation and anti-tumor effects.

    PubMed

    Peng, Chiung-Huei; Su, Jeng-De; Chyau, Charng-Cherng; Sung, Tzu-Ying; Ho, Shin-Shien; Peng, Chiung-Chi; Peng, Robert Y

    2007-09-01

    Supercritical fluid SF-CO2 treatment of Rosemarinus officinalis L. fresh leaves under optimum conditions (80 degrees C at 5,000 psi) yielded 5.3% of extract supercritical fluid extraction (SFE)-80, in which five major active principles were identified by liquid chromatography/mass spectrometry (LC/MS), viz., rosmarinic acid, carnosol, 12-methoxycarnosic acid, carnosic acid, and methyl carnosate. Total phenolic content was 155.8 mg/ gallic acid equivalent (GAE)/g in SFE-80, which showed 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging of 81.86% at 0.01 mg/ml. When treated in RAW 264.7, apparent dose-dependent NO inhibition occurred at dosages of 1.56 to 6.25 microg/ml, and more drastically at 12.5 and 25 microg/ml. At 0.5 to 5.0 microg/ml, SFE-80 exhibited dose-dependent viability suppression and significant tumor necrosis factor alpha (TNF-alpha) production in Hep 3B, whereas no effect was found in Chang liver cells. Furthermore, no effect was observed in RAW 264.7 at dosages of 3.13 to 25 microg/ml, indicating that SFE-80 exhibited a noncytotoxic character. Conclusively, rosemary can be considered an herbal anti-inflammatory and anti-tumor agent. PMID:17827696

  19. Antitumor effect of temsirolimus against oral squamous cell carcinoma associated with bone destruction.

    PubMed

    Okui, Tatsuo; Shimo, Tsuyoshi; Fukazawa, Takuya; Kurio, Naito; Hassan, Nur Mohammad Monsur; Honami, Tatsuki; Takaoka, Munenori; Naomoto, Yoshio; Sasaki, Akira

    2010-11-01

    The mammalian target of rapamycin (mTOR) is engaged in the molecular pathogenesis of oral squamous cell carcinoma, which frequently invades the maxilla or the mandible. However, the effects of a mTOR inhibitor on bone destruction associated with oral squamous cell carcinoma are still unclear. In this study, we investigated the antitumor effect of temsirolimus-mediated mTOR inhibition against advanced oral squamous cell carcinoma. Temsirolimus inhibited the proliferation and migration of HSC-2 oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. Significantly, we clearly show that temsirolimus inhibited osteoclast formation both in vitro and in vivo. Reverse transcriptase-PCR analysis showed that temsirolimus decreased the mRNA expression of receptor activator for nuclear factor-κB ligand, known as an osteoclast differentiation factor in bone stromal ST2 cells. Moreover, temsirolimus normalized blood-free calcium concentration in mouse models for humoral hypercalcemia. These findings suggest that mTOR signaling is a potential target of oral squamous cell carcinoma associated with bone destruction, and hence we describe the efficacy of temsirolimus for the treatment of advanced oral squamous carcinoma. PMID:20858724

  20. Effect of anti-asthma Chinese medicine Chuankezhi on the anti-tumor activity of cytokine-induced killer cells

    PubMed Central

    Zhao, Jing-Jing; Pan, Ke; Wang, Qi-Jing; Xu, Zheng-Di; Weng, De-Sheng; Li, Jian-Jun; Li, Yong-Qiang; Xia, Jian-Chuan

    2013-01-01

    Chuankezhi (CKZ), a new Chinese medicine, plays an important role in immunoregulation. Cytokine-induced killer (CIK) cells have been commonly used for immunotherapy in recent years. In this study, we aimed to investigate the immunoregulatory effect of CKZ on CIK cells. Peripheral blood monocytes were isolated from healthy donors, and CIK cells were generated by culturing monocytes with interferon-gamma (IFN-γ) and interleukin 2. Different concentrations of CKZ were added on day 2. After incubation for 14 days in culture, the antitumor effects of CIK cells were measured by cytotoxicity assay. Flow cytometry was used to explore the effect of CKZ on CIK cell immunophenotype, intracellular cytokine production, and apoptosis. The effect of CKZ on the antitumor activity of CIK cells in nude mice was also investigated. CKZ increased the percentage of CD3+CD56+ CIK cells but did not significantly change the percentage of CD4+, CD8+, or CD4+CD25+ CIK cells. CKZ-conditioned CIK cells showed a greater ability to kill tumor cells, as well as a higher frequency of IFN-γ and TNF-α production, compared with the CIK cells in the control group. CKZ also suppressed the apoptosis of CIK cells in vitro. Furthermore, CKZ combined with CIK cells had a stronger suppressive effect on tumor growth in vivo than the CIK, CKZ, or normal saline control groups. Our results indicate that CKZ enhances the antitumor activity of CIK cells and is a potential medicine for tumor immunotherapy. PMID:23470144

  1. Combine therapy of gefitinib and fulvestrant enhances antitumor effects on NSCLC cell lines with acquired resistance to gefitinib.

    PubMed

    Xu, Ruitong; Shen, Hua; Guo, Renhua; Sun, Jing; Gao, Wen; Shu, Yongqian

    2012-07-01

    Gefitinib, an EGFR receptor tyrosine kinase inhibitor, is approved for clinical use in the treatment of non-small cell lung cancer (NSCLC), but the emergence of mutations resistant to these inhibitors, such as T790M, has become a clinical problem. According to statistics, female patients, the presence of adenocarcinoma or non-smokers experienced a higher response rate. This may be involved in interaction between the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR). To test whether inhibition of the ER signaling pathway affects the antitumor effect of gefitinib, gefitinib and an ER antagonist, fulvestrant, were administered to NSCLC cell lines with acquired resistance to gefitinib. Compared with treatment of either fulvestrant or gefitinib alone, drug combination obviously decreased proliferation of H1976, H1650 and PC-9 cells coming from adenocarcinoma. Rapid activations of EGFR pathway by E2β were observed in H1975 cells with T790M mutation. Additionally, EGFR and ERs expression were down-regulated respectively in response to estrogen and EGF but up-regulated in response to fulvestrant and gefitinib in vitro. These results suggest that there is a functional cross-signaling between the EGFR/ER pathways in NSCLC with acquired resistance to gefitinib, possibly providing rationale for combining gefitinib with anti-estrogen therapy for advanced NSCLC treatment. PMID:22560634

  2. Development, characterization and anti-tumor effect of a sequential sustained-release preparation containing ricin and cobra venom cytotoxin.

    PubMed

    Zhang, Xiu-Juan; Ke, Li-Ming; Yang, Jing; Lin, Li-Wu; Xue, En-Sheng; Wang, Yan; Yu, Li-Yun; Chen, Zhi-Kui

    2012-07-01

    Cobra venom cytotoxin (CVC) loaded in poly (lactide-co-glycolide) (PLGA) microspheres was mixed with ricin and encapsulated in a thermosensitive PLGA-PEG-PLGA hydrogel for this study. This sequential sustained-release preparation (SSRP) containing ricin and CVC could avoid burst release effect of CVC from microspheres. In addition, in SSRP, the two biotoxins have different drug release rates and antitumor mechanisms, which can be complementary to each other. Ricin has a faster release rate than CVC. It can combine with the tumor cell membrane and enter the cell, inhibiting protein synthesis within 2 weeks. Whereas CVC releases slowly in 5 weeks directly dissolving the tumor cell membrane and killing the cells which are less-sensitive to ricin. The in vivo experiments showed that intratumoral injection of SSRP could inhibit hepatocellular carcinoma growth significantly, and the tumor growth inhibition rate reached 73.5%. It appears that a new medicine preparation for cancer local treatment should be further studied for clinical applications. PMID:22888519

  3. Bystander Activation and Anti-Tumor Effects of CD8+ T Cells Following Interleukin-2 Based Immunotherapy Is Independent of CD4+ T Cell Help

    PubMed Central

    Grossenbacher, Steven K.; Hsiao, Hui-Hua; Zamora, Anthony E.; Mirsoian, Annie; Koehn, Brent; Blazar, Bruce R.; Weiss, Jonathan M.; Wiltrout, Robert H.; Sckisel, Gail D.; Murphy, William J.

    2014-01-01

    We have previously demonstrated that immunotherapy combining agonistic anti-CD40 and IL-2 (IT) results in synergistic anti-tumor effects. IT induces expansion of highly cytolytic, antigen-independent “bystander-activated” (CD8+CD44high) T cells displaying a CD25−NKG2D+ phenotype in a cytokine dependent manner, which were responsible for the anti-tumor effects. While much attention has focused on CD4+ T cell help for antigen-specific CD8+ T cell expansion, little is known regarding the role of CD4+ T cells in antigen-nonspecific bystander-memory CD8+ T cell expansion. Utilizing CD4 deficient mouse models, we observed a significant expansion of bystander-memory T cells following IT which was similar to the non-CD4 depleted mice. Expanded bystander-memory CD8+ T cells upregulated PD-1 in the absence of CD4+ T cells which has been published as a hallmark of exhaustion and dysfunction in helpless CD8+ T cells. Interestingly, compared to CD8+ T cells from CD4 replete hosts, these bystander expanded cells displayed comparable (or enhanced) cytokine production, lytic ability, and in vivo anti-tumor effects suggesting no functional impairment or exhaustion and were enriched in an effector phenotype. There was no acceleration of the post-IT contraction phase of the bystander memory CD8+ response in CD4-depleted mice. The response was independent of IL-21 signaling. These results suggest that, in contrast to antigen-specific CD8+ T cell expansion, CD4+ T cell help is not necessary for expansion and activation of antigen-nonspecific bystander-memory CD8+ T cells following IT, but may play a role in regulating conversion of these cells from a central memory to effector phenotype. Additionally, the expression of PD-1 in this model appears to be a marker of effector function and not exhaustion. PMID:25119341

  4. Antisense oligonucleotides and all-trans retinoic acid have a synergistic anti-tumor effect on oral squamous cell carcinoma

    PubMed Central

    Xu, Qin; Zhang, Zhiyuan; Zhang, Ping; Chen, Wantao

    2008-01-01

    Background 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. Methods 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. Results 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. Conclusion 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. PMID:18522733

  5. The HSP70 and autophagy inhibitor pifithrin-μ enhances the antitumor effects of TRAIL on human pancreatic cancer.

    PubMed

    Monma, Hiroyuki; Harashima, Nanae; Inao, Touko; Okano, Shinji; Tajima, Yoshitsugu; Harada, Mamoru

    2013-04-01

    TRAIL and agonistic death receptor-specific antibodies can induce apoptosis in cancer cells with little cytotoxicity to normal cells. To improve TRAIL-induced antitumor effects, we tested its effectiveness in combination with pifithrin (PFT)-μ, which has the potential to inhibit HSP70 function and autophagy, both of which participate in TRAIL resistance in cancer cells. Among the four human pancreatic cancer cell lines tested, MiaPaca-2, Panc-1, and BxPC-3 cells showed varying sensitivities to TRAIL. In MiaPaca-2 and Panc-1 cells, knockdown of HSP70 or beclin-1, the latter an autophagy-related molecule, by RNA interference augmented TRAIL-induced antitumor effects, decreasing cell viability, and increasing apoptosis. On the basis of these findings, we next determined whether the TRAIL-induced antitumor effects could be augmented by its combination with PFT-μ. The combination of TRAIL plus PFT-μ significantly decreased the viability and colony-forming ability of MiaPaca-2 and Panc-1 cells compared with cells treated with either agent alone. When applied alone, PFT-μ increased Annexin V(+) cells in both caspase-dependent and -independent manners. It also promoted TRAIL-induced apoptosis and arrested cancer cell growth. Furthermore, PFT-μ antagonized TRAIL-associated NF-κB activation in cancer cells. In a xenograft mouse model, combination therapy significantly inhibited MiaPaca-2 tumor growth compared with treatment with either agent alone. The results of this study suggest protective roles for HSP70 and autophagy in TRAIL resistance in pancreatic cancer cells and suggest that PFT-μ is a promising agent for use in therapies intended to enhance the antitumor effects of TRAIL. PMID:23371857

  6. Evaluation of antitumor, immunomodulatory and free radical scavenging effects of a new herbal prescription seaweed complex preparation

    NASA Astrophysics Data System (ADS)

    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.

  7. Effects of IRF1 and IFN-β interaction on the M1 polarization of macrophages and its antitumor function

    PubMed Central

    XIE, CHANGLI; LIU, CUIYING; WU, BITAO; LIN, YAN; MA, TINGTING; XIONG, HAIYU; WANG, QIN; LI, ZIWEI; MA, CHENYU; TU, ZHIGUANG

    2016-01-01

    Macrophages that differentiate from precursor monocytes can be polarized into a classically activated (M1) or alternatively activated (M2) status depending on different stimuli. Generally, interferon (IFN)-γ and lipopolysaccharide (LPS) are considered the classical stimuli with which to establish M1 polarization. IFN regulatory factor (IRF)1 and IFN-β are two crucial molecules involved in IFN-γ- and LPS-initialed signaling. However, the association between IRF1 and IFN-β in the context of the M1 polarization of macrophages is not yet fully understood. In this study, we demonstrate that U937-derived macrophages, in response to IFN-γ and LPS stimulation, readily acquire an M1 status, indicated by the increased expression of interleukin (IL)-12, IL-6, IL-23, tumor necrosis factor (TNF)-α and the M1-specific cell surface antigen, CD86, and the decreased expression of the M2-specific mannose receptor, CD206. However, the knockdown of IRF1 in U937-derived macrophages led to an impaired M1 status, as indicated by the decreased expression of the above-mentioned M1 markers, and the increased expression of the M2 markers, CD206 and IL-10. A similar phenomenon was observed in the M1 macrophages in which IFN-β was inhibited. Furthermore, we demonstrated that IRF1 and IFN-β may interact with each other in the IFN-γ- and LPS-initiated signaling pathway, and contribute to the IRF5 regulation of M1 macrophages. In addition, the conditioned medium collected from the M1 macrophages in which IRF1 or IFN-β were inhibited, exerted pro-tumor effects on the HepG2 and SMMC-7721 cells, as indicated by an increase in proliferation, the inhibition of apoptosis and an enhanced invasion capability. The findings of our study suggest that the interactions of IRF1, IFN-β and IRF5 are involved in the M1 polarization of macro phages and have antitumor functions. These data may provide a novel antitumor strategy for targeted cancer therapy. PMID:27176664

  8. The combination therapy of α-galactosylceramide and 5-fluorouracil showed antitumor effect synergistically against liver tumor in mice.

    PubMed

    Aketa, Hiroshi; Tatsumi, Tomohide; Kohga, Keisuke; Tsunematsu, Hinako; Aono, Satoshi; Shimizu, Satoshi; Kodama, Takahiro; Nawa, Takatoshi; Shigekawa, Minoru; Hikita, Hayato; Sakamori, Ryotaro; Hosui, Atsushi; Miyagi, Takuya; Hiramatsu, Naoki; Kanto, Tatsuya; Hayashi, Norio; Takehara, Tetsuo

    2013-09-01

    α-Galactosylceramide (α-GalCer) has been reported to be therapeutic against metastatic liver tumors in mice. However, little is known regarding the efficacy of combined chemo-immunotherapy using α-GalCer and anticancer drugs. In this study, we evaluated the antitumor effect of the combination therapy of α-GalCer and 5-fluorouracil (5-FU) against liver tumors of MC38 colon cancer cells. The liver weights of tumor-bearing mice treated with the combination were significantly lower than those of nontreated mice and of mice treated with 5-FU or α-GalCer alone. No toxic effects on the liver and renal functions were observed in any of the treatment groups. α-GalCer treatment induced significant activation of liver NK cells in vivo, but 5-FU treatment did not. 5-FU treatment resulted in a significant upregulation of NKG2D activating molecules (Rae-1 and H60) and DNAM-1 ligands (CD112 and CD155) on MC38 cells, but α-GalCer did not. The cytolytic activity of α-GalCer-activated liver mononuclear cells against 5-FU-treated MC38 cells was significantly higher than that against nontreated cells. The increase of the cytolytic activity induced by 5-FU partially depended on NKG2D-Rae-1 or H60 signals. Depletion of NK cells significantly inhibited the antitumor efficacy of 5-FU against MC38 liver tumors, which suggested that the antitumor effect of 5-FU partially depended on the cytolytic activity of NK cells. These results demonstrated that the combination therapy of α-GalCer and 5-FU produced synergistic antitumor effects against liver tumors by increasing the expression of NK activating molecules on cancer cells. This study suggests a promising new chemo-immunotherapy against metastatic liver cancer. PMID:23420533

  9. High Intra-abdominal Pressure Enhances the Penetration and Antitumor Effect of Intraperitoneal Cisplatin on Experimental Peritoneal Carcinomatosis

    PubMed Central

    Esquis, Philippe; Consolo, David; Magnin, Guy; Pointaire, Philippe; Moretto, Philippe; Ynsa, Maria Dolores; Beltramo, Jean-Luc; Drogoul, Carole; Simonet, Michel; Benoit, Laurent; Rat, Patrick; Chauffert, Bruno

    2006-01-01

    Objective: To investigate the role of increased intra-abdominal pressure (IAP) on the intratumoral accumulation and the antitumor effect of intraperitoneal cisplatin in rats with advanced peritoneal carcinomatosis. To evaluate the tolerance of IAP in pigs, as it is a large animal with a body size equivalent to humans. Summary Background Data: To investigate if an active convection, driven by a positive IAP, increases cisplatin penetration and antitumor effectiveness in a model of advanced peritoneal carcinomatosis in rats. Experimental Design: BDIX rats with macroscopic peritoneal tumors received cisplatin administered as intravenous injection (IV), conventional intraperitoneal injection (IP), or sustained intraperitoneal injection of cisplatin given in a large volume of solvent for maintaining IAP for 1 hour. Platinum tissue concentration was measured by atomic absorption spectroscopy (AAS), and platinum distribution into the tumor nodules was assessed by the particular-induced x-ray emission (PIXE) method. The antitumor effect was assessed in a survival experiment. The hemodynamic, local, and systemic tolerance of IAP, with or without cisplatin, was evaluated in Large White pigs. Results: The maximum tolerated IAP was 22 mm Hg for 1 hour in nonventilated rats. IAP, in comparison with IV or conventional IP injections, resulted in the increased concentration and depth of diffusion of platinum into diaphragm and peritoneal tumor nodules. Consequently, IAP treatment induced an extended survival of rats treated at an advanced stage of carcinomatosis. In 7 50- to 70-kg ventilated pigs, a 40-mm Hg IAP was well tolerated when maintained stable for 2 hours. Renal failure occurred in pigs receiving a total dose of 200 and 400 mg of cisplatin with IAP, but a dose of 100 mg was well tolerated. Conclusions: Intraperitoneal chemotherapy with increased IAP, in comparison with conventional IP or IV chemotherapy, improved the tumor accumulation and the antitumor effect of

  10. Anti-Tumor Effects of Second Generation β-Hydroxylase Inhibitors on Cholangiocarcinoma Development and Progression

    PubMed Central

    Chung, Waihong; de la Monte, Suzanne; Thomas, John-Michael; Olsen, Mark; Carlson, Rolf; Yu, Tunan; Dong, Xiaoqun; Wands, Jack

    2016-01-01

    Cholangiocarcinoma (CCA) has a poor prognosis due to widespread intrahepatic spread. Aspartate β-hydroxylase (ASPH) is a transmembrane protein and catalyzes the hydroxylation of aspartyl and asparaginyl residues in calcium binding epidermal growth factor (cbEGF)-like domains of various proteins, including Notch receptors and ligands. ASPH is highly overexpressed (>95%) in human CCA tumors. We explored the molecular mechanisms by which ASPH mediated the CCA malignant phenotype and evaluated the potential of ASPH as a therapeutic target for CCA. The importance of expression and enzymatic activity of ASPH for CCA growth and progression was examined using shRNA “knockdown” and a mutant construct that reduced its catalytic activity. Second generation small molecule inhibitors (SMIs) of β-hydroxylase activity were developed and used to target ASPH in vitro and in vivo. Subcutaneous and intrahepatic xenograft rodent models were employed to determine anti-tumor effects on CCA growth and development. It was found that the enzymatic activity of ASPH was critical for mediating CCA progression, as well as inhibiting apoptosis. Mechanistically, ASPH overexpression promoted Notch activation and modulated CCA progression through a Notch1-dependent cyclin D1 pathway. Targeting ASPH with shRNAs or a SMI significantly suppressed CCA growth in vivo. PMID:26954680

  11. Mechanisms underlying the anti-tumoral effects of Citrus Bergamia juice.

    PubMed

    Delle Monache, Simona; Sanità, Patrizia; Trapasso, Elena; Ursino, Maria Rita; Dugo, Paola; Russo, Marina; Ferlazzo, Nadia; Calapai, Gioacchino; Angelucci, Adriano; Navarra, Michele

    2013-01-01

    Based on the growing deal of data concerning the biological activity of flavonoid-rich natural products, the aim of the present study was to explore in vitro the potential anti-tumoral activity of Citrus Bergamia (bergamot) juice (BJ), determining its molecular interaction with cancer cells. Here we show that BJ reduced growth rate of different cancer cell lines, with the maximal growth inhibition observed in neuroblastoma cells (SH-SY5Y) after 72 hs of exposure to 5% BJ. The SH-SY5Y antiproliferative effect elicited by BJ was not due to a cytotoxic action and it did not induce apoptosis. Instead, BJ stimulated the arrest in the G1 phase of cell cycle and determined a modification in cellular morphology, causing a marked increase of detached cells. The inhibition of adhesive capacity on different physiologic substrates and on endothelial cells monolayer were correlated with an impairment of actin filaments, a reduction in the expression of the active form of focal adhesion kinase (FAK) that in turn caused inhibition of cell migration. In parallel, BJ seemed to hinder the association between the neural cell adhesion molecule (NCAM) and FAK. Our data suggest a mechanisms through which BJ can inhibit important molecular pathways related to cancer-associated aggressive phenotype and offer new suggestions for further studies on the role of BJ in cancer treatment. PMID:23613861

  12. Magnetic properties and antitumor effect of nanocomplexes of iron oxide and doxorubicin.

    PubMed

    Orel, Valerii; Shevchenko, Anatoliy; Romanov, Andriy; Tselepi, Marina; Mitrelias, Thanos; Barnes, Crispin H W; Burlaka, Anatoliy; Lukin, Sergey; Shchepotin, Igor

    2015-01-01

    We present a technology and magneto-mechanical milling chamber for the magneto-mechano-chemical synthesis (MMCS) of magneto-sensitive complex nanoparticles (MNC) comprising nanoparticles Fe3O4 and anticancer drug doxorubicin (DOXO). Magnetic properties of MNC were studied with vibrating magnetometer and electron paramagnetic resonance. Under the influence of mechano-chemical and MMCS, the complex show a hysteresis curve, which is typical for soft ferromagnetic materials. We also demonstrate that Lewis lung carcinoma had a hysteresis loop typical for a weak soft ferromagnet in contrast to surrounding tissues, which were diamagnetic. Combined action of constant magnetic field and radio frequency moderate inductive hyperthermia (RFH) below 40°C and MNC was found to induce greater antitumor and antimetastatic effects as compared to conventional DOXO. Radiospectroscopy shows minimal activity of FeS-protein electron transport chain of mitochondria, and an increase in the content of non-heme iron complexes with nitric oxide in the tumor tissues under the influence of RFH and MNC. PMID:25101880

  13. Controlled Release and Antitumor Effect of Pluronic F127 Mixed with Cisplatin in a Rabbit Model

    SciTech Connect

    Sonoda, Akinaga Nitta, Norihisa; Ohta, Shinich; Nitta-Seko, Ayumi; Morikawa, Shigehiro; Tabata, Yasuhiko; Takahashi, Masashi; Murata, Kiyoshi

    2010-02-15

    The purpose of this study was to evaluate pluronic F127 for the controlled release of cisplatin in a rabbit model. Pluronic F127 becomes liquid at temperatures <25{sup o}C and converts to a gelatinous state at temperatures between 25 and 60{sup o}C. Six Japanese white rabbits were injected with pluronic + cisplatin (n = 3, renal group A) or saline + cisplatin (n = 3, renal group B) to measure the platinum concentration in kidneys. Another 25 rabbits with VX2 liver tumors were divided into five equal groups. They were injected with saline, saline + cisplatin, iodized oil + cisplatin, pluronic alone, or pluronic + cisplatin and labeled as liver groups A, B, C, D, and E, respectively. The antitumor effect of pluronic was then assessed. In the presence of pluronic, the platinum concentration in the kidneys of rabbits remained relatively high. In animals with liver tumors, the delivery of pluronic + cisplatin produced higher tumor reduction rates (P < 0.05) than in the other groups, without apparent damage to normal liver tissue. We conclude that pluronic is useful for the controlled release of cisplatin in a rabbit model.

  14. Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase {alpha}

    SciTech Connect

    Maeda, Naoki; Kokai, Yasuo; Ohtani, Seiji; Sahara, Hiroeki; Kuriyama, Isoko; Kamisuki, Shinji; Takahashi, Shunya; Sakaguchi, Kengo; Sugawara, Fumio; Yoshida, Hiromi; Sato, Noriyuki; Mizushina, Yoshiyuki . E-mail: mizushin@nutr.kobegakuin.ac.jp

    2007-01-12

    In the screening of selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin was found to be an inhibitor of pol {alpha} from a fungus (Alternaria tennuis). We succeeded in chemically synthesizing dehydroaltenusin, and the compound inhibited only mammalian pol {alpha} with IC{sub 50} value of 0.5 {mu}M, and did not influence the activities of other replicative pols such as pols {delta} and {epsilon}, but also showed no effect on pol {alpha} activity from another vertebrate, fish, or from a plant species. Dehydroaltenusin also had no influence on the other pols and DNA metabolic enzymes tested. The compound also inhibited the proliferation of human cancer cells with LD{sub 50} values of 38.0-44.4 {mu}M. In an in vivo anti-tumor assay on nude mice bearing solid tumors of HeLa cells, dehydroaltenusin was shown to be a promising suppressor of solid tumors. Histopathological examination revealed that increased tumor necrosis and decreased mitotic index were apparently detected by the compound in vivo. Therefore, dehydroaltenusin could be of interest as not only a mammalian pol {alpha}-specific inhibitor, but also as a candidate drug for anti-cancer treatment.

  15. Antitumor effect of murine dendritic and tumor cells transduced with IL-2 gene.

    PubMed

    Wojas-Turek, Justyna; Pajtasz-Piasecka, Elżbieta; Rossowska, Joanna; Piasecki, Egbert; Duś, Danuta

    2012-01-01

    Interleukin (IL-) 2 acts on a number of types of immune cells promoting their effector functions. To replace systemic administration of recombinant form of this cytokine, various genetically modified cells have been used indifferent preclinical models for tumor growth inhibition. In this study, dendritic or tumor cells transduced with retroviral vector carrying IL-2 gene (JAWS II/IL-2, X63/IL-2, MC38/IL-2 cells) alone or combined with tumor antigen-stimulated dendritic cells (JAWS II/TAg) were exploited to treat colon carcinoma MC38-bearing mice. After the peritumoral injection of vaccine cells, the tumor growth delay and the increase in the number of tumor infiltrating CD4⁺ and CD8⁺ T lymphocytes were noted. A considerable increase in CD4⁺ cell influx into tumor tissue was observed when JAWS II/IL-2 cells or JAWS II/TAg with syngeneic MC38/IL-2 cells were applied. The increase in intensity of CD8⁺ cell infiltration was associated with immune reaction triggered by the same combination of applied cells or JAWS II/TAg with allogeneic X63/IL-2 cells. The effect observed in vivo was accompanied by MC38/0 cell specific cytotoxic activity of spleen cells in vitro. Thus, the application of vaccines, including IL-2-secreting cells of various origins, was able to induce different antitumor responses polarized by exogenous IL-2 and the encountered tumor antigen. PMID:23042272

  16. Design, Synthesis of Novel Platinum(II) Glycoconjugates, and Evaluation of Their Antitumor Effects.

    PubMed

    Han, Jianbin; Gao, Xiangqian; Liu, Ran; Yang, Jinna; Zhang, Menghua; Mi, Yi; Shi, Ying; Gao, Qingzhi

    2016-06-01

    A new series of sugar-conjugated (trans-R, R-cyclohexane-1, 2-diamine)-2-halo-malonato-platinum(II) complexes were designed and synthesized to target tumor-specific glucose transporters (GLUTs). The water solubility of the sugar-conjugated platinum (II) complexes was greatly improved by average of 570-fold, 33-fold, and 94-fold, respectively, compared to cisplatin (1.0 mg/mL), carboplatin (17.1 mg/mL), and the newest generation of clinical drug oxaliplatin (6.0 mg/mL). Despite the high water solubility, the platinum(II) glycoconjugates exhibited a notable increase in cytotoxicity by a margin of 1.5- to 6.0-fold in six different human cancer cell lines with respect to oxaliplatin. The potential GLUT1 transportability of the complexes was investigated through a molecular docking study and was confirmed with GLUT1 inhibitor-mediated cytotoxicity dependency evaluation. The results showed that the sugar-conjugated platinum(II) complexes can be recognized by the glucose recognition binding site of GLUT1 and their cell killing effect depends highly on the GLUT1 inhibitor, quercetin. The research presenting a prospective concept for targeted therapy anticancer drug design, and with the analysis of the synthesis, water solubility, antitumor activity, and the transportability of the platinum(II) glycoconjugates, this study provides fundamental data supporting the inherent potential of these designed conjugates as lead compounds for GLUT-mediated tumor targeting. PMID:26706102

  17. Mechanisms Underlying the Anti-Tumoral Effects of Citrus bergamia Juice

    PubMed Central

    Delle Monache, Simona; Sanità, Patrizia; Trapasso, Elena; Ursino, Maria Rita; Dugo, Paola; Russo, Marina; Ferlazzo, Nadia; Calapai, Gioacchino; Angelucci, Adriano; Navarra, Michele

    2013-01-01

    Based on the growing deal of data concerning the biological activity of flavonoid-rich natural products, the aim of the present study was to explore in vitro the potential anti-tumoral activity of Citrus Bergamia (bergamot) juice (BJ), determining its molecular interaction with cancer cells. Here we show that BJ reduced growth rate of different cancer cell lines, with the maximal growth inhibition observed in neuroblastoma cells (SH-SY5Y) after 72 hs of exposure to 5% BJ. The SH-SY5Y antiproliferative effect elicited by BJ was not due to a cytotoxic action and it did not induce apoptosis. Instead, BJ stimulated the arrest in the G1 phase of cell cycle and determined a modification in cellular morphology, causing a marked increase of detached cells. The inhibition of adhesive capacity on different physiologic substrates and on endothelial cells monolayer were correlated with an impairment of actin filaments, a reduction in the expression of the active form of focal adhesion kinase (FAK) that in turn caused inhibition of cell migration. In parallel, BJ seemed to hinder the association between the neural cell adhesion molecule (NCAM) and FAK. Our data suggest a mechanisms through which BJ can inhibit important molecular pathways related to cancer-associated aggressive phenotype and offer new suggestions for further studies on the role of BJ in cancer treatment. PMID:23613861

  18. Antitumor effects and immune regulation activities of a purified polysaccharide extracted from Juglan regia.

    PubMed

    Ruijun, Wang; Shi, Wang; Yijun, Xia; Mengwuliji, Tu; Lijuan, Zhang; Yumin, Wang

    2015-01-01

    A water-soluble polysaccharide, named as JRP1, was extracted and fractioned from the epicarp of immature fruit of Juglans mandshurica Maxim. The determination of the monosaccharide composition in JRP1 with gas chromatography (GC) showed that JRP1 was composed of Gal (43.1%), Glu (23.6%), Ara (16.2%), Rha (9.8%) and Fru (7.3%). The results in vitro showed that 25, 50 and 100 μg/mL of JRP1 could present a significant inhibition on the growth of S180 cells, and furthermore, a significant improvement on the proliferation ability of lymphocytes and the phagocytic activity of macrophages. The results in vivo showed that compared with those in the control group, the inhibition rates of different doses of JRP1 on S180 cells in the tumor-bearing mice were 35.3%, 40.6% and 48.1%, respectively, and serum immune cytokine levels such as IL-2, TNF-α and IFN-γ were significantly improved. Our results confirm that JRP1 has the activities of effective antitumor and immunomodulatory function. PMID:25265339

  19. Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis

    PubMed Central

    Klement, Rainer J.; Champ, Colin E.; Otto, Christoph; Kämmerer, Ulrike

    2016-01-01

    Background Currently ketogenic diets (KDs) are hyped as an anti-tumor intervention aimed at exploiting the metabolic abnormalities of cancer cells. However, while data in humans is sparse, translation of murine tumor models to the clinic is further hampered by small sample sizes, heterogeneous settings and mixed results concerning tumor growth retardation. The aim was therefore to synthesize the evidence for a growth inhibiting effect of KDs when used as a monotherapy in mice. Methods We conducted a Bayesian random effects meta-analysis on all studies assessing the survival (defined as the time to reach a pre-defined endpoint such as tumor volume) of mice on an unrestricted KD compared to a high carbohydrate standard diet (SD). For 12 studies meeting the inclusion criteria either a mean survival time ratio (MR) or hazard ratio (HR) between the KD and SD groups could be obtained. The posterior estimates for the MR and HR averaged over four priors on the between-study heterogeneity τ2 were MR = 0.85 (95% highest posterior density interval (HPDI) = [0.73, 0.97]) and HR = 0.55 (95% HPDI = [0.26, 0.87]), indicating a significant overall benefit of the KD in terms of prolonged mean survival times and reduced hazard rate. All studies that used a brain tumor model also chose a late starting point for the KD (at least one day after tumor initiation) which accounted for 26% of the heterogeneity. In this subgroup the KD was less effective (MR = 0.89, 95% HPDI = [0.76, 1.04]). Conclusions There was an overall tumor growth delaying effect of unrestricted KDs in mice. Future experiments should aim at differentiating the effects of KD timing versus tumor location, since external evidence is currently consistent with an influence of both of these factors. PMID:27159218

  20. Clostridium butyricum MIYAIRI 588 shows antitumor effects by enhancing the release of TRAIL from neutrophils through MMP-8.

    PubMed

    Shinnoh, Masahide; Horinaka, Mano; Yasuda, Takashi; Yoshikawa, Sae; Morita, Mie; Yamada, Takeshi; Miki, Tsuneharu; Sakai, Toshiyuki

    2013-03-01

    Bacillus Calmette-Guérin (BCG) intravesical therapy against superficial bladder cancer is one of the most successful immunotherapies in cancer, though the precise mechanism has not been clarified. Recent studies have demonstrated urinary tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels to be higher in BCG-responsive patients than non-responders and shown that polymorphonuclear neutrophils (PMNs) migrating to the bladder after BCG instillation release large amounts of TRAIL. To establish a safer and more effective intravesical therapy than BCG, we examined whether other bacteria induced similar effects. We stimulated PMNs or peripheral blood mononuclear cells (PBMCs) with BCG or other bacteria, and then aliquots of the culture supernatants or cell lysates were assayed for TRAIL. We examined the signaling pathway regulating the release of TRAIL from PMNs and evaluated the antitumor effects of BCG or other bacteria in vitro and in vivo. We have found that Clostridium butyricum MIYAIRI 588 (CBM588) induces the release of endogenous TRAIL from PMNs as well as BCG. In addition, we have shown that matrix metalloproteinase 8 (MMP-8) is one of the key factors responsible for the release. Interestingly, TLR2/4 signaling pathway has been suggested to be important for the release of TRAIL by MMP-8. CBM588 has been proven to be as effective as BCG against cancer cells by inducing apoptosis in vivo as well as in vitro. Taken together, these results strongly suggest that CBM588 is promising for a safer and more effective therapy against bladder cancer. PMID:23354042

  1. Optimized anti-tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule.

    PubMed

    Ehrhardt, Harald; Schrembs, David; Moritz, Christian; Wachter, Franziska; Haldar, Subrata; Graubner, Ulrike; Nathrath, Michaela; Jeremias, Irmela

    2011-12-01

    Application of anthracyclines and Vinca alkaloids on the same day represents a hallmark of polychemotherapy protocols for hematopoietic malignancies. Here we show, for the first time, that both drugs might act most efficiently if they are applied on different days. Proof-of-concept studies in 18 cell lines revealed that anthracyclines inhibited cell death by Vinca alkaloids in 83% of cell lines. Importantly, in a preclinical mouse model, doxorubicin reduced the anti-tumor effect of vincristine. Both drugs acted in a sequence-dependent manner and the strongest anti-tumor effect was obtained if both drugs were applied on different days. Most notably for clinical relevance, in 34% of 35 fresh primary childhood leukemia cells tested in vitro, doxorubicin reduced the anti-tumor effect of vincristine. As underlying mechanism, doxorubicin activated p53, p53 induced cell-cycle arrest, and cell-cycle arrest disabled inactivation of antiapoptotic Bcl-2 family members by vincristine; therefore, vincristine was unable to activate downstream apoptosis signaling. As molecular proof, antagonism was rescued by knockdown of p53, whereas knockdown of cyclin A inhibited vincristine-induced apoptosis. Our data suggest evaluating anthracyclines and Vinca alkaloids on different days in future trials. Selecting drug combinations based on mechanistic understanding represents a novel conceptional strategy for potent polychemotherapy protocols. PMID:21926351

  2. Oyster (Crassostrea gigas) Hydrolysates Produced on a Plant Scale Have Antitumor Activity and Immunostimulating Effects in BALB/c Mice

    PubMed Central

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

    2010-01-01

    Oyster extracts have been reported to have many bioactive peptides. But the function of oyster peptides produced by proteolysis is still unknown. In this study, the oligopeptide-enriched hydrolysates from oyster (Crassostrea gigas) were produced using the protease from Bacillus sp. SM98011 at laboratory level, and scaled up to pilot (100 L) and plant (1,000 L) levels with the same conditions. And the antitumor activity and immunostimulating effects of the oyster hydrolysates in BALB/c mice were investigated. The growth of transplantable sarcoma-S180 was obviously inhibited in a dose-dependent manner in BALB/c mice given the oyster hydrolysates. Mice receiving 0.25, 0.5 and 1 mg/g of body weight by oral gavage had 6.8%, 30.6% and 48% less tumor growth, respectively. Concurrently, the weight coefficients of the thymus and the spleen, the activity of natural killer (NK) cells, the spleen proliferation of lymphocytes and the phagocytic rate of macrophages in S180-bearing mice significantly increased after administration of the oyster hydrolysates. These results demonstrated that oyster hydrolysates produced strong immunostimulating effects in mice, which might result in its antitumor activity. The antitumor and immunostimulating effects of oyster hydrolysates prepared in this study reveal its potential for tumor therapy and as a dietary supplement with immunostimulatory activity. PMID:20390104

  3. Relationship between antitumor effect and metabolites of 5-fluorouracil in combination treatment with 5-fluorouracil and guanosine in ascites Sarcoma 180 tumor system

    SciTech Connect

    Iigo, M.; Kuretani, K.; Hoshi, A.

    1983-12-01

    The antitumor activity of (6-14C)5-fluorouracil ((6-14C)FUra) against ascites Sarcoma 180 was significantly enhanced by coadministration of guanosine, and slightly by adenosine, but not by cytidine or uridine. In advanced ascites Sarcoma 180, guanosine also enhanced the action of FUra, but adenosine, uridine, and cytidine did not. The potentiation of antitumor activity by guanosine was reversed by addition of cytidine. The antitumor activity of FUra was significantly potentiated when guanosine was administered either 0 to 15 min before or 5 min after FUra. Changes in metabolites of FUra after potentiation by guanosine were investigated. The potentiation of antitumor activity of FUra by guanosine was considered to be due to an increase in incorporation of FUra into FUra-nucleotides and RNA in the tumor cells.

  4. Combination of TRAIL and actinomycin D liposomes enhances antitumor effect in non-small cell lung cancer

    PubMed Central

    Guo, Liangran; Fan, Li; Ren, Jinfeng; Pang, Zhiqing; Ren, Yulong; Li, Jingwei; Wen, Ziyi; Qian, Yong; Zhang, Lin; Ma, Hang; Jiang, Xinguo

    2012-01-01

    The intractability of non-small cell lung cancer (NSCLC) to multimodality treatments plays a large part in its extremely poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cytokine for selective induction of apoptosis in cancer cells; however, many NSCLC cell lines are resistant to TRAIL-induced apoptosis. The therapeutic effect can be restored by treatments combining TRAIL with chemotherapeutic agents. Actinomycin D (ActD) can sensitize NSCLC cells to TRAIL-induced apoptosis by upregulation of death receptor 4 (DR4) or 5 (DR5). However, the use of ActD has significant drawbacks due to the side effects that result from its nonspecific biodistribution in vivo. In addition, the short half-life of TRAIL in serum also limits the antitumor effect of treatments combining TRAIL and ActD. In this study, we designed a combination treatment of long-circulating TRAIL liposomes and ActD liposomes with the aim of resolving these problems. The combination of TRAIL liposomes and ActD liposomes had a synergistic cytotoxic effect against A-549 cells. The mechanism behind this combination treatment includes both increased expression of DR5 and caspase activation. Moreover, systemic administration of the combination of TRAIL liposomes and ActD liposomes suppressed both tumor formation and growth of established subcutaneous NSCLC xenografts in nude mice, inducing apoptosis without causing significant general toxicity. These results provide preclinical proof-of-principle for a novel therapeutic strategy in which TRAIL liposomes are safely combined with ActD liposomes. PMID:22619505

  5. Antitumor effect and mechanism of an ellagic acid derivative on the HepG2 human hepatocellular carcinoma cell line

    PubMed Central

    ZHANG, HUI; GUO, ZENG-JUN; XU, WEN-MING; YOU, XIAO-JUAN; HAN, LING; HAN, YAN-XIA; DAI, LIU-JIANG

    2014-01-01

    In the present study, to identify the effective components of Chinese traditional herbs, Euphorbia hylonoma Hand.-Mazz. (Euphorbiaceae), a folk herb that has been used among the Qinling mountain area for hundreds of years, was investigated. 3,3′-Di-O-methyl ellagic acid-4′-O-β-d-xylopyranoside (JNE2), an ellagic acid derivative, was isolated from the acetone extract of the herb and its antitumor activity against human hepatoma HepG2 cells was detected in vitro. The results showed that JNE2 inhibited the proliferation of HepG2 cells in a dose- and time-dependent manner and blocked the cell cycle at the G1/S phase. A high dosage of JNE2 induced apoptosis of the tumor cells, but no significant differences were identified between the treatment groups. The invasiveness of HepG2 cells was also inhibited by JNE2. The mechanism of the antitumor effect of JNE2 at the molecular level was presumed to be due to the upregulation of the protein expression of Bax and caspase-3, and the downregulation of the protein expression of Bcl-2 and CCND1. The results suggested that JNE2 is a potential antitumor agent that merits further investigation. PMID:24396481

  6. Effect of the antitumoral alkylating agent 3-bromopyruvate on mitochondrial respiration: role of mitochondrially bound hexokinase.

    PubMed

    Rodrigues-Ferreira, Clara; da Silva, Ana Paula Pereira; Galina, Antonio

    2012-02-01

    The alkylating agent 3-Bromopyruvate (3-BrPA) has been used as an anti-tumoral drug due to its anti-proliferative property in hepatomas cells. This propriety is believed to disturb glycolysis and respiration, which leads to a decreased rate of ATP synthesis. In this study, we evaluated the effects of the alkylating agent 3-BrPA on the respiratory states and the metabolic steps of the mitochondria of mice liver, brain and in human hepatocarcinoma cell line HepG2. The mitochondrial membrane potential (ΔΨ(m)), O(2) consumption and dehydrogenase activities were rapidly dissipated/or inhibited by 3-BrPA in respiration medium containing ADP and succinate as respiratory substrate. 3-BrPA inhibition was reverted by reduced glutathione (GSH). Respiration induced by yeast soluble hexokinase (HK) was rapidly inhibited by 3-BrPA. Similar results were observed using mice brain mitochondria that present HK naturally bound to the outer mitochondrial membrane. When the adenine nucleotide transporter (ANT) was blocked by the carboxyatractiloside, the 3-BrPA effect was significantly delayed. In permeabilized human hepatoma HepG2 cells that present HK type II bound to mitochondria (mt-HK II), the inhibiting effect occurred faster when the endogenous HK activity was activated by 2-deoxyglucose (2-DOG). Inhibition of mt-HK II by glucose-6-phosphate retards the mitochondria to react with 3-BrPA. The HK activities recovered in HepG2 cells treated or not with 3-BrPA were practically the same. These results suggest that mitochondrially bound HK supporting the ADP/ATP exchange activity levels facilitates the 3-BrPA inhibition reaction in tumors mitochondria by a proton motive force-dependent dynamic equilibrium between sensitive and less sensitive SDH in the electron transport system. PMID:22322891

  7. Antitumor effects of immunotoxins are enhanced by lowering HCK or treatment with SRC kinase inhibitors.

    PubMed

    Liu, Xiu-Fen; Xiang, Laiman; FitzGerald, David J; Pastan, Ira

    2014-01-01

    Recombinant immunotoxins (RIT) are agents being developed for cancer treatment. They are composed of an Fv that binds to a cancer cell, fused to a 38-kDa fragment of Pseudomonas exotoxin A. SS1P is a RIT that targets mesothelin, a protein expressed on mesothelioma as well as pancreatic, ovarian, lung, and other cancers. Because the protein tyrosine kinase family regulates a variety of cellular processes and pathways, we hypothesized that tyrosine kinases might regulate susceptibility to immunotoxin killing. To investigate their role, we used siRNAs to lower the level of expression of the 88 known tyrosine kinases. We identified five tyrosine kinases, INSR, HCK, SRC, PDGFRβ, and BMX that enhance the activity of SS1P when their level of expression is lowered by siRNAs. We further investigated the Src family member HCK in this study. Knocking down of SRC slightly increased SS1P killing in A431/H9 cells, but knocking down HCK substantially enhanced killing by SS1P. We investigated the mechanism of enhancement and found that HCK knockdown enhanced SS1P cleavage by furin and lowered levels of Mcl-1 and raised Bax. We then found that Src inhibitors mimic the stimulatory effect of HCK knockdown; both SU6656 and SKI-606 (bosutinib) enhanced immunotoxin killing of mesothelin-expressing cells by SS1P and CD22-expressing cells by HA22 (moxetumomab pasudotox). SU6656 also enhanced the antitumor effects of SS1P and HA22 in mouse xenograft tumor models. Our data suggest that the combination of immunotoxin with tyrosine kinase inhibitors may be an effective way to treat some cancers. PMID:24145282

  8. Promotion of initial anti-tumor effect via polydopamine modified doxorubicin-loaded electrospun fibrous membranes

    PubMed Central

    Yuan, Ziming; Zhao, Xin; Wang, Xiaohu; Qiu, Wangwang; Chen, Xinliang; Zheng, Qi; Cui, Wenguo

    2014-01-01

    Drug-loaded electrospun PLLA membranes are not conducive to adhesion between materials and tissues due to the strong hydrophobicity of PLLA, which possibly attenuate the drugs’ effect loaded on the materials. In the present work, we developed a facile method to improve the hydrophilicity of doxorubicin (DOX)-loaded electrospun PLLA fibrous membranes, which could enhance the anti-tumor effect at the early stage after implantation. A mussel protein, polydopamine (PDA), could be easily grafted on the surface of hydrophobic DOX-loaded electrospun PLLA membranes (PLLA-DOX/pDA) in water solution. The morphology analysis of PLLA-DOX/pDA fibers displayed that though the fiber diameter was slightly swollen, they still maintained a 3D fibrous structure, and the XPS analysis certified that pDA had successfully been grafted onto the surface of the fibers. The results of surface wettability analysis showed that the contact angle decreased from 136.7° to 0° after grafting. In vitro MTT assay showed that the cytotoxicity of PLLA-DOX/pDA fibers was the strongest, and the stereologic cell counting assay demonstrated that the adhesiveness of PLLA/pDA fiber was significantly better than PLLA fiber. In vivo tumor-bearing mice displayed that, after one week of implantation, the tumor apoptosis and necrosis of PLLA-DOX/pDA fibers were the most obvious from histopathology and TUNEL assay. The caspase-3 activity of PLLA-DOX/pDA group was the highest using biochemical techniques, and the Bax: Bcl-2 ratio increased significantly in PLLA-DOX/pDA group through qRT-PCR analysis. All the results demonstrated that pDA can improve the affinity of the electrospun PLLA membranes and enhance the drug effect on tumors. PMID:25337186

  9. MDM2 antagonists boost antitumor effect of androgen withdrawal: implications for therapy of prostate cancer

    PubMed Central

    2011-01-01

    Background Hormone therapy is the standard of care for newly diagnosed or recurrent prostate cancers. It uses anti-androgen agents, castration, or both to eliminate cancer promoting effect of testicular androgen. The p53 tumor suppressor controls a major pathway that can block cell proliferation or induce apoptosis in response to diverse forms of oncogenic stress. Activation of the p53 pathway in cancer cells expressing wild-type p53 has been proposed as a novel therapeutic strategy and recently developed MDM2 antagonists, the nutlins, have validated this in preclinical models of cancer. The crosstalk between p53 and androgen receptor (AR) signaling suggest that p53 activation could augment antitumor outcome of androgen ablation in prostate cancer. Here, we test this hypothesis in vitro and in vivo using the MDM2 antagonist, nutlin-3 and the p53 wild-type prostate cancer cell line, LNCaP. Results Using charcoal-stripped serum as a cellular model of androgen deprivation, we show an increased apoptotic effect of p53 activation by nutlin-3a in the androgen-dependent LNCaP cells and to a lesser extent in androgen-independent but responsive 22Rv1 cell line. This effect is due, at least in part, to an enhanced downregulation of AR expression by activated p53. In vivo, androgen deprivation followed by two weeks of nutlin administration in LNCaP-bearing nude mice led to a greater tumor regression and dramatically increased survival. Conclusions Since majority of prostate tumors express wild-type p53, its activation by MDM2 antagonists in combination with androgen depletion may offer an efficacious new approach to prostate cancer therapy. PMID:21539745

  10. Antitumor effects of different administration sequences of cisplatin and Endostar on Lewis lung carcinoma

    PubMed Central

    FAN, JUAN; DU, JIANGRONG; WU, JINGBO; FU, SHAOZHI; HU, DEFENG; WAN, QIANG

    2015-01-01

    Angiogenesis plays an essential role in the growth and metastasis of a number of tumors. Anti-angiogenic drugs are able to normalize tumor vasculature and inhibit tumor growth. Therefore, it has been hypothesized that the combination of cytotoxic chemotherapy drugs and angiogenesis inhibitors may exert complementary therapeutic benefits in the treatment of cancer. In the present study, the effect of the angiogenesis inhibitor, recombinant human endostatin (Endostar), in combination with cisplatin, was evaluated in C57/BL/6 mouse xenografts under different administration sequences. The drug combinations and sequences of administration were analyzed within the cancer xenografts for any inhibitory effects. Changes in the cell cycle distribution of the cells were monitored using flow cytometry. The effects of Endostar, particularly a reduction in the density of microvessels, were assessed using a method that employed anti-cluster of differentiation 31 antibodies. The concentration of cisplatin in the blood and tumor tissue at various time-points following administration was detected by high-performance liquid chromatography. The tumor tissues that received simultaneous Endostar and cisplatin exhibited increased inhibition of tumor growth and improved cell cycle distribution compared with those that received cisplatin alone, or those in which Endostar was administered prior to cisplatin. The simultaneous administration of the drugs resulted in the lowest microvessel density in the xenografts. Under these conditions, the concentration of cisplatin was revealed to be the highest in the grafted tumor tissue. The results of the present study suggest that the co-administration of Endostar and cisplatin may aid in the optimization of the antitumor activity of cisplatin. PMID:25624906

  11. Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma.

    PubMed

    Moriya, Makio; Yamada, Tadaaki; Tamura, Masaya; Ishikawa, Daisuke; Hoda, Mir Alireza; Matsumoto, Isao; Klepetko, Walter; Oda, Makoto; Yano, Seiji; Watanabe, Go

    2014-03-01

    The mTOR inhibitor temsirolimus has antitumor and antiangiogenic activity against several carcinomas, yet few reports document the efficacy of temsirolimus against malignant pleural mesothelioma (MPM). Therefore, we evaluated the efficacy of temsirolimus and the antiangiogenic effect of temsirolimus in the treatment of MPM. We examined the efficacy of temsirolimus alone and the efficacy of the combination of temsirolimus and cisplatin or pemetrexed against four MPM cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The effect of temsirolimus on the production of proangiogenic cytokines by MPM cell lines was examined by enzyme-linked immunosorbent assay (ELISA). Expression of mTOR and proangiogenic cytokines in clinical specimens from MPM patients was determined by immunohistochemistry. Temsirolimus inhibited cell viability and suppressed cell proliferation of all MPM cell lines. Combined treatment with temsirolimus and cisplatin inhibited the viability of all MPM cell lines more effectively than temsirolimus alone. Temsirolimus strongly inhibited the phosphorylation of p70s6k, a downstream molecule of mTOR, in all MPM cell lines and led to an increase in the levels of cleaved caspase-3 in the H226 and Y-meso14 cells. Temsirolimus also inhibited the production of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-AA (PDGF-AA). Phosphorylated mTOR and high expression of VEGF and PDGF were detected in 2 and 3, respectively, out of the 5 MPM specimens. These results suggest that temsirolimus has activity against MPM cells by inhibition of cell proliferation and angiogenesis, and may be beneficial for a subset of MPM patients with high mTOR expression. PMID:24378576

  12. Tumor targetability and antitumor effect of docetaxel-loaded hydrophobically modified glycol chitosan nanoparticles.

    PubMed

    Hwang, Ho-Young; Kim, In-San; Kwon, Ick Chan; Kim, Yong-Hee

    2008-05-22

    Hydrophobically modified glycol chitosan (HGC) nanoparticles, a new nano-sized drug carrier, were prepared by introducing a hydrophobic molecule, cholanic acid, to water soluble glycol chitosan. The HGC nanoparticles were easily loaded with the anticancer drug docetaxel (DTX) using a dialysis method, and the resulting docetaxel-loaded HGC (DTX-HGC) nanoparticles formed spontaneously self-assembled aggregates with a mean diameter of 350 nm in aqueous condition. The DTX-HGC nanoparticles were well dispersed and stable for 2 weeks under physiological conditions (pH 7.4 and 37 degrees C) and a sustained drug release profile, in vitro. In addition, the DTX-HGC nanoparticles were reasonably stable in the presence of excess bovine serum albumin, which suggested that the DTX-HGC nanoparticles might also be stable in the blood stream. The DTX-HGC nanoparticles exhibited a distinctive deformability in aqueous conditions, in that they could easily pass through a filter membrane with 200 nm pores despite their mean diameter of 350 nm. We also evaluated the time-dependent excretion profile, in vivo biodistribution, prolonged circulation time, and tumor targeting ability of DTX-HGC nanoparticles by using a non-invasive live animal imaging technology. Finally, under optimal conditions for cancer therapy, the DTX-HGC nanoparticles showed higher antitumor efficacy such as reduced tumor volume and increased survival rate in A549 lung cancer cells-bearing mice and strongly reduced the anticancer drug toxicity compared to that of free DTX in tumor-bearing mice. Together our results showed that the anticancer loaded nano-sized drug carriers are a promising nano-sized drug formulation for cancer therapy. PMID:18374444

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

    NASA Astrophysics Data System (ADS)

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

    2012-05-01

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

  14. In vitro and in vivo antitumor effects of the Egyptian scorpion Androctonus amoreuxi venom in an Ehrlich ascites tumor model.

    PubMed

    Salem, Mohamed L; Shoukry, Nahla M; Teleb, Wafaa K; Abdel-Daim, Mohamed M; Abdel-Rahman, Mohamed A

    2016-01-01

    Scorpion venom is a highly complex mixture of about 100-700 different components, where peptides are the major constituents with various biological and pharmacological properties including anticancer activities. In this study, anticancer efficacy of the venom of the Egyptian scorpion Androctonus amoreuxi has been evaluated. In vitro, the human breast cancer MCF-7 cell line was treated with the venom and the IC50 was estimated. In vivo studies, Ehrlich ascites carcinoma (EAC) cells were inoculated into CD-1 mice intraperitoneally to form liquid tumor or subcutaneously to form solid tumor and then treated with intraperitoneal injection with venom (0.22 mg/kg) every other day. The total tumor cells in the ascitic fluid and the size of the solid tumor were assessed after 14 and 30 days, respectively. In addition, the mean survival time (MST), body weight, tumor volume, PCV, viability of tumor cells, CBC, AST, ALP, creatinine, oxidative stress biomarkers (GSH, MDA, PCC), tumor marker Ki67, growth factor VEGF and caspase-3 were measured in normal control, EAC control and venom-treated groups (n = 6). Treatment with venom induced anti-tumor effects against liquid and in solid tumors as indicated by a significant (P < 0.05) reduction in tumor volume/size, count of viable EAC cells, expression of Ki67 and VEGF as well as by remarkable increases in MST and caspase-3 expression as compared to non-treated group. Interestingly, the venom restored the altered hematological and biochemical parameters of tumor-bearing animals and significantly increased their life span. These data indicate to (1) the cytotoxic potential effects of A. amoreuxi on tumor cells via anti-proliferative, apoptotic and anti-angiogenic activities; (2) opening a new avenue for further studies on the anti-cancer effects of this agent. PMID:27247867

  15. Synthesis, properties, and antitumor effects of a new mixed phosphine gold(I) compound in human colon cancer cells.

    PubMed

    Lupidi, Giulio; Avenali, Luca; Bramucci, Massimo; Quassinti, Luana; Pettinari, Riccardo; Khalife, Hala K; Gali-Muhtasib, Hala; Marchetti, Fabio; Pettinari, Claudio

    2013-07-01

    The antineoplastic potential of a new stable mixed phosphine gold(I) complex containing tris(tert-butyl)phosphine (tBu3P) and bis(diphenylphosphino)ethene (dppet), namely [Au(tBu3P)(dppet)Cl], has been investigated in the human colon cancer HCT-116 cell line. The (31)P NMR solution study, confirms the structural features observed in the solid state and, in addition, indicates partial formation of dinuclear cationic [Au(tBu3P)2](+) and [Au(dppet)2](+) species. The ionic character and strong Au-P bonds of this gold(I) species are similar to those of the most active antitumor gold compounds so far studied. The title compound was found to exhibit strong cytotoxicity, showing 85 fold greater toxicity than cisplatin (IC50=0.45μM vs IC50=39.16 for cisplatin at 24h) on the HCT-116 line. The cytotoxic effects were, at least partly, mediated by the induction of apoptotic cell death as evidenced by the sub-G1 cell accumulation, oligonucleosomal DNA fragmentation, caspase-3 activation and the release of cytochrome c from the mitochondria. The gold(I) compound showed little interaction with DNA measured through fluorescence quenching studies with calf thymus DNA. The inhibitory effect of the gold(I) compound on intracellular redox proteins has been also observed in pretreated HCT-116 cells. The compound was particularly effective in inhibiting thioredoxin reductase, that is likely responsible for the increased ROS production, and subsequent apoptosis induction via the mitochondrial pathway. PMID:23632460

  16. Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects

    SciTech Connect

    Dufour, Marc; Dormond-Meuwly, Anne; Pythoud, Catherine; Demartines, Nicolas; Dormond, Olivier

    2013-08-16

    Highlights: •PI3K inhibitors inhibit AKT only transiently. •Re-activation of AKT limits the anti-cancer effect of PI3K inhibitors. •The results suggest to combine PI3K and AKT inhibitors in cancer therapy. -- Abstract: Targeting the phosphatidylinositol-3-kinase (PI3K) is a promising approach in cancer therapy. In particular, PI3K blockade leads to the inhibition of AKT, a major downstream effector responsible for the oncogenic activity of PI3K. However, we report here that small molecule inhibitors of PI3K only transiently block AKT signaling. Indeed, treatment of cancer cells with PI3K inhibitors results in a rapid inhibition of AKT phosphorylation and signaling which is followed by the reactivation of AKT signaling after 48 h as observed by Western blot. Reactivation of AKT signaling occurs despite effective inhibition of PI3K activity by PI3K inhibitors. In addition, wortmannin, a broad range PI3K inhibitor, did not block AKT reactivation suggesting that AKT signals independently of PI3K. In a therapeutical perspective, combining AKT and PI3K inhibitors exhibit stronger anti-proliferative and pro-apoptotic effects compared to AKT or PI3K inhibitors alone. Similarly, in a tumor xenograft mouse model, concomitant PI3K and AKT blockade results in stronger anti-cancer activity compared with either blockade alone. This study shows that PI3K inhibitors only transiently inhibit AKT which limits their antitumor activities. It also provides the proof of concept to combine PI3K inhibitors with AKT inhibitors in cancer therapy.

  17. Combination of treatment with death receptor 5-specific antibody with therapeutic HPV DNA vaccination generates enhanced therapeutic anti-tumor effects.

    PubMed

    Tseng, Chih Wen; Monie, Archana; Trimble, Cornelia; Alvarez, Ronald D; Huh, Warner K; Buchsbaum, Donald J; Straughn, J Michael; Wang, Mei-Cheng; Yagita, Hideo; Hung, Chien-Fu; Wu, T-C

    2008-08-12

    There is currently a vital need for the development of novel therapeutic strategies for the control of advanced stage cancers. Antigen-specific immunotherapy and the employment of antibodies against the death receptor 5 (DR5) have emerged as two potentially promising strategies for cancer treatment. In the current study, we hypothesize that the combination of treatment with the anti-DR5 monoclonal antibody, MD5-1 with a DNA vaccine encoding calreticulin (CRT) linked to human papillomavirus type 16 (HPV-16) E7 antigen (CRT/E7(detox)) administered via gene gun would lead to further enhancement of E7-specific immune responses as well as anti-tumor effects. Our results indicated that mice bearing the E7-expressing tumor, TC-1 treated with MD5-1 monoclonal antibody followed by CRT/E7(detox) DNA vaccination generated the most potent therapeutic anti-tumor effects as well as highest levels of E7-specific CD8+ T cells among all the groups tested. In addition, treatment with MD5-1 monoclonal antibody was capable of rendering the TC-1 tumor cells more susceptible to lysis by E7-specific cytotoxic T lymphocytes. Our findings serve as an important foundation for future clinical translation. PMID:18598733

  18. In vitro and in vivo antitumor effects of novel actinomycin D analogs with amino acid substituted in the cyclic depsipeptides.

    PubMed

    Zhang, Bang-zhi; Wang, Kai-rong; Yan, Jie-xi; Zhang, Wei; Song, Jing-jing; Ni, Jing-man; Wang, Rui

    2010-04-01

    The actinomycin D (AMD) analogs in which the D-valine residues (the second amino acid residue in the cyclic depsipeptide of AMD) and the N-methyl-L-valine residues (the fifth amino acid residue in the cyclic depsipeptide of AMD) were replaced with D-Phe or l- and D-forms N-methylvalines, N-methylisoleucine, N-methylleucine, N-methylphenylalanine, N-methylalanine, and sarcosine were synthesized. The antimicrobial activity and cytotoxic activities of these compounds in vitro were investigated. The results showed that most D-valine substituted analogs had much lower antimicrobial activity and cytotoxic activities in vitro than AMD itself, but three N-methyl-L-valine substituted analogs had comparable or even more remarkable cytotoxic activities in vitro than AMD. Acute toxicities and antitumor effects of the N-methyl-L-valine substituted analogs in mice were also examined. The result showed that the acute toxicity of compound 4 L-methylleucine(5)-AMD analog is comparable to AMD itself and that of compound 3(L-Methylisoleucine(5)-AMD analog) is slightly more toxic, about 1.25-fold than AMD. However, the acute toxicity of compound 5 D-methylleucine5-AMD analog is about 2-fold lower than AMD. This suggested that the N-methyl-D-amino acid replacement in the cyclic ring might play a vital role in their decreased acute toxicities, and perhaps the N-methyl-D-leucine substituent is more favorable, though there may be a slight loss of antitumor activity. This finding may be helpful for the design and development of more potent antitumor agents together with low acute toxicity, and suggests that the N-methyl-D-leucine substituent has the potential to be used as antitumor drug lead. PMID:20045716

  19. Gecko Proteins Exert Anti-Tumor Effect against Cervical Cancer Cells Via PI3-Kinase/Akt Pathway

    PubMed Central

    Jeong, Ae-Jin; Chung, Chung-Nam; Kim, Hye-Jin; Bae, Kil Soo; Choi, Song; Jun, Woo Jin; Shim, Sang In; Kang, Tae-Hong; Leem, Sun-Hee

    2012-01-01

    Anti-tumor activity of the proteins from Gecko (GP) on cervical cancer cells, and its signaling mechanisms were assessed by viable cell counting, propidium iodide (PI) staining, and Western blot analysis. GP induced the cell death of HeLa cells in a dose-dependent manner while it did not affect the viability of normal cells. Western blot analysis showed that GP decreased the activation of Akt, and co-administration of GP and Akt inhibitors synergistically exerted anti-tumor activities on HeLa cells, suggesting the involvement of PI3-kinase/Akt pathway in GP-induced cell death of the cancer cells. Indeed, the cytotoxic effect of GP against HeLa cells was inhibited by overexpression of constituvely active form of Akt in HeLa cells. The candidates of the functional proteins in GP were analyzed by Mass-spectrum. Taken together, our results suggest that GP elicits anti-tumor activity against HeLa cells by inhibition of PI3-kinase/Akt pathway. PMID:23118562

  20. Gecko Proteins Exert Anti-Tumor Effect against Cervical Cancer Cells Via PI3-Kinase/Akt Pathway.

    PubMed

    Jeong, Ae-Jin; Chung, Chung-Nam; Kim, Hye-Jin; Bae, Kil Soo; Choi, Song; Jun, Woo Jin; Shim, Sang In; Kang, Tae-Hong; Leem, Sun-Hee; Chung, Jin Woong

    2012-10-01

    Anti-tumor activity of the proteins from Gecko (GP) on cervical cancer cells, and its signaling mechanisms were assessed by viable cell counting, propidium iodide (PI) staining, and Western blot analysis. GP induced the cell death of HeLa cells in a dose-dependent manner while it did not affect the viability of normal cells. Western blot analysis showed that GP decreased the activation of Akt, and co-administration of GP and Akt inhibitors synergistically exerted anti-tumor activities on HeLa cells, suggesting the involvement of PI3-kinase/Akt pathway in GP-induced cell death of the cancer cells. Indeed, the cytotoxic effect of GP against HeLa cells was inhibited by overexpression of constituvely active form of Akt in HeLa cells. The candidates of the functional proteins in GP were analyzed by Mass-spectrum. Taken together, our results suggest that GP elicits anti-tumor activity against HeLa cells by inhibition of PI3-kinase/Akt pathway. PMID:23118562

  1. Anti-Tumor Effect of Pinus massoniana Bark Proanthocyanidins on Ovarian Cancer through Induction of Cell Apoptosis and Inhibition of Cell Migration

    PubMed Central

    Liu, Jia; Bai, Jing; Jiang, Guoqiang; Li, Xinli; Wang, Jing; Wu, Dachang; Owusu, Lawrence; Zhang, Ershao; Li, Weiling

    2015-01-01

    Pinus massoniana bark proanthocyanidins (PMBPs), an active component isolated from Pinus massoniana bark, has been reported to possess a wide range of biochemical properties. Here, we investigated the anti-tumor effect of PMBPs on ovarian cancer. The results indicated that PMBPs significantly reduced the growth of ovarian cancer cells and induced dose-dependent apoptosis. The underlying mechanisms involved were elucidated to include the loss of mitochondrial membrane potential, down-regulation of the anti-apoptotic protein Bcl-2 and the activation of Caspase 3/9, suggesting that PMBPs triggered apoptosis through activation of mitochondria-associated apoptotic pathway. In addition, wound healing and transwell chamber assays revealed that PMBPs could suppress migration and invasion of ovarian cancer cells. PMBPs dramatically inhibited MMP-9 activity and expression, blocked the activity of NFκB and the activation of ERK1/2 and p38 MAPK. Our findings suggest that PMBPs has the potential to be developed as an anti-tumor drug for ovarian cancer treatment and/ or disease management. PMID:26539720

  2. Addition agents effects on hydrocarbon fuels burning

    NASA Astrophysics Data System (ADS)

    Larionov, V. M.; Mitrofanov, G. A.; Sakhovskii, A. V.

    2016-01-01

    Literature review on addition agents effects on hydrocarbon fuels burning has been conducted. The impact results in flame pattern and burning velocity change, energy efficiency increase, environmentally harmful NOx and CO emission reduction and damping of self-oscillations in flow. An assumption about water molecules dissociation phenomenon existing in a number of practical applications and being neglected in most explanations for physical- chemical processes taking place in case of injection of water/steam into combustion zone has been noted. The hypothesis about necessity of water dissociation account has been proposed. It can be useful for low temperature combustion process control and NOx emission reduction.

  3. Gamma delta T cells are activated by polysaccharide K (PSK) and contribute to the anti-tumor effect of PSK

    PubMed Central

    Inatsuka, Carol; Yang, Yi; Gad, Ekram; Rastetter, Lauren; Disis, Mary L.

    2013-01-01

    Polysaccharide K (PSK) is a widely used mushroom extract that has shown anti-tumor and immunomodulatory effects in both preclinical and clinical studies. Therefore, it is important to understand the mechanism of actions of PSK. We recently reported that PSK can activate toll-like receptor 2 and enhances the function of NK cells. The current study was undertaken to study the effect of PSK on gamma delta (γδ) T cells, another important arm of the innate immunity. In vitro experiments using mouse splenocytes showed that γδ T cells produce IFN-γ after treatment with PSK and have up-regulated expression of CD25, CD69, and CD107a. To investigate whether the effect of PSK on γδ T cells is direct or indirect, purified γδ T cells were cultured either alone or together with bone marrow-derived DC in a co-culture or trans-well system and then stimulated with PSK. Results showed that direct cell-to-cell contact between γδ T cells and DC is required for optimal activation of γδ T cells. There was also reciprocal activation of DC by PSK-activated γδ T cells, as demonstrated by higher expression of costimulatory molecules and enhanced production of IL-12 by DC in the presence of γδ T cells. PSK can also co-stimulate γδ T cells with anti-TCR and anti-CD3 stimulation, in the absence of DC. Finally, in vivo treatment with PSK activates γδ T cells among the tumor infiltrating lymphocytes, and depleting γδ T cells during PSK treatment attenuated the anti-tumor effect of PSK. All together, these results demonstrated that γδ T cells are activated by PSK and contribute to the anti-tumor effect of PSK. PMID:23685781

  4. Delivery of baicalein and paclitaxel using self-assembled nanoparticles: synergistic antitumor effect in vitro and in vivo

    PubMed Central

    Wang, Wei; Xi, Mei; Duan, Xuezhong; Wang, Yong; Kong, Fansheng

    2015-01-01

    Purpose Combination anticancer therapy is promising to generate synergistic anticancer effects to maximize the treatment effect and overcome multidrug resistance. The aim of the study reported here was to develop multifunctional, dual-ligand, modified, self-assembled nanoparticles (NPs) for the combination delivery of baicalein (BCL) and paclitaxel (PTX) prodrugs. Methods Prodrug of PTX and prodrug of BCL, containing dual-targeted ligands of folate (FA) and hyaluronic acid (HA), were synthesized. Multifunctional self-assembled NPs for combination delivery of PTX prodrug and BCL prodrug (PTX-BCL) were prepared and the synergistic antitumor effect was evaluated in vitro and in vivo. The in vitro transfection efficiency of the novel modified vectors was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/PTX cells. The in vivo antitumor efficiency and systemic toxicity of different formulations were further investigated in mice bearing A549/PTX drug-resistant human lung cancer xenografts. Results The size of the PTX-BCL NPs was approximately 90 nm, with a positive zeta potential of +3.3. The PTX-BCL NPs displayed remarkably better antitumor activity over a wide range of drug concentrations, and showed an obvious synergism effect with CI50 values of 0.707 and 0.513, indicating that double-ligand modification and the co-delivery of PTX and BCL prodrugs with self-assembled NPs had remarkable superiority over other formulations. Conclusion The prepared PTX-BCL NP drug-delivery system was proven efficient by its targeting of drug-resistant human lung cancer cells and delivering of BCL and PTX prodrugs. Enhanced synergistic anticancer effects were achieved by PTX-BCL NPs, and multidrug resistance of PTX was overcome by this promising targeted nanomedicine. PMID:26045664

  5. Targeted Delivery of Chemotherapeutic Agents Using Improved Radiosensitive Liquid Core Microcapsules and Assessment of Their Antitumor Effect

    SciTech Connect

    Harada, Satoshi Ehara, Shigeru; Ishii, Keizo; Yamazaki, Hiromichi; Matsuyama, Shigeo; Sato, Takahiro; Oikawa, Shyoichi; Kamiya, Tomihiro; Arakawa, Kazuo; Yokota, Wataru; Sera, Koichiro; Ito, Jyun

    2009-10-01

    Purpose: Radiation-sensitive microcapsules composed of alginate and hyaluronic acid are being developed. We report the development of improved microcapsules that were prepared using calcium- and yttrium-induced polymerization. We previously reported on the combined antitumor effect of carboplatin-containing microcapsules and radiotherapy. Methods and Materials: We mixed a 0.1% (wt/vol) solution of hyaluronic acid with a 0.2% alginate solution. Carboplatin (l mg) and indocyanine green (12.5 {mu}g) were added to this mixture, and the resultant material was used for capsule preparation. The capsules were prepared by spraying the material into a mixture containing a 4.34% CaCl{sub 2} solution supplemented with 0-0.01% yttrium. These capsules were irradiated with single doses of 0.5, 1.0, 1.5, or 2 Gy {sup 60}Co {gamma}-rays. Immediately after irradiation, the frequency of microcapsule decomposition was determined using a microparticle-induced X-ray emission camera. The amount of core content released was estimated by particle-induced X-ray emission and colorimetric analysis with 0.25% indocyanine green. The antitumor effect of the combined therapy was determined by monitoring its effects on the diameter of an inoculated Meth A fibrosarcoma. Results: Microcapsules that had been polymerized using a 4.34% CaCl{sub 2} solution supplemented with 5.0 x 10{sup -3}% (10{sup -3}% meant or 10%{sup -3}) yttrium exhibited the maximal decomposition, and the optimal release of core content occurred after 2-Gy irradiation. The microcapsules exhibited a synergistic antitumor effect combined with 2-Gy irradiation and were associated with reduced adverse effects. Conclusion: The results of our study have shown that our liquid core microcapsules can be used in radiotherapy for targeted delivery of chemotherapeutic agents.

  6. Comparative antitumor effect among GM-CSF, IL-12 and GM-CSF+IL-12 genetically modified tumor cell vaccines.

    PubMed

    Miguel, A; Herrero, M J; Sendra, L; Botella, R; Algás, R; Sánchez, M; Aliño, S F

    2013-10-01

    Genetically modified cells have been shown to be one of the most effective cancer vaccine strategies. An evaluation is made of the efficacy of both preventive and therapeutic antitumor vaccines against murine melanoma, using C57BL/6 mice and irradiated B16 tumor cells expressing granulocyte and macrophage colony-stimulating factor (GM-CSF), interleukin-12 (IL-12) or both. Tumor was transplanted by the injection of wild-type B16 cells. Tumor growth and survival were measured to evaluate the efficacy of vaccination. Specific humoral response and immunoglobulin G (IgG) switch were evaluated measuring total IgG and IgG1 and IgG2a subtypes against tumor membrane proteins of B16 cells. In preventive vaccination, all treated groups showed delayed tumor growth. In addition, the group vaccinated to express only GM-CSF achieved 100% animal survival (P<0.005). Vaccination with GM-CSF+IL-12-producing B16 cells yielded lesser results (60% survival, P<0.005). Furthermore, all surviving animals remained disease-free after second tumor implantation 1 year later. The therapeutic vaccination strategies resulted in significantly delayed tumor growth, mainly using B16 cells producing GM-CSF+IL-12 cytokines, with 70% tumor growth inhibition (P<0.001)-although none of the animals reached overall survival. The results obtained suggest that the GM-CSF+IL-12 combination only increases the efficacy of therapeutic vaccines. No differences in classical regulatory T cells were found among the different groups. PMID:23969885

  7. Downregulation of survivin expression exerts antitumoral effects on mouse breast cancer cells in vitro and in vivo

    PubMed Central

    MA, WEN-HUI; LIU, YONG-CHAO; XUE, MEI-LAN; ZHENG, ZHENG; GE, YIN-LIN

    2016-01-01

    Metastasis constantly occurs in the majority of cases of primary breast cancer at late stage or following surgical treatment. Survivin, a member of the inhibitor of apoptosis protein family, has long been recognized as a promising anticancer target, but its antitumor effects remain largely unexplored. In order to elucidate the role of survivin in breast cancer metastasis, short interfering RNA (siRNA) was used in the present study to specifically downregulate survivin expression in the murine breast cancer cell line 4T1. The results demonstrated that blocking the expression of survivin by siRNA inhibited the proliferation, migration and invasion abilities of murine breast cancer cells in vitro. Vascular endothelial growth factor (VEGF)-C is a lymphatic endothelial cell-stimulating factor that may lead to the formation of lymphatic vessels in lymph nodes. In the present study, the inhibition of survivin by siRNA was able to reduce the overexpression of VEGF-C in 4T1 cells. Furthermore, intratumoral injections of the survivin-siRNA significantly inhibited the growth of orthotopically transplanted 4T1 tumors in vivo. In addition, the number of pulmonary metastases and the microlymphatic vessel density were significantly reduced in vivo, following transfection with survivin-siRNA. The results of the present study suggested that the Akt/hypoxia-inducible factor-1α signaling pathway participates in the survivin-mediated downregulation of VEGF-C expression observed in breast cancer cells treated with survivin-siRNA. Therefore, the use of siRNA specifically targeting survivin may be a potential anticancer method in the future. PMID:26870183

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

    NASA Astrophysics Data System (ADS)

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

    2015-12-01

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

  9. Allogeneic mRNA-based electrotransfection of autologous dendritic cells and specific antitumor effects against osteosarcoma in rats.

    PubMed

    Yu, Zhe; Qian, Jixian; Wu, Jiachang; Gao, Jie; Zhang, Minghua

    2012-12-01

    Vaccination with dendritic cells (DCs) transfected with tumor-derived mRNA antigen has emerged as a promising strategy for generating protective immunity in mammals. However, the integration of allogeneic osteosarcoma mRNA and autologous DCs has not been fully examined. This study was designed to investigate the antitumor effects of tumor vaccine produced by autologous DCs transfected of allogeneic osteosarcoma mRNA through electroporation in tumor-bearing rats model. In the present study, extraction of Wistar rat tumor mRNA was performed as a two-step procedure. First, total RNA was extracted by use of Trizol; then, mRNA purification was performed by use of polyT-coated magnetic beads. Then, we transfected the allogeneic-derived tumor mRNA to Sprague-Dawley (SD) rat bone marrow-derived DCs through electroporation. The tumor vaccine was applied to tumor-bearing rats model, and the specific antitumor effects of the tumor vaccine were observed. The immunization using autologous DCs electrotransfected with allogeneic osteosarcoma total RNA induced specific CTL responses, which were statistically significant (P < 0.05), and the cytotoxic activity was confirmed in cold target inhibition assays and using mAbs blocking MHC class I molecules. In in vivo experiments, 70 % of the rats immunized with allogeneic osteosarcoma RNA transfected to DCs were typically able to reject tumor challenge and remained tumor-free. Vaccinated survivors developed long immunological memory and were able to reject a subsequent rechallenge with the same tumor cells but not a syngeneic unrelated tumor line. In the present study, we demonstrated that allogeneic tumor mRNA isolated from rat osteosarcoma cell line could be applied to produce tumor vaccine inducing specific antitumor effects, especially in DC-based immunotherapy strategy. This study also provides the foundations for an effective and broadly applicable treatment to a wide range of cancer indications for which tumor-associated antigens

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

    PubMed

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

    2015-12-18

    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. PMID:26580675

  11. Cyclooxygenase inhibitors - invitro and invivo effects on antitumor alkylating-agents in the emt-6 murine mammary-carcinoma.

    PubMed

    Teicher, B; Holden, S; Ara, G; Liu, J; Robinson, M; Flodgren, P; Dupuis, N; Northey, D

    1993-02-01

    reduced with the addition of the antitumor alkylating agents. These results indicate that agents which inhibit signaling pathways among tumor cells and between tumor cells and normal cells can be useful additions to cytotoxic therapies. PMID:21573528

  12. CCR4 is critically involved in effective antitumor immunity in mice bearing intradermal B16 melanoma.

    PubMed

    Matsuo, Kazuhiko; Itoh, Tatsuki; Koyama, Atsushi; Imamura, Reira; Kawai, Shiori; Nishiwaki, Keiji; Oiso, Naoki; Kawada, Akira; Yoshie, Osamu; Nakayama, Takashi

    2016-08-01

    CCR4 is a major chemokine receptor expressed by Treg cells and Th17 cells. While Treg cells are known to suppress antitumor immunity, Th17 cells have recently been shown to enhance the induction of antitumor cytotoxic T lymphocytes. Here, CCR4-deficient mice displayed enhanced tumor growth upon intradermal inoculation of B16-F10 melanoma cells. In CCR4-deficient mice, while IFN-γ+CD8+ effector T cells were decreased in tumor sites, IFN-γ+CD8+ T cells and Th17 cells were decreased in regional lymph nodes. In wild-type mice, CD4+IL-17A+ cells, which were identified as CCR4+CD44+ memory Th17, were found to be clustered around dendritic cells expressing MDC/CCL22, a ligand for CCR4, in regional lymph nodes. Compound 22, a CCR4 antagonist, also enhanced tumor growth and decreased Th17 cells in regional lymph nodes in tumor-bearing mice treated with Dacarbazine. In contrast, CCR6 deficiency did not affect the tumor growth and the numbers of Th17 cells in regional lymph nodes. These findings indicate that CCR4 is critically involved in regional lymph node DC-Th17 cell interactions that are necessary for Th17 cell-mediated induction of antitumor CD8+ effector T cells in mice bearing B16 melanoma. PMID:27132989

  13. Comparison of the Anti-tumor Effects of Two Platinum Agents (Miriplatin and Fine-Powder Cisplatin)

    SciTech Connect

    Watanabe, Shobu Nitta, Norihisa Ohta, Shinichi Sonoda, Akinaga Otani, Hideji Tomozawa, Yuki Nitta-Seko, Ayumi Tsuchiya, Keiko Tanka, Toyohiko Takahashi, Masashi Murata, Kiyoshi

    2012-04-15

    Purpose: This study was designed to evaluate the anti-tumor effects of miriplatin-lipidol and fine-powder cisplatin-lipiodol suspensions. Methods: Assessment of the cytotoxicity of two drugs was performed: a soluble derivative of miriplatin (DPC) and fine-powder cisplatin. We randomly divided 15 rabbits with transplanted VX2 liver tumors into three equal groups. They were infused via the proper hepatic artery with a miriplatin-lipiodol suspension (ML), a fine-powder cisplatin-lipiodol suspension (CL), or saline (control) and the tumor growth rate was determined on MR images acquired before and 7 days after treatment. The concentration of platinum (PCs) in blood was assayed immediately, and 10, 30, and 60 min, and 24 h and 7 days after drug administration. Its concentration in tumor and surrounding normal liver tissues was determined at 7 days postadministration. Results: At high concentrations, fine-powder cisplatin exhibited stronger cytotoxicity than DPC. At low concentrations, both agents manifested weak cytotoxicity. While there was no difference between the tumor growth rate of the ML and the CL groups, the difference between the controls and ML- and CL-treated rabbits was significant. The blood PCs peaked at 10 min and then gradually decreased over time. On the other hand, no platinum was detected at any point after the administration of ML. There was no difference between the ML and CL groups in the PCs in tumor tissues; however, in normal hepatic tissue, the PCs were higher in ML- than CL-treated rabbits. Conclusions: We confirmed the anti-tumor effect of ML and CL. There was no significant difference between the anti-tumor effect of ML and CL at 7 days postadministration.

  14. Antitumor Effects of Oncolytic Adenovirus-Carrying siRNA Targeting Potential Oncogene EphA3

    PubMed Central

    Zhao, Yali; Li, Hailiang; Wu, Ruiqin; Li, Shanhu; Wang, Peng; Wang, Hongtao; Wang, Jian; Zhou, Jianguang

    2015-01-01

    Conditionally replicating adenoviruses (CRAds) armed with antitumor transgenes hold promise for cancer treatment. In previous studies, we showed that the 1504-siRNA targeting potential oncogene EphA3 was an efficient therapeutic transgene and that the telomerase reverse transcriptase promoter (TERTp) driving the CRAd was a more advanced generation of CRAd. Therefore, we combined Ad-TERTp-E1A-1504 by inserting 1504-siRNA into the CRAd to study its antitumor effects and mechanism of action, using Ad-TERTp-E1A-NC and nonreplicating adenovirus carrying 1504-siRNA as controls. Cell viability assays and ED50 studies of growth inhibition confirmed that Ad-TERTp-E1A-1504 has 3.5- and 1,400-fold greater ability to kill EphA3- and TERT-expressing tumor cells compared to Ad-TERTp-E1A-NC and Ad-ΔE1A-1504, respectively. Also, Ad-TERTp-E1A-1504 had little effect on cells that modestly expressed EphA3 and TERT such as 2BS. The antitumor efficacy of Ad-TERTp-E1A-1504 was also validated in vivo. Furthermore, the virus yield of Ad-TERTp-E1A-1504 in C4-2B was ~1,000 times greater than that in 2BS. No obvious differences were observed between Ad-TERTp-E1A-1504 and Ad-TERTp-E1A-NC. Both acridine orange staining and Beclin1 protein measurements indicated that autophagy with Ad-TERTp-E1A-1504 at 5 and 10 MOI was higher than that of Ad-TERTp-E1A-NC. Finally, the classical negatively regulated autophagy signaling pathway, PI3K/AKT/mTOR, was suppressed (reduced phosphorylated form) in contrast to NC, and that this was mediated by 1504-siRNA. Thus, Ad- TERTp-E1A-1504 does not harm normal cells but has dual inhibiting and killing effects on TERT- and EphA3-positive tumor cells, and this effect is mediated by the AKT/mTOR signaling pathway via induction of autophagy. These data may offer a foundation for novel antitumor therapies targeting this mechanism. PMID:25978371

  15. Synergistic antitumor effect with indoleamine 2,3-dioxygenase inhibition and temozolomide in a murine glioma model.

    PubMed

    Hanihara, Mitsuto; Kawataki, Tomoyuki; Oh-Oka, Kyoko; Mitsuka, Kentaro; Nakao, Atsuhito; Kinouchi, Hiroyuki

    2016-06-01

    OBJECT Indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (Trp) metabolism, is involved in tumor-derived immune suppression through depletion of Trp and accumulation of the metabolite kynurenine, resulting in inactivation of natural killer cells and generation of regulatory T cells (Tregs). It has been reported that high expression of IDO in cancer cells is associated with suppression of the antitumor immune response and is consistent with a poor prognosis. Thus, IDO may be a therapeutic target for malignant cancer. The authors have recently shown that IDO expression is markedly increased in human glioblastoma and secondary glioblastoma with malignant change, suggesting that IDO targeting may also have therapeutic potential for patients with glioma. The aim of this study was to investigate the antitumor effect of IDO inhibition and to examine the synergistic function of IDO inhibitor and temozolomide (TMZ) in a murine glioma model. METHODS Murine glioma GL261 cells and human glioma U87 cells were included in this study. The authors used 3 mouse models to study glioma cell growth: 1) a subcutaneous ectopic model, 2) a syngeneic intracranial orthotopic model, and 3) an allogenic intracranial orthotopic model. IDO inhibition was achieved via knockdown of IDO in GL261 cells using short hairpin RNA (shRNA) and through oral administration of the IDO inhibitor, 1-methyl-l-tryptophan (1-MT). Tumor volume in the subcutaneous model and survival time in the intracranial model were evaluated. RESULTS In the subcutaneous model, oral administration of 1-MT significantly suppressed tumor growth, and synergistic antitumor effects of 1-MT and TMZ were observed (p < 0.01). Mice containing intracranially inoculated IDO knockdown cells had a significantly longer survival period as compared with control mice (p < 0.01). CONCLUSIONS These results suggest that IDO expression is implicated in immunosuppression and tumor progression in glioma cells. Therefore, combining IDO

  16. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  17. Combination of gambogic acid with cisplatin enhances the antitumor effects on cisplatin-resistant lung cancer cells by downregulating MRP2 and LRP expression

    PubMed Central

    Zhang, Wendian; Zhou, Hechao; Yu, Ying; Li, Jingjing; Li, Haiwen; Jiang, Danxian; Chen, Zihong; Yang, Donghong; Xu, Zumin; Yu, Zhonghua

    2016-01-01

    Cisplatin resistance is a main clinical problem of lung cancer therapy. Gambogic acid (GA) could prohibit the proliferation of a variety of human cancer cells. However, the effects of GA on cisplatin-resistant lung cancer are still unclear. The objective of the present study was to find out the antitumor effects of GA on cisplatin-resistant human lung cancer A549/DDP cells and further explore its underlying mechanisms. Cell Counting Kit-8 assay was used to observe the impacts of GA and/or cisplatin on the proliferation of lung cancer cells; flow cytometry was used to detect the effects of GA on cell cycle and apoptosis; Western blot was used to examine the effects of GA on the expression of lung resistance protein (LRP) and multidrug resistance-associated protein 2 (MRP2) protein in A549/DDP cells. Our results showed that GA dose- and time-dependently prohibited the proliferation and induced significant cell apoptosis in A549 and A549/DDP cells. GA also induced G0/G1 arrest in both A549/DDP and A549 cells. Moreover, GA upregulated protein expression level of cleaved caspase-3 and Bax and downregulated protein expression level of pro-caspase-9 and Bcl-2 in time- and dose-dependent way in A549/DDP cells. GA combined with cisplatin enhanced the cells apoptotic rate and reduced the cisplatin resistance index in A549/DDP cells. In addition, GA reduced the MRP2 and LRP protein expression level in A549/DDP cells. GA inhibits the proliferation, induces cell cycle arrest and apoptosis in A549/DDP cells. Combination of GA with cisplatin enhances the antitumor effects on cisplatin-resistant lung cancer cells by downregulating MRP2 and LRP expression. PMID:27330316

  18. Acute inflammation induces immunomodulatory effects on myeloid cells associated with anti-tumor responses in a tumor mouse model.

    PubMed

    Salem, Mohamed L; Attia, Zeinab I; Galal, Sohaila M

    2016-03-01

    Given the self nature of cancer, anti-tumor immune response is weak. As such, acute inflammation induced by microbial products can induce signals that result in initiation of an inflammatory cascade that helps activation of immune cells. We aimed to compare the nature and magnitude of acute inflammation induced by toll-like receptor ligands (TLRLs) on the tumor growth and the associated inflammatory immune responses. To induce acute inflammation in tumor-bearing host, CD1 mice were inoculated with intraperitoneal (i.p.) injection of Ehrlich ascites carcinoma (EAC) (5 × 10(5) cells/mouse), and then treated with i.p. injection on day 1, day 7 or days 1 + 7 with: (1) polyinosinic:polycytidylic (poly(I:C)) (TLR3L); (2) Poly-ICLC (clinical grade of TLR3L); (3) Bacillus Calmette Guerin (BCG) (coding for TLR9L); (4) Complete Freund's adjuvant (CFA) (coding for TLR9L); and (5) Incomplete Freund's Adjuvant (IFA). Treatment with poly(I:C), Poly-ICLC, BCG, CFA, or IFA induced anti-tumor activities as measured by 79.1%, 75.94%, 73.94%, 71.88% and 47.75% decreases, respectively in the total number of tumor cells collected 7 days after tumor challenge. Among the tested TLRLs, both poly(I:C) (TLR3L) and BCG (contain TLR9L) showed the highest anti-tumor effects as reflected by the decrease in the number of EAc cells. These effects were associated with a 2-fold increase in the numbers of inflammatory cells expressing the myeloid markers CD11b(+)Ly6G(+), CD11b(+)Ly6G(-), and CD11b(+)Ly6G(-). We concluded that Provision of the proper inflammatory signal with optimally defined magnitude and duration during tumor growth can induce inflammatory immune cells with potent anti-tumor responses without vaccination. PMID:26966565

  19. Acute inflammation induces immunomodulatory effects on myeloid cells associated with anti-tumor responses in a tumor mouse model

    PubMed Central

    Salem, Mohamed L.; Attia, Zeinab I.; Galal, Sohaila M.

    2015-01-01

    Given the self nature of cancer, anti-tumor immune response is weak. As such, acute inflammation induced by microbial products can induce signals that result in initiation of an inflammatory cascade that helps activation of immune cells. We aimed to compare the nature and magnitude of acute inflammation induced by toll-like receptor ligands (TLRLs) on the tumor growth and the associated inflammatory immune responses. To induce acute inflammation in tumor-bearing host, CD1 mice were inoculated with intraperitoneal (i.p.) injection of Ehrlich ascites carcinoma (EAC) (5 × 105 cells/mouse), and then treated with i.p. injection on day 1, day 7 or days 1 + 7 with: (1) polyinosinic:polycytidylic (poly(I:C)) (TLR3L); (2) Poly-ICLC (clinical grade of TLR3L); (3) Bacillus Calmette Guerin (BCG) (coding for TLR9L); (4) Complete Freund’s adjuvant (CFA) (coding for TLR9L); and (5) Incomplete Freund’s Adjuvant (IFA). Treatment with poly(I:C), Poly-ICLC, BCG, CFA, or IFA induced anti-tumor activities as measured by 79.1%, 75.94%, 73.94%, 71.88% and 47.75% decreases, respectively in the total number of tumor cells collected 7 days after tumor challenge. Among the tested TLRLs, both poly(I:C) (TLR3L) and BCG (contain TLR9L) showed the highest anti-tumor effects as reflected by the decrease in the number of EAc cells. These effects were associated with a 2-fold increase in the numbers of inflammatory cells expressing the myeloid markers CD11b+Ly6G+, CD11b+Ly6G−, and CD11b+Ly6G−. We concluded that Provision of the proper inflammatory signal with optimally defined magnitude and duration during tumor growth can induce inflammatory immune cells with potent anti-tumor responses without vaccination. PMID:26966565

  20. GSK-3 inhibition in vitro and in vivo enhances antitumor effect of sorafenib in renal cell carcinoma (RCC)

    SciTech Connect

    Kawazoe, Hisashi; Bilim, Vladimir N.; Ugolkov, Andrey V.; Yuuki, Kaori; Naito, Sei; Nagaoka, Akira; Kato, Tomoyuki; Tomita, Yoshihiko

    2012-07-06

    Highlights: Black-Right-Pointing-Pointer Sorafenib treatment upregulated GSK-3{beta} levels in RCC cells. Black-Right-Pointing-Pointer Pharmacologic inhibition of GSK-3 suppressed xenograft RCC tumor growth. Black-Right-Pointing-Pointer Inhibition of GSK-3 enhanced antitumor effect of sorafenib in vitro and in vivo. -- Abstract: Sorafenib is a multikinase inhibitor approved for the systemic treatment of renal cell carcinoma (RCC). However, sorafenib treatment has a limited effect due to acquired chemoresistance of RCC. Previously, we identified glycogen synthase kinase-3 (GSK-3) as a new therapeutic target in RCC. Here, we observed that sorafenib inhibits proliferation and survival of RCC cells. Significantly, we revealed that sorafenib enhances GSK-3 activity in RCC cells, which could be a potential mechanism of acquired chemoresistance. We found that pharmacological inhibition of GSK-3 potentiates sorafenib antitumor effect in vitro and in vivo. Our results suggest that combining GSK-3 inhibitor and sorafenib might be a potential new therapeutic approach for RCC treatment.

  1. Ferulic acid prevents liver injury and increases the anti-tumor effect of diosbulbin B in vivo *

    PubMed Central

    Wang, Jun-ming; Sheng, Yu-chen; Ji, Li-li; Wang, Zheng-tao

    2014-01-01

    The present study is designed to investigate the protection by ferulic acid against the hepatotoxicity induced by diosbulbin B and its possible mechanism, and further observe whether ferulic acid augments diosbulbin B-induced anti-tumor activity. The results show that ferulic acid decreases diosbulbin B-increased serum alanine transaminase/aspartate transaminase (ALT/AST) levels. Ferulic acid also decreases lipid peroxide (LPO) levels which are elevated in diosbulbin B-treated mice. Histological evaluation of the liver demonstrates hydropic degeneration in diosbulbin B-treated mice, while ferulic acid reverses this injury. Moreover, the activities of copper- and zinc-containing superoxide dismutase (CuZn-SOD) and catalase (CAT) are decreased in the livers of diosbulbin B-treated mice, while ferulic acid reverses these decreases. Further results demonstrate that the mRNA expressions of CuZn-SOD and CAT in diosbulbin B-treated mouse liver are significantly decreased, while ferulic acid prevents this decrease. In addition, ferulic acid also augments diosbulbin B-induced tumor growth inhibition compared with diosbulbin B alone. Taken together, the present study shows that ferulic acid prevents diosbulbin B-induced liver injury via ameliorating diosbulbin B-induced liver oxidative stress injury and augments diosbulbin B-induced anti-tumor activity. PMID:24903991

  2. A HER2-specific Modified Fc Fragment (Fcab) Induces Antitumor Effects Through Degradation of HER2 and Apoptosis

    PubMed Central

    Leung, Kin-Mei; Batey, Sarah; Rowlands, Robert; Isaac, Samine J; Jones, Phil; Drewett, Victoria; Carvalho, Joana; Gaspar, Miguel; Weller, Sarah; Medcalf, Melanie; Wydro, Mateusz M; Pegram, Robert; Mudde, Geert C; Bauer, Anton; Moulder, Kevin; Woisetschläger, Max; Tuna, Mihriban; Haurum, John S; Sun, Haijun

    2015-01-01

    FS102 is a HER2-specific Fcab (Fc fragment with antigen binding), which binds HER2 with high affinity and recognizes an epitope that does not overlap with those of trastuzumab or pertuzumab. In tumor cells that express high levels of HER2, FS102 caused profound HER2 internalization and degradation leading to tumor cell apoptosis. The antitumor effect of FS102 in patient-derived xenografts (PDXs) correlated strongly with the HER2 amplification status of the tumors. Superior activity of FS102 over trastuzumab or the combination of trastuzumab and pertuzumab was observed in vitro and in vivo when the gene copy number of HER2 was equal to or exceeded 10 per cell based on quantitative polymerase chain reaction (qPCR). Thus, FS102 induced complete and sustained tumor regression in a significant proportion of HER2-high PDX tumor models. We hypothesize that the unique structure and/or epitope of FS102 enables the Fcab to internalize and degrade cell surface HER2 more efficiently than standard of care antibodies. In turn, increased depletion of HER2 commits the cells to apoptosis as a result of oncogene shock. FS102 has the potential of a biomarker-driven therapeutic that derives superior antitumor effects from a unique mechanism-of-action in tumor cells which are oncogenically addicted to the HER2 pathway due to overexpression. PMID:26234505

  3. Anti-Tumor Effect of Steamed Codonopsis lanceolata in H22 Tumor-Bearing Mice and Its Possible Mechanism

    PubMed Central

    Li, Wei; Xu, Qi; He, Yu-Fang; Liu, Ying; Yang, Shu-Bao; Wang, Zi; Zhang, Jing; Zhao, Li-Chun

    2015-01-01

    Although previous studies confirmed that steaming and the fermentation process could significantly improve the cognitive-enhancement and neuroprotective effects of Codonopsis lanceolata, the anti-tumor efficacy of steamed C. lanceolata (SCL) and what mechanisms are involved remain largely unknown. The present study was designed to evaluate the anti-tumor effect in vivo of SCL in H22 tumor-bearing mice. The results clearly indicated that SCL could not only inhibit the tumor growth, but also prolong the survival time of H22 tumor-bearing mice. Besides, the serum levels of cytokines, such as interferon gamma (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-2 (IL-2), were enhanced by SCL administration. The observations of Hoechst 33258 staining demonstrated that SCL was able to induce tumor cell apoptosis. Finally, immunohistochemical analysis revealed that SCL treatment significantly increased Bax expression and decreased Bcl-2 and vascular endothelial growth factor (VEGF) expression of H22 tumor tissues in a dose-dependent manner. Moreover, LC/MS analysis of SCL indicated that it mainly contained lobetyolin and six saponins. Taken all together, the findings in the present study clearly demonstrated that SCL inhibited the H22 tumor growth in vivo at least partly via improving the immune functions, inducing apoptosis and inhibiting angiogenesis. PMID:26426041

  4. Molecular characterization of antitumor effects of the rhizome extract from Curcuma zedoaria on human esophageal carcinoma cells.

    PubMed

    Hadisaputri, Yuni Elsa; Miyazaki, Tatsuya; Suzuki, Shigemasa; Kubo, Norio; Zuhrotun, Ade; Yokobori, Takehiko; Abdulah, Rizky; Yazawa, Shin; Kuwano, Hiroyuki

    2015-12-01

    Curcuma zedoaria has been used as a traditional agent against malignant diseases. To elucidate detailed mechanisms producing such an activity, characterization and determination of molecular mechanisms of its antitumor effects was conducted. Inhibiting activities against cell proliferation, invasion and colony formation, and expression levels of corresponding molecules were investigated using human esophageal cancer TE-8 cells treated with the rhizome extract from C. zedoaria. Antitumor effect of the extract administered orally was also examined in tumor-bearing mice. The extract possessed strong anti-proliferation and invasion activities against TE-8 cells. Further, upregulated PTEN and downregulated phosphorylated Akt, mTOR and STAT3 expressions in the cells were induced shortly after treatment with the extract, followed by attenuation of FGFR1 and MMP-2, activation of caspase-9, caspase-3 and PARP, and suppression of Bcl-2 expressions, which led the cells to apoptotic cell death. Furthermore, tumor formation in mice was significantly suppressed through the oral administration of the extract. Taken together, these results suggest that the C. zedoaria extract could be a promising agent against esophageal cancer. PMID:26498695

  5. Cell-specific expression of artificial microRNAs targeting essential genes exhibit potent antitumor effect on hepatocellular carcinoma cells

    PubMed Central

    Mao, Chenyu; Liu, Hao; Chen, Ping; Ye, Jingjia; Teng, Lisong; Jia, Zhenyu; Cao, Jiang

    2015-01-01

    To achieve specific and potent antitumor effect of hepatocyte carcinoma cells, replication defective adenoviral vectors, namely rAd/AFP-amiRG, rAd/AFP-amiRE and rAd/AFP-amiRP, were constructed which were armed with artificial microRNAs (amiRs) targeting essential functional genes glyceraldehyde-3-phosphate dehydrogenase, eukaryotic translation initiation factor 4E and DNA polymerase α respectively under the control of a recombinant promoter comprised of human α-fetoprotein enhancer and basal promoter. The AFP enhancer/promoter showed specific high transcription activity in AFP-positive HCC cells Hep3B, HepG2 and SMMC7721, while low in AFP-negative cell Bcap37. All artificial microRNAs exhibited efficient knockdown of target genes. Decreased ATP production and protein synthesis was observed in rAd/AFP-amiRG and rAd/AFP-amiRE treated HCC cells. All three recombinant adenoviruses showed efficient blockage of cell cycle progression and significant suppression of HCC cells in vitro. In nude mice model bearing Hep3B xenograft, administration of rAd/AFP-amiRG showed potent antitumor effect. The strategy of tumor-specific knockdown of genes essential for cell survival and proliferation may suggest a novel promising approach for HCC gene therapy. PMID:25691059

  6. Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations.

    PubMed

    Suzawa, Ken; Toyooka, Shinichi; Sakaguchi, Masakiyo; Morita, Mizuki; Yamamoto, Hiromasa; Tomida, Shuta; Ohtsuka, Tomoaki; Watanabe, Mototsugu; Hashida, Shinsuke; Maki, Yuho; Soh, Junichi; Asano, Hiroaki; Tsukuda, Kazunori; Miyoshi, Shinichiro

    2016-01-01

    Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations. PMID:26545934

  7. Preparation and in vitro antitumor effects of cytosine arabinoside-loaded genipin-poly-l-glutamic acid-modified bacterial magnetosomes

    PubMed Central

    Liu, Yuan-Gang; Dai, Qing-Lei; Wang, Shi-Bin; Deng, Qiong-Jia; Wu, Wen-Guo; Chen, Ai-Zheng

    2015-01-01

    To solve the problem of synthesized magnetic nanoparticles in cancer therapy, a new drug delivery system synthesized from bacteria was used to load cytosine arabinoside (Ara-C). Genipin (GP) and poly-l-glutamic acid (PLGA) were selected as dual cross-linkers. The preparation and characterization of Ara-C-loaded GP-PLGA-modified bacterial magnetosomes (BMs) (ABMs-P), as well as their in vitro antitumor effects, were all investigated. Transmission electron micrographs (TEM) and Fourier transform infrared (FTIR) spectroscopy suggested that Ara-C could be bound to the membrane of BMs modified by GP-PLGA. The diameters of the BMs and ABMs-P were 42.0±8.6 nm and 74.9±8.2 nm, respectively. The zeta potential revealed that the nanoparticles were stable. Moreover, this system exhibited optimal drug-loading properties and long-term release behavior. The optimal encapsulation efficiency and drug-loading were 64.1%±6.6% and 38.9%±2.4%, respectively, and ABMs-P could effectively release 90% Ara-C within 40 days, without the release of an initial burst. In addition, in vitro antitumor experiments elucidated that ABMs-P is cytotoxic to HL-60 cell lines, with an inhibition rate of 95%. The method of coupling drugs on BMs using dual cross-linkers is effective, and our results reveal that this new system has potential applications for drug delivery in the future. PMID:25733831

  8. Anti-Tumor Effect of a Novel Soluble Recombinant Human Endostatin: Administered as a Single Agent or in Combination with Chemotherapy Agents in Mouse Tumor Models

    PubMed Central

    Jiang, Wenhong; Dai, Wei; Jiang, Yongping

    2014-01-01

    Background Angiogenesis has become an attractive target in cancer treatment. Endostatin is one of the potent anti-angiogenesis agents. Its recombinant form expressed in the yeast system is currently under clinical trials. Endostatin suppresses tumor formation through the inhibition of blood vessel growth. It is anticipated that combined therapy using endostatin and cytotoxic compounds may exert an additive effect. In the present study, we expressed and purified recombinant human endostatin (rhEndostatin) that contained 3 additional amino acid residues (arginine, glycine, and serine) at the amino-terminus and 6 histidine residues in its carboxyl terminus. The recombinant protein was expressed in E. Coli and refolded into a soluble form in a large scale purification process. The protein exhibited a potent anti-tumor activity in bioassays. Furthermore, rhEndostatin showed an additive effect with chemotherapy agents including cyclophosphamide (CTX) and cisplatin (DDP). Methods rhEndostatin cDNA was cloned into PQE vector and expressed in E. Coli. The protein was refolded through dialysis with an optimized protocol. To establish tumor models, nude mice were subcutaneously injected with human cancer cells (lung carcinoma A549, hepatocellular carcinoma QGY-7703, or breast cancer Bcap37). rhEndostatin and/or DDP was administered peritumorally to evaluate the rate of growth inhibition of A549 tumors. For the tumor metastasis model, mice were injected intravenously with mouse melanoma B16 cells. One day after tumor cell injection, a single dose of rhEndostatin, or in combination with CTX, was administered intravenously or at a site close to the tumor. Results rhEndostatin reduced the growth of A549, QGY-7703, and Bcap37 xenograft tumors in a dose dependent manner. When it was administered peritumorally, rhEndostatin exhibited a more potent inhibitory activity. Furthermore, rhEndostatin displayed an additive effect with CTX or DDP on the inhibition of metastasis of B16 tumors

  9. Intratumoral delivery of low doses of anti-CD40 mAb combined with monophosphoryl lipid A induces local and systemic antitumor effects in immunocompetent and T cell-deficient mice

    PubMed Central

    Van De Voort, Tyler J.; Felder, Mildred A. R.; Yang, Richard K.; Sondel, Paul M.; Rakhmilevich, Alexander L.

    2012-01-01

    In this study, an agonistic anti-CD40 monoclonal antibody was combined with monophosphoryl lipid A (MPL), a nontoxic derivative of LPS and agonist of toll-like receptor 4, to assess the immunomodulatory and antitumor synergy between the two agents in mice. Anti-CD40 was capable of priming macrophages to subsequent ex vivo activation by MPL in immunocompetent and T cell-depleted mice. Intraperitoneal injections of anti-CD40+MPL induced additive to synergistic suppression of poorly immunogenic B16-F10 melanoma growing subcutaneously in syngeneic mice. When anti-CD40+MPL were injected directly into the subcutaneous tumor, the combination treatment was more effective, even with a 25-fold reduction in dose. Low-dose intratumoral treatment also slowed the growth of a secondary tumor growing simultaneously at a distant, untreated site. Antitumor effects were also induced in immunodeficient SCID mice and in T cell-depleted C57BL/6 mice. Taken together, our results show that the antitumor effects of anti-CD40 are enhanced by subsequent treatment with MPL, even in T cell-deficient hosts. These preclinical data suggest that an anti-CD40+MPL combined regimen is appropriate for clinical testing in human patients, including cancer patients that may be immunosuppressed from prior chemotherapy. PMID:23211623

  10. Subtherapeutic doses of interleukin-15 augment the antitumor effect of interleukin-12 in a B16F10 melanoma model in mice.

    PubMed

    Lasek, W; Golab, J; Maśliński, W; Switaj, T; Bałkowiec, E Z; Stokłosa, T; Giermasz, A; Malejczyk, M; Jakóbisiak, M

    1999-09-01

    Interleukin-12 (IL-12) is a potent immunoregulatory cytokine that exhibits antitumor activity in many experimental tumor models. In the present study, we investigated the ability of IL-15, a cytokine sharing many functions of IL-2, to modulate antitumor effectiveness of IL-12 against B16F10 melanoma in mice. In a model of locally growing tumor, intratumoral (i.t.) administration of IL-12, in three cycles of five consecutive daily injections (0.1 mug) followed by 2 days of rest, led to considerable delay of tumor development but no curative response was achieved. When combined with IL-12, subtherapeutic doses of IL-15 (0.4 mug) pontentiated the antitumor effects of IL-12 and induced complete tumor regressions in 50% of mice. Similar results were obtained in a model in which tumor-bearing mice were intravenously co-injected with melanoma cells to induce metastases. Combined administration of IL-12 and IL-15 yielded greater antitumor activity than injections of either cytokine alone and resulted in prolonged survival of mice bearing locally growing tumor and metastases. Studies of immunological parameters in mice treated with both IL-12 and IL-15 have shown enhanced NK activity (against YAC-1 cells) in the spleen and stimulation of both NK activity and specific anti-B16F10 cytotoxic effector cells in tumor-draining lymph nodes (LN). The strong antitumor effect of the IL-12 + IL-15 combination correlated with a high serum level of IFN-gamma in the treated mice. Moreover, increased expression of IL-15Ralpha was demonstrated in LN lymphocytes isolated from mice injected with IL-12. This result together with findings of other authors showing enhanced expression of IL-12 receptor by IL-15 [1] suggests that the augmentation of the antitumor effect during the course of IL-12/IL-15-based therapy could result from reciprocal upregulation of receptors by both cytokines and synergistic effects on IFN-gamma induction. PMID:10477391

  11. Augmented anti-tumor effect of dendritic cells genetically engineered by interleukin-12 plasmid DNA.

    PubMed

    Yoshida, Masataka; Jo, Jun-Ichiro; Tabata, Yasuhiko

    2010-01-01

    The objective of this study was to genetically engineer dendritic cells (DC) for biological activation and evaluate their anti-tumor activity in a tumor-bearing mouse model. Mouse DC were incubated on the surface of culture dishes which had been coated with the complexes of a cationized dextran and luciferase plasmid DNA complexes plus a cell adhesion protein, Pronectin, for gene transfection (reverse transfection). When compared with the conventional transfection where DC were transfected in the medium containing the complexes, the level of gene expression by the reverse method was significantly higher and the time period of gene expression was prolonged. Following the reverse transfection of DC by a plasmid DNA of mouse interleukin-12 (mIL-12) complexed with the cationized dextran, the mIL-12 protein was secreted at higher amounts for a longer time period. When injected intratumorally into mice carrying a mass of B16 tumor cells, the DC genetically activated showed significant anti-tumor activity. PMID:20338099

  12. Tamoxifen nanostructured lipid carriers: enhanced in vivo antitumor efficacy with reduced adverse drug effects.

    PubMed

    Shete, Harshad K; Selkar, Nilakash; Vanage, Geeta R; Patravale, Vandana B

    2014-07-01

    A novel approach of enhancing the Tamoxifen uptake via Intestinal Lymphatic System is executed by developing long chain lipid and oil based nanostructured lipid carrier system (Tmx-NLC). The aim was to achieve improved systemic bioavailability of Tamoxifen, prevent systemic and hepatotoxicity and enhance antitumor efficacy. Following the proof of concept achieved in cell culture experiments and in vivo pharmacokinetic and biodistribution study, the current work focuses on investigation of antitumor efficacy and treatment associated toxicity in murine mammary tumor mice model. The efficacy study demonstrated greater tumor suppression and 100% survival with 1.5 and 3 mg/kg Tmx-NLC compared to 3 mg/kg Tamoxifen suspension and Mamofen(®) (Khandelwal Pharmaceuticals, Mumbai, India). Tmx-NLC treatment for a month demonstrated improved systemic toxicity profile and no evidences of hepatotoxicity. Thus, developed Tmx-NLC could prove to be a promising delivery strategy to confer superior therapeutic efficacy and ability to address the biopharmaceutical and toxicity associated issues of drug. PMID:24704438

  13. Mannosylated protamine as a novel DNA vaccine carrier for effective induction of anti-tumor immune responses.

    PubMed

    Zeng, Zhaoyan; Dai, Shuang; Jiao, Yan; Jiang, Lei; Zhao, Yuekui; Wang, Bo; Zong, Li

    2016-06-15

    Gene immunotherapy has been developed as a promising strategy for inhibition of tumor growth. In the study, mannosylated protamine sulphate (MPS) was used as a novel DNA vaccine carrier to enhance transfection efficiency and anti-tumor immune responses. Anti-GRP DNA vaccine (pGRP) was selected as a model gene and condensed by MPS to form MPS/pGRP nanoparticles. The cellular uptake and transfection efficiency of MPS/pGRP nanoparticles in macrophages were evaluated. The effect of the nanoparticles in enhancing GRP-specific humoral immune response was then evaluated by nasal vaccination of nanoparticles in mice. The results demonstrated that both the cellular uptake and transfection efficiency of MPS nanoparticles in macrophages were higher than those of protamine nanoparticles. MPS/pGRP nanoparticles stimulated the production of higher titers (3.9×10(3)) of specific antibodies against GRP than those of protamine/pGRP nanoparticles (6.4×10(2), p<0.01) and intramuscular injection pGRP solution (2.5×10(3), p<0.05). Furthermore, the inhibitory rate in MPS/pGRP nanoparticles group (65.80%) was significantly higher than that in protamine/pGRP nanoparticles group (35.13%) and pGRP solution group (43.39%). Hence, it is evident that MPS is an efficient targeting gene delivery carrier which could improve in vitro transfection efficiency as well as anti-tumor immunotherapy in mice. PMID:27106528

  14. Direct and immune-mediated cytotoxicity of interleukin-21 contributes to antitumor effects in mantle cell lymphoma

    PubMed Central

    Bhatt, Shruti; Matthews, Julie; Parvin, Salma; Sarosiek, Kristopher A.; Zhao, Dekuang; Jiang, Xiaoyu; Isik, Elif; Letai, Anthony

    2015-01-01

    Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin lymphoma characterized by overexpression of cyclin D1 in 95% of patients. MCL patients experience frequent relapses resulting in median survival of 3 to 5 years, requiring more efficient therapeutic regimens. Interleukin (IL)-21, a member of the IL-2 cytokine family, possesses potent antitumor activity against a variety of cancers not expressing the IL-21 receptor (IL-21R) through immune activation. Previously, we established that IL-21 exerts direct cytotoxicity on IL-21R–expressing diffuse large B-cell lymphoma cells. Herein, we demonstrate that IL-21 possesses potent cytotoxicity against MCL cell lines and primary tumors. We identify that IL-21–induced direct cytotoxicity is mediated through signal transducer and activator of transcription 3-dependent cMyc upregulation, resulting in activation of Bax and inhibition of Bcl-2 and Bcl-XL. IL-21–mediated cMyc upregulation is only observed in IL-21–sensitive cells. Further, we demonstrate that IL-21 leads to natural killer (NK)-cell–dependent lysis of MCL cell lines that were resistant to direct cytotoxicity. In vivo treatment with IL-21 results in complete FC-muMCL1 tumor regression in syngeneic mice via NK- and T-cell–dependent mechanisms. Together, these data indicate that IL-21 has potent antitumor activity against MCL cells via direct cytotoxic and indirect, immune-mediated effects. PMID:26194763

  15. In vivo tumor targeting and anti-tumor effects of 5-fluororacil loaded, folic acid targeted quantum dot system.

    PubMed

    Bwatanglang, Ibrahim Birma; Mohammad, Faruq; Yusof, Nor Azah; Abdullah, Jaafar; Alitheen, Noorjahan Banu; Hussein, Mohd Zubir; Abu, Nadiah; Mohammed, Nurul Elyani; Nordin, Noraini; Zamberi, Nur Rizi; Yeap, Swee Keong

    2016-10-15

    In this study, we modulated the anti-cancer efficacy of 5-Fluorouracil (5-FU) using a carrier system with enhanced targeting efficacy towards folate receptors (FRs) expressing malignant tissues. The 5-FU drug was loaded onto Mn-ZnS quantum dots (QDs) encapsulated with chitosan (CS) biopolymer and conjugated with folic acid (FA) based on a simple wet chemical method. The formation of 5-FU drug loaded composite was confirmed using Fourier transform infrared spectroscopy (FTIR), thermo gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Furthermore, the in vivo biodistribution and tumor targeting specificity of the 5-FU@FACS-Mn:ZnS in the tumor-bearing mice was conducted based on the Zn(2+) tissue bioaccumulation using inductively coupled plasma (ICP) spectroscopy. In addition to the characterization, the in vitro release profile of 5-FU from the conjugates investigated under diffusion controlled method demonstrated a controlled release behaviour as compared against the release behaviour of free 5-FU drug. The as-synthesized 5-FU@FACS-Mn:ZnS nanoparticle (NP) systemically induced higher level of apoptosis in breast cancer cells in vitro as compared to cells treated with free 5-FU drug following both cell cycle and annexin assays, respectively. Also, the in vivo toxicity assessment of the 5-FU@FACS-Mn:ZnS NPs as compared to the control did not cause any significant increase in the activities of the liver and kidney function biomarkers, malondialdehyde (MDA) and nitric oxide (NO) levels. However, based on the FA-FRs chemistry, the 5-FU@FACS-Mn:ZnS NPs specifically accumulated in the tumor of the tumor-bearing mice and thus contributed to the smaller tumor size and less event of metastasis was observed in the lungs when compared to the tumor-bearing mice groups treated with the free 5-FU drug. In summary, the results demonstrated that the 5-FU@FACS-Mn:ZnS QDs exhibits selective anti-tumor effect in MDA-MB231 breast cancer cells in vitro and 4TI breast

  16. Effects of Lactobacillus salivarius, Lactobacillus reuteri, and Pediococcus acidilactici on the nematode Caenorhabditis elegans include possible antitumor activity.

    PubMed

    Fasseas, Michael K; Fasseas, Costas; Mountzouris, Konstantinos C; Syntichaki, Popi

    2013-03-01

    This study examined the effects of three lactic acid bacteria (LAB) strains on the nematode Caenorhabditis elegans. Lactobacillus salivarius, Lactobacillus reuteri, and Pediococcus acidilactici were found to inhibit the development and growth of the worm. Compared to Escherichia coli used as the control, L. reuteri and P. acidilactici reduced the lifespan of wild-type and short-lived daf-16 worms. On the contrary, L. salivarius extended the lifespan of daf-16 worms when used live, but reduced it as UV-killed bacteria. The three LAB induced the expression of genes involved in pathogen response and inhibited the growth of tumor-like germ cells, without affecting DAF16 localization or increasing corpse cells. Our results suggest the possible use of C. elegans as a model for studying the antitumor attributes of LAB. The negative effects of these LAB strains on the nematode also indicate their potential use against parasitic nematodes. PMID:22923095

  17. The Effect of MicroRNA-124 Overexpression on Anti-Tumor Drug Sensitivity

    PubMed Central

    Chen, Shiau-Mei; Chou, Wen-Cheng; Hu, Ling-Yueh; Hsiung, Chia-Ni; Chu, Hou-Wei; Huang, Yuan-Ling; Hsu, Huan-Ming; Yu, Jyh-Cherng; Shen, Chen-Yang

    2015-01-01

    MicroRNAs play critical roles in regulating various physiological processes, including growth and development. Previous studies have shown that microRNA-124 (miR-124) participates not only in regulation of early neurogenesis but also in suppression of tumorigenesis. In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs). We then examined which DNA repair–related genes, particularly the genes of SB repair, were regulated by miR-124. Two SB repair–related genes, encoding ATM interactor (ATMIN) and poly (ADP-ribose) polymerase 1 (PARP1), were strongly affected by miR-124 overexpression, by binding of miR-124 to the 3¢-untranslated region of their mRNAs. As a result, the capacity of cells to repair DNA SBs, such as those resulting from homologous recombination, was significantly reduced upon miR-124 overexpression. A particularly important therapeutic implication of this finding is that overexpression of miR-124 enhanced cell sensitivity to multiple DNA-damaging agents via ATMIN- and PARP1-mediated mechanisms. The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy. These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents. PMID:26115122

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

    PubMed Central

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

    2013-01-01

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

  19. Preparation of camptothecin-loaded targeting nanoparticles and their antitumor effects on hepatocellular carcinoma cell line H22.

    PubMed

    Yang, Anshu; Liu, Zhiyong; Yan, Bin; Zhou, Ming; Xiong, Xiangyuan

    2016-06-01

    Camptothecin (CPT) is an effective anticancer agent against various cancers but the clinical application is limited because of its poor water solubility, low bioavailability and severe toxic side effects. The aim of the present study was to evaluate the feasibility of using targeted NPs as a high-performance CPT delivery system that targets liver cancer cells through intravenous (i.v.) administration route. CPT was incorporated into biotin-F127-PLA or F127-PLA polymeric nanoparticles (NPs) by a dialysis method. The preparation of the targeting NPs was performed by conjugating biotin-F127-PLA NPs with anti-3A5 antibody. The antitumor effect of the CPT-loaded nanoparticles against H22 cells in vitro was determined using an MTT assay. Tissue distribution and tumor inhibition in vivo were also evaluated. Survivin mRNA expression was assessed by real-time polymerase chain reaction. Results showed that the targeted CPT NPs exhibited regular spherical shapes with a mean diameter of approximately 180 nm. In vitro release of the targeted CPT NPs exhibited an initial burst (40%) within 12 h, followed by a slow release. Cytotoxicity test against H22 cells indicated that the targeted CPT NPs exerted significant antitumor effects. Compared with free CPT and non-targeted CPT NPs, the targeted CPT NPs showed superior inhibition ratio against tumor in vivo, which may be associated with reduced survivin mRNA expression. The results suggested that the new targeted CPT NPs may be a promising injectable delivery system for cancer therapy. PMID:25148540

  20. Comparison of the Anti-tumor Effects of Selective Serotonin Reuptake Inhibitors as Well as Serotonin and Norepinephrine Reuptake Inhibitors in Human Hepatocellular Carcinoma Cells.

    PubMed

    Kuwahara, Jun; Yamada, Takaaki; Egashira, Nobuaki; Ueda, Mitsuyo; Zukeyama, Nina; Ushio, Soichiro; Masuda, Satohiro

    2015-01-01

    The anti-tumor effects of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) on several types of cancer cells have been reported. However, comparison of the anti-tumor effects of these drugs on human hepatocellular carcinoma (HepG2) cells has not been studied. We compared the anti-tumor effects of four SSRIs and two SNRIs on HepG2 cells. SSRIs and duloxetine dose-dependently decreased cell viability. Milnacipran had no effect on cell viability. The half-maximal inhibitory concentration was lower in the order of: sertraline, paroxetine, duloxetine, fluvoxamine, escitalopram, and milnacipran. Exposure to sertraline (2 µM) significantly increased caspase-3/7 activity. These results suggest that, of the agents tested here, sertraline had the highest sensitivity to HepG2 cells, and activation of the caspase pathway is involved in the anti-tumor effects of sertraline in HepG2 cells. PMID:26328498

  1. In vivo pharmacokinetics, biodistribution and anti-tumor effect of paclitaxel-loaded targeted chitosan-based polymeric micelle.

    PubMed

    Rezazadeh, Mahboubeh; Emami, Jaber; Hasanzadeh, Farshid; Sadeghi, Hojjat; Minaiyan, Mohsen; Mostafavi, Abolfazl; Rostami, Mahboubeh; Lavasanifar, Afsaneh

    2016-06-01

    A water-insoluble anti-tumor agent, paclitaxel (PTX) was successfully incorporated into novel-targeted polymeric micelles based on tocopherol succinate-chitosan-polyethylene glycol-folic acid (PTX/TS-CS-PEG-FA). The aim of the present study was to evaluate the pharmacokinetics, tissue distribution and efficacy of PTX/TS-CS-PEG-FA in comparison to Anzatax® in tumor bearing mice. The micellar formulation showed higher in vitro cytotoxicity against mice breast cancer cell line, 4T1, due to the folate receptor-mediated endocytosis. The IC50 value of PTX, a concentration at which 50% cells are killed, was 1.17 and 0.93 µM for Anzatax® and PTX/TS-CS-PEG-FA micelles, respectively. The in vivo anti-tumor efficacy of PTX/TS-CS-PEG-FA, as measured by reduction in tumor volume of 4T1 mouse breast cancer injected in Balb/c mice was significantly greater than that of Anzatax®. Pharmacokinetic study in tumor bearing mice revealed that the micellar formulation prolonged the systemic circulation time of PTX and the AUC of PTX/TS-CS-PEG-FA was obtained 0.83-fold lower than Anzatax®. Compared with Anzatax®, the Vd, T1/2ß and MRT of PTX/TS-CS-PEG-FA was increased by 2.76, 2.05 and 1.68-fold, respectively. As demonstrated by tissue distribution, the PTX/TS-CS-PEG-FA micelles increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Taken together, our evaluations show that PTX/TS-CS-PEG-FA micelle is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for intravenous administration of PTX. PMID:25188785

  2. Combination treatment with oncolytic Vaccinia virus and cyclophosphamide results in synergistic antitumor effects in human lung adenocarcinoma bearing mice

    PubMed Central

    2014-01-01

    Background The capacity of the recombinant Vaccinia virus GLV-1h68 as a single agent to efficiently treat different human or canine cancers has been shown in several preclinical studies. Currently, its human safety and efficacy are investigated in phase I/II clinical trials. In this study we set out to evaluate the oncolytic activity of GLV-1h68 in the human lung adenocarcinoma cell line PC14PE6-RFP in cell cultures and analyzed the antitumor potency of a combined treatment strategy consisting of GLV-1h68 and cyclophosphamide (CPA) in a mouse model of PC14PE6-RFP lung adenocarcinoma. Methods PC14PE6-RFP cells were treated in cell culture with GLV-1h68. Viral replication and cell survival were determined by plaque assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, respectively. Subcutaneously implanted PC14PE6-RFP xenografts were treated by systemic injection of GLV-1h68, CPA or a combination of both. Tumor growth and viral biodistribution were monitored and immune-related antigen profiling of tumor lysates was performed. Results GLV-1h68 efficiently infected, replicated in and lysed human PC14PE6-RFP cells in cell cultures. PC14PE6-RFP tumors were efficiently colonized by GLV-1h68 leading to much delayed tumor growth in PC14PE6-RFP tumor-bearing nude mice. Combination treatment with GLV-1h68 and CPA significantly improved the antitumor efficacy of GLV-1h68 and led to an increased viral distribution within the tumors. Pro-inflammatory cytokines and chemokines were distinctly elevated in tumors of GLV-1h68-treated mice. Factors expressed by endothelial cells or present in the blood were decreased after combination treatment. A complete loss in the hemorrhagic phenotype of the PC14PE6-RFP tumors and a decrease in the number of blood vessels after combination treatment could be observed. Conclusions CPA and GLV-1h68 have synergistic antitumor effects on PC14PE6-RFP xenografts. We strongly suppose that in the PC14PE6-RFP model the

  3. Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

    PubMed Central

    Lin, Yu-Ling; Chang, Kai-Fu; Huang, Xiao-Fan; Hung, Che-Lun; Chen, Shyh-Chang; Chao, Wan-Ru; Liao, Kuang-Wen; Tsai, Nu-Man

    2015-01-01

    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 that of free BP (~4.5- to 8.5-fold). This increased cytotoxic activity of BP/LPPC is attributable to its rapid transport across the cell membrane. In an animal study, a subcutaneously xenografted glioblastoma multiforme mouse that was treated with BP by intratumoral and intravenous administration showed inhibited tumor growth. The same dose of BP/LPPC was significantly more effective in terms of tumor inhibition. Conclusion LPPC encapsulation technology is able to protect BP’s structural stability and enhance its antitumor effects, thus providing a better tool for use in cancer therapy. PMID:26451107

  4. Augmenting the antitumor effect of TRAIL by SOCS3 with double-regulated replicating oncolytic adenovirus in hepatocellular carcinoma.

    PubMed

    Wei, Rui-Cheng; Cao, Xin; Gui, Jing-Hua; Zhou, Xiu-Mei; Zhong, Dan; Yan, Qiao-Lin; Huang, Wei-Dan; Qian, Qi-Jun; Zhao, Feng-Li; Liu, Xin-Yuan

    2011-09-01

    Aberrant JAK/STAT3 pathway has been reported to be related to hepatocellular carcinoma (HCC) in many cell lines. In this study, a double-regulated oncolytic adenovirus vector that can replicate and induce a cytopathic effect in alpha-fetoprotein (AFP)-positive HCC cell lines with p53 dysfunction was successfully constructed. Two therapeutic genes, suppressor of cytokine signaling 3 (SOCS3) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were chosen and incorporated into this vector system, respectively. The combined treatment of AFP-D55-SOCS3 and AFP-D55-TRAIL (2:3 ratio) exhibited potent antitumor activity in AFP-positive HCC cell lines compared with any other treatment both in vitro and in vivo. Specific replication and low progeny yield in AFP-positive HCC cell lines rendered these double-regulated oncolytic adenoviruses remarkably safe. Our data demonstrated that restoration of SOCS3, which inhibits the JAK/STAT3 pathway, by AFP-D55-SOCS3 not only could antagonize HCC therapeutic resistance to TRAIL and adenoviruses, but could also induce cell cycle arrest in HCC cell lines. SOCS3 could down-regulate Cyclin D1 and anti-apoptotic proteins such as XIAP, Survivin, Bcl-xL, and Mcl-1, which are responsible for the synergistic inhibitory effects of AFP-D55-SOCS3 and AFP-D55-TRAIL. Dual gene and double-regulated oncolytic adenoviruses may provide safety and excellent antitumor effects for liver cancer, which is the advantage of a cancer-targeting gene virotherapy strategy. PMID:21361790

  5. Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy

    PubMed Central

    Kwong, Brandon; Liu, Haipeng; Irvine, Darrell J.

    2011-01-01

    Immunostimulatory therapies that activate immune response pathways are of great interest for overcoming the immunosuppression present in advanced tumors. Agonistic anti-CD40 antibodies and CpG oligonucleotides have previously demonstrated potent, synergistic anti-tumor effects, but their clinical use even as monotherapies is hampered by dose-limiting inflammatory toxicity provoked upon systemic exposure. We hypothesized that by anchoring immuno-agonist compounds to lipid nanoparticles we could retain the bio-activity of therapeutics in the local tumor tissue and tumor-draining lymph node, but limit systemic exposure to these potent molecules. We prepared PEGylated liposomes bearing surface-conjugated anti-CD40 and CpG and assessed their therapeutic efficacy and systemic toxicity compared to soluble versions of the same immuno-agonists, injected intratumorally in the B16F10 murine model of melanoma. Anti-CD40/CpG-liposomes significantly inhibited tumor growth and induced a survival benefit similar to locally injected soluble anti-CD40+CpG. Biodistribution analyses following local delivery showed that the liposomal carriers successfully sequestered anti-CD40 and CpG in vivo, reducing leakage into systemic circulation while allowing draining to the tumor-proximal lymph node. Contrary to locally administered soluble immunotherapy, anti-CD40/CpG liposomes did not elicit significant increases in serum levels of ALT enzyme, systemic inflammatory cytokines, or overall weight loss, confirming that off-target inflammatory effects had been minimized. The development of a delivery strategy capable of inducing robust anti-tumor responses concurrent with minimal systemic side effects is crucial for the continued progress of potent immunotherapies toward widespread clinical translation. PMID:21514665

  6. Chidamide and 5-flurouracil show a synergistic antitumor effect on human colon cancer xenografts in nude mice.

    PubMed

    Liu, L; Qiu, S; Liu, Y; Liu, Z; Zheng, Y; Su, X; Chen, B; Chen, H

    2016-01-01

    Chidamide is a novel histone deacetylase (HDAC) inhibitor that increases the acetylation of histone H3 by inhibiting the activity of HDAC1 and HDAC2. We previously found that treatment of human colon cancer cells with chidamide led to cell apoptosis and cell cycle arrest at G0/1 phase in vitro. The present study extended the observations in vivo and explored the underlying molecular mechanisms. In nude mice bearing human colon cancer LoVo cell xenografts, chidamide alone or in combination with 5-flurouracil (5-Fu) reduced the expression of HDAC1 and HDAC2, accompanied with increased acetylation of histone H3. Chidamide alone inhibited the tumor growth and induce cell apoptosis in tumor-bearing mice. Combined treatment of chidamide with 5-Fu enhanced the anti-tumor activity of 5-Fu. Western blotting analysis showed that chidamide alone or in combination with 5-Fu upregulated the expressions of cleaved Caspase-3 and cleaved poly-ADP (adenosine diphosphate)-ribose polymerase (PARP). In addition, chidamide alone or in combination with 5-Fu increased the p53, phosphorylated-p53 (p-p53), p21 and γH2AX levels, but suppressed cyclin dependent kinase 4 (CDK4) expression in tumor cells. Chidamide alone or in combination with 5-Fu down regulated the expressions of p-AKT, p-mammalian target of rapamycin (mTOR), p-p70S6K, p-Raf, and p44/42 mitogen activated protein kinase (Erk1/2), indicating the blockage of these signaling pathways. The results demonstrated that chidamide alone or in combination with 5-Fu exerted anti-tumor activity in nude mice bearing human colon cancer LoVo cell xenografts, and several signaling pathways might be involved in the chidamide-induced tumor growth inhibition and tumor cell apoptosis. PMID:26774139

  7. Human soluble delta-like 1 homolog exerts antitumor effects in vitro and in vivo.

    PubMed

    Lee, Donghee; Yoon, Sun Ha; Lee, Hyun Ju; Jo, Ki Won; Park, Bum-Chan; Kim, In Seop; Choi, Yunseon; Lim, Jung Chae; Park, Young Woo

    2016-06-24

    Proteolysis of delta-like 1 homolog (DLK1), a cell-surface transmembrane protein, produces an active soluble form of DLK1 (sDLK1). Both membrane-bound DLK1 and sDLK1 modulate multiple developmental processes including adipogenesis, osteogenesis, chondrogenesis and myogenesis. However, cancer-related functions of DLK1 have not yet been established. We thus evaluated the roles of extracellular sDLK1, comprising six EGF-like domains and juxtamembrane regions, in human pancreatic cancer MIA PaCa-2 cells in vitro and in vivo. We observed that sDLK1 exerted antitumor effects not only in cancer cell migration and anchorage-independent cell growth but also in in vivo tumor growth. PMID:27191393

  8. Anti-tumor effect of Radix Paeoniae Rubra extract on mice bladder tumors using intravesical therapy

    PubMed Central

    Lin, Mei-Yi; Chiang, Su-Yin; Li, Yi-Zhen; Chen, Mei-Fang; Chen, Yueh-Sheng; Wu, Jin-Yi; Liu, Yi-Wen

    2016-01-01

    Radix Paeoniae Rubra (RPR) is the dried root of Paeonia lactiflora Pallas and Paeonia veitchii Lynch, and is a herbal medicine that is widely used in traditional Chinese medicine for the treatment of blood-heat and blood-stasis syndrome, similarly to Cortex Moutan. The present study identified the same three components in RPR and Cortex Moutan extracts. In addition, it has been reported that RPR has an anti-cancer effect. Bladder cancer is the seventh most common type of cancer worldwide. Due to the high recurrence rate, identifying novel drugs for bladder cancer therapy is essential. In the present study, RPR extract was evaluated as a bladder cancer therapy in vitro and in vivo. The present results revealed that RPR extract reduced the cell viability of bladder cancer cells with a half maximal inhibitory concentration of 1–3 mg/ml, and had an extremely low cytotoxic effect on normal urothelial cells. Additionally, RPR decreased certain cell cycle populations, predominantly cells in the G1 phase, and caused a clear sub-G increase. In a mouse orthotopic bladder tumor model, intravesical application of RPR extract decreased the bladder tumor size without altering the blood biochemical parameters of the mice. In summary, the present results demonstrate the anti-proliferative properties of RPR extract on bladder cancer cells, and its anti-bladder tumor effect in vivo. Compared to Cortex Moutan extract, RPR extract may provide a more effective alternative therapeutic strategy for the intravesical therapy of superficial bladder cancer. PMID:27446367

  9. Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine.

    PubMed

    Peng, Shiwen; Lyford-Pike, Sofia; Akpeng, Belinda; Wu, Annie; Hung, Chien-Fu; Hannaman, Drew; Saunders, John R; Wu, T-C; Pai, Sara I

    2013-01-01

    Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8(+) T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8(+) T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8(+) T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic antitumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8(+) T cells, which led to higher ratios of CD8(+)/Treg and CD8(+)/CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8(+) T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells. PMID:23011589

  10. Antitumor effects of methotrexate-monoclonal anti-prostatic acid phosphatase antibody conjugate on human prostate tumor

    SciTech Connect

    Deguchi, T.; Chu, T.M.; Leong, S.S.; Horoszewicz, J.S.; Lee, C.L.

    1986-03-01

    Methotrexate (MTX) was conjugated to an IgG/sub 1/ monoclonal antibody (MCA) specific for human prostatic acid phosphatase (PAP) by an active ester method, resulting in a molar ratio of MTX to IgG/sub 1/ of 14. MTX-MCA conjugate retained 94% of free antibody activity and preserved 90% of dihydrofolate reductase inhibitory activity of free MTX. MTX-MCA conjugate was shown to be accumulated in vitro by prostate tumor cells (LNCaP) 1.3 times higher than that of MTX conjugate to normal mouse IgG (NIgG) and 6.2 times higher than that of free MTX. Antitumor activity in vitro exhibited that MTX-MCA conjugate is more effective on inhibition (52%) of /sup 3/H-deoxyuridine incorporation into LNCaP cells than that of MTX-NIgG (39%), but both were less effective than free MTX (70%). The in vivo distribution of /sup 3/H-MTX-MCA conjugate in human prostate tumor xenograft (tumor: blood ratio 5.1) was higher than those of /sup 3/H-MTX-NIgG conjugate (1.1) and of free /sup 3/H-MTX (1.5). Anti-tumor activity in vivo demonstrated that MTX-MCA conjugate retarded the growth of xenografted human prostate tumor greatly and persistently, as compared with the control groups. These results suggested that MTX-monoclonal anti-PAP antibody conjugate represents a potential reagent for immunochemotherapy of human prostate tumor (NIH CA-34536, CA-15437 and ACS CH-269.

  11. Antitumor Effects of Synthetic 6,7-Annulated-4-substituted Indole Compounds in L1210 Leukemic Cells In Vitro

    PubMed Central

    PERCHELLET, JEAN-PIERRE H.; WATERS, ANDREW M.; PERCHELLET, ELISABETH M.; THORNTON, PAUL D.; BROWN, NEIL; HILL, DAVID; NEUENSWANDER, BEN; LUSHINGTON, GERALD H.; SANTINI, CONRAD; CHANDRASOMA, NALIN; BUSZEK, KEITH R.

    2014-01-01

    Background Because annulated indoles have almost no representation in the PubChem or MLSMR databases, an unprecedented class of an indole-based library was constructed, using the indole aryne methodology, and screened for antitumor activity. Sixty-six novel 6,7-annulated-4-substituted indole compounds were synthesized, using a strategic combination of 6,7-indolyne cycloaddition and cross-coupling reactions under both Suzuki-Miyaura and Buchwald-Hartwig conditions, and tested for their effectiveness against murine L1210 tumor cell proliferation in vitro. Materials and Methods Various markers of tumor cell metabolism, DNA degradation, mitotic disruption, cytokinesis and apoptosis were assayed in vitro to evaluate drug cytotoxicity. Results Most compounds inhibited the metabolic activity of leukemic cells in a time- and concentration-dependent manner but only 9 of them were sufficiently potent to inhibit L1210 tumor cell proliferation by 50% in the low-μM range after 2 (IC50: 4.5–20.4 μM) and 4 days (0.5–4.0 μM) in culture. However, the antiproliferative compounds that were the most effective at day 4 were not necessarily the most potent at day 2, suggesting different speeds of action. A 3-h treatment with antiproliferative annulated indole was sufficient to inhibit, in a concentration-dependent manner, the rate of DNA synthesis measured in L1210 cells over a 0.5-h period of pulse-labeling with 3H-thymidine. Four of the antiproliferative compounds had weak DNA-binding activities but one compound reduced the fluorescence of the ethidium bromide-DNA complex by up to 53%, suggesting that some annulated indoles might directly interact with double-stranded DNA to disrupt its integrity and prevent the dye from intercalating into DNA base pairs. However, all 9 antiproliferative compounds induced DNA cleavage at 24 h in L1210 cells, containing 3H-thymidine-prelabeled DNA, suggesting that these antitumor annulated indoles might trigger an apoptotic pathway of DNA

  12. The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells.

    PubMed

    Ujhelyi, Zoltán; Kalantari, Azin; Vecsernyés, Miklós; Róka, Eszter; Fenyvesi, Ferenc; Póka, Róbert; Kozma, Bence; Bácskay, Ildikó

    2015-01-01

    The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations. PMID:26197311

  13. A calicheamicin conjugate with a fully humanized anti-MUC1 antibody shows potent antitumor effects in breast and ovarian tumor xenografts.

    PubMed

    Hamann, Philip R; Hinman, Lois M; Beyer, Carl F; Lindh, Delores; Upeslacis, Janis; Shochat, Dan; Mountain, Andrew

    2005-01-01

    Murine CTM01 is an internalizing murine IgG(1) monoclonal antibody that recognizes the MUC1 antigen expressed on many solid tumors of epithelial origin. Calicheamicin conjugates of this antibody have previously been shown to be potent, selective antitumor agents in preclinical models. A conjugate has now been made with a genetically engineered human version of this antibody, hCTM01. The hCTM01 is an IgG(4) isotype, has an immunoaffinity approximately 30% higher than mCTM01 by competitive RIA, and is efficiently internalized into target cells. The hCTM01-NAc-gamma calicheamicin DM amide conjugate, referred to as CMB-401, shows targeted killing of MUC1-expressing cells in vitro and produces pronounced dose-related antitumor effects over an 8-fold dose range against a MUC1-expressing, ovarian xenograft tumor, OvCar-3. The specificity of CMB-401 was confirmed by comparing its antitumor effects with those of an isotype-matched nonspecific conjugate against the MX-1 breast carcinoma. CMB-401, given either ip or iv, was highly active in these models in single and multiple dose regimens and gave complete regressions at the highest doses examined with good overall therapeutic ratios. CMB-401 also gave good antitumor effects at similar doses with a cisplatin-resistant MUC1-expressing cell line. PMID:15769089

  14. Evaluating the microbicidal, antiparasitic and antitumor effects of CR-LAAO from Calloselasma rhodostoma venom.

    PubMed

    Costa, Tássia R; Menaldo, Danilo L; Prinholato da Silva, Cássio; Sorrechia, Rodrigo; de Albuquerque, Sérgio; Pietro, Rosemeire C L R; Ghisla, Sandro; Antunes, Lusânia M Greggi; Sampaio, Suely V

    2015-09-01

    CR-LAAO is an L-amino acid oxidase from Calloselasma rhodostoma snake venom that has been broadly studied regarding its structural and biochemical characteristics, however, few studies have investigated its pharmacological effects. The present study aimed at the evaluation of the biotechnological potential of CR-LAAO by determining its bactericidal, antifungal, leishmanicidal and trypanocidal activity, as well as its cytotoxicity on human tumor and non-tumor cell lines. After 24 h of preincubation, CR-LAAO showed bactericidal effects against both Staphylococcus aureus (MIC 0.78 μg/mL) and Escherichia coli (MIC 31.25 μg/mL) strains, inducing dismantle of bacterial cell walls. After 6 h of preincubation with Candida albicans, CR-LAAO was able to inhibit 80% of the yeast growth, and it also showed cytotoxic activity on Leishmania species and Trypanosoma cruzi. Additionally, CR-LAAO showed high cytotoxicity on HepG2 and HL-60 tumor cells (IC50 10.78 and 1.7 μg/mL), with lower effects on human mononuclear cells (PBMC). The cytotoxic effects of CR-LAAO were significantly inhibited in the presence of catalase, which suggests the involvement of hydrogen peroxide in its mechanisms of toxicity. Therefore, CR-LAAO showed promising pharmacological effects, and these results provide important information for the development of therapeutic strategies with directed action, such as more effective antimicrobial agents. PMID:26162245

  15. Fiber-mutant technique can augment gene transduction efficacy and anti-tumor effects against established murine melanoma by cytokine-gene therapy using adenovirus vectors.

    PubMed

    Okada, Yuka; Okada, Naoki; Nakagawa, Shinsaku; Mizuguchi, Hiroyuki; Kanehira, Makiko; Nishino, Naoko; Takahashi, Koichi; Mizuno, Nobuyasu; Hayakawa, Takao; Mayumi, Tadanori

    2002-03-01

    Melanoma cells are relatively resistant to adenovirus vector (Ad)-mediated gene transfer due to the low expression of Coxsackie-adenovirus receptor (CAR), which acts as a primitive Ad-receptor. Therefore, extremely high doses of Ad are required for effective gene therapy against melanoma. In the present study, we investigated whether fiber-mutant Ad containing the Arg-Gly-Asp (RGD) sequence in the fiber knob could promote gene delivery and anti-tumor effects in the murine B16 BL6 tumor model. B16 BL6 cells (in vitro) and tumors (in vivo) infected with RGD fiber-mutant Ad containing a tumor necrosis factor alpha gene (Ad-RGD-TNFalpha) produced more TNFalpha than those infected with conventional Ad-TNFalpha. In addition, Ad-RGD-TNFalpha required about one-tenth the dosage of Ad-TNFalpha for induction of equal therapeutic effects upon intratumoral injection into established B16 BL6 tumors. Furthermore, the combination of both TNFalpha- and interleukin 12-expressing RGD fiber-mutant Ads exhibited more effective tumor regression than the Ad expressing each alone. These results suggested that the fiber-mutant for altering Ad-tropism is a very potent technology for advancing gene therapy for melanoma. PMID:11809531

  16. Antitumor Effect of the Mannich Base(1,3-bis-((3-Hydroxynaphthalen-2-yl)phenylmethyl)urea) on Hepatocellular Carcinoma.

    PubMed

    Vedarethinam, Vadanasundari; Dhanaraj, Karthik; Ilavenil, Soundharrajan; Arasu, Mariadhas Valan; Choi, Ki Choon; Al-Dhabi, Naif Abdullah; Srisesharam, Srigopalram; Lee, Kyung Dong; Kim, Da Hye; Dhanapal, Tamilvenvendan; Sivanesan, Ravikumar; Choi, Han Sung; Kim, Young Ock

    2016-01-01

    The present study was designed to evaluate the antitumor effects of the synthetic Mannich base 1,3-bis-((3-hydroxynaphthalen-2-yl)phenylmethyl)urea (1,3-BPMU) against HEP-G2 hepatoma cells and diethylnitrosamine (DEN)-induced hepatocarcinoma (HCC) in albino rats. In vitro analysis results revealed that 1,3-BPMU showed significant cytotoxicity and cell growth inhibition in HEP-G2 hepatoma cells in a concentration-dependent manner. Furthermore, flow cytometry results indicated that 1,3-BPMU enhanced early and late apoptosis. The maximum apoptosis was exhibited at a concentration of 100 μg/mL of 1,3-BPMU. In in vivo analysis, DEN treatment increased the content of nucleic acids, LPO and the activities of AST, ALT, ALP, LDH, γGT and 5'NT with decreased antioxidant activity as compared to control rats. However, 1,3-BPMU treatment to DEN-induced rats decreased the content of nucleic acids, LPO and the activities of AST, ALT, ALP, LDH, γGT and 5'NT and increased the activities of SOD, CAT, GPx, GST and GR (p < 0.05). Furthermore, 1,3-BPMU enhanced the apoptosis via upregulation of caspase-3 and caspase-9 and the downregulation of Bcl-2 and Bcl-XL mRNA expression as compared to DEN-induced rats. Histological and ultrastructural investigation showed that 1,3-BPMU treatment renovated the internal architecture of the liver in DEN-induced rats. In this study, the molecular and pre-clinical results obtained by treatment of DEN-induced rats with 1,3-BPMU suggested that 1,3-BPMU might be considered as an antitumor compound in the future. PMID:27187346

  17. Metabolomics study on the antitumor effect of marine natural compound flexibilide in HCT-116 colon cancer cell line.

    PubMed

    Gao, Dan; Wang, Yini; Xie, Weiyi; Yang, Ti; Jiang, Yuyang; Guo, Yuewei; Guan, Jin; Liu, Hongxia

    2016-03-01

    A marine natural compound flexibilide isolated from the soft coral Sinularia flexibilis has been found to have antitumor activity. However, its pharmacological mechanism on tumor cells has not been studied. Herein, an ultra-performance liquid chromatography coupled to quadrupole time of-flight mass spectrometry (UPLC/Q-TOF MS) based metabolomics approach was established to investigate the antitumor effect of flexibilide on HCT-116 cells and its action mechanism. Q-TOF MS and MS/MS were used to identify significantly different metabolites. Comparing flexibilide-treated HCT-116 cells group with control group (dimethyl sulfoxide), 19 distinct metabolites involved in sphingolipid metabolism, alanine, aspartate and glutamate metabolism, d-glutamine and d-glutamate metabolism, glycerophospholipid metabolism, pyrimidine metabolism and others were discovered and identified. The significant decrease of phosphatidylcholine (PC) and phosphocholine levels and increase of lysophosphatidylcholine (LysoPC) levels in flexibilide treated cells suggested down-regulation of PC biosynthesis pathway. The decrease of sphingolipids reflected the lesions of cell membrane, and the up-regulation of sphingosine-1-phosphate indicated that TRAF2 and caspase-8 were likely to be activated by flexibilide and further caused cell apoptosis. Furthermore, TCA cycle was deemed to be down-regulated after flexibilide treatment, which might lead to an unsustainable of mitochondrial transmembrane potential MMP). The further measured descreased MMP with the increasing concentration of flexibilide treatment indiciated the dysfunction of mitochondrial which might finally lead to apoptosis. The UPLC/Q-TOF MS based metabolomics approach provides new insights into the mechanistic studies of flexibilide on tumor cells, which benefit its further improvement and application. PMID:26859520

  18. In vitro and in vivo antitumor effects of folate-targeted ursolic acid stealth liposome.

    PubMed

    Yang, Guang; Yang, Tan; Zhang, Wendian; Lu, Miao; Ma, Xiang; Xiang, Guangya

    2014-03-12

    The antitumor efficacy of ursolic acid (UA) was limited by poor hydrophilicity and low bioavailability. To overcome this issue, UA was encapsulated in liposomes modified with folate conjugates for better solubility and bioavailability. This novel agent was prepared by a thin-film dispersion method and characterized by mean diameter, zeta potential, and entrapment efficiency (160.1 nm, -21.2 mV, and 88.9%, respectively). In vitro, cellular uptake efficiency, cytotoxicity, apoptosis, and cell cycle analyses were performed to show that folate-receptor (FR) positive cells endocytose more FR-targeted liposome (FTL-UA) than nontargeted PEGylated liposome (PL-UA) and that FTL-UA induced more cytotoxicity and higher apoptosis than PL-UA. Pharmacokinetic assessments showed advantages of systemic bioavailability of FTL-UA (AUC = 218.32 mg/L·h, t1/2 = 7.61 h) over free UA (AUC = 36.88 mg/L·h, t1/2 = 0.78 h). In vivo, FTL-UA showed significantly higher human epidermoid carcinoma (KB) inhibition in Balb/c nu/nu mice compared to PL-UA or free UA. The results indicate the great potential of FTL-UA against KB tumor. PMID:24528163

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

    PubMed Central

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

    2014-01-01

    Topical 5-fluorouracil (5-FU) is approved for the treatment of superficial basal cell carcinoma and actinic keratosis. However, 5-FU suffers from poor skin permeation. Microneedles have been successfully applied to improve the skin permeability of small and large molecules, and even nanoparticles, by creating micron-sized pores in the stratum corneum layer of the skin. In this report, the feasibility of using microneedles to increase the skin permeability of 5-FU was tested. Using full thickness mouse skin mounted on Franz diffusion apparatus, it was shown that the flux of 5-FU through the skin was increased by up to 4.5-fold when the skin was pretreated with microneedles (500 μm in length, 50 μm in base diameter). In a mouse model with B16-F10 mouse melanoma cells implanted in the subcutaneous space, the antitumor activity of a commercially available 5-FU topical cream (5%) was significantly enhanced when the cream was applied on a skin area that was pretreated with microneedles, as compared to when the cream was simply applied on a skin area, underneath which the tumor cells were implanted, and without pretreatment of the skin with microneedles. Fluorouracil is not approved for melanoma therapy, but the clinical efficacy of topical 5-FU against tumors such as basal cell carcinoma may be improved by integrating microneedle technology into the therapy. PMID:25313350

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

    PubMed Central

    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

  1. Adenovirus-mediated FIR demonstrated TP53-independent cell-killing effect and enhanced antitumor activity of carbon-ion beams.

    PubMed

    Kano, M; Matsushita, K; Rahmutulla, B; Yamada, S; Shimada, H; Kubo, S; Hiwasa, T; Matsubara, H; Nomura, F

    2016-01-01

    Combination therapy of carbon-ion beam with the far upstream element-binding protein (FBP)-interacting repressor, FIR, which interferes with DNA damage repair proteins, was proposed as an approach for esophageal cancer treatment with low side effects regardless of TP53 status. In vivo therapeutic antitumor efficacy of replication-defective adenovirus (E1 and E3 deleted adenovirus serotype 5) encoding human FIR cDNA (Ad-FIR) was demonstrated in the tumor xenograft model of human esophageal squamous cancer cells, TE-2. Bleomycin (BLM) is an anticancer agent that introduces DNA breaks. The authors reported that Ad-FIR involved in the BLM-induced DNA damage repair response and thus applicable for other DNA damaging agents. To examine the effect of Ad-FIR on DNA damage repair, BLM, X-ray and carbon-ion irradiation were used as DNA damaging agents. The biological effects of high linear energy transfer (LET) radiotherapy used with carbon-ion irradiation are more expansive than low-LET conventional radiotherapy, such as X-rays or γ rays. High LET radiotherapy is suitable for the local control of tumors because of its high relative biological effectiveness. Ad-FIR enhanced BLM-induced DNA damage indicated by γH2AX in vitro. BLM treatment increased endogenous nuclear FIR expression in TE-2 cells, and P27Kip1 expression was suppressed by TP53 siRNA and BLM treatment. Further, Ad-FIRΔexon2, a dominant-negative form of FIR that lacks exon2 transcriptional repression domain, decreased Ku86 expression. The combination of Ad-FIR and BLM in TP53 siRNA increased DNA damage. Additionally, Ad-FIR showed synergistic cell toxicity with X-ray in vitro and significantly increased the antitumor efficacy of carbon-ion irradiation in the xenograft mouse model of TE-2 cells (P=0.03, Mann-Whitney's U-test) and was synergistic with the sensitization enhancement ratio (SER) value of 1.15. Therefore, Ad-FIR increased the cell-killing activity of the carbon-ion beam that avoids late

  2. In Vitro and in Vivo Antitumoral Effects of Combinations of Polyphenols, or Polyphenols and Anticancer Drugs: Perspectives on Cancer Treatment

    PubMed Central

    Fantini, Massimo; Benvenuto, Monica; Masuelli, Laura; Frajese, Giovanni Vanni; Tresoldi, Ilaria; Modesti, Andrea; Bei, Roberto

    2015-01-01

    Carcinogenesis is a multistep process triggered by genetic alterations that activate different signal transduction pathways and cause the progressive transformation of a normal cell into a cancer cell. Polyphenols, compounds ubiquitously expressed in plants, have anti-inflammatory, antimicrobial, antiviral, anticancer, and immunomodulatory properties, all of which are beneficial to human health. Due to their ability to modulate the activity of multiple targets involved in carcinogenesis through direct interaction or modulation of gene expression, polyphenols can be employed to inhibit the growth of cancer cells. However, the main problem related to the use of polyphenols as anticancer agents is their poor bioavailability, which might hinder the in vivo effects of the single compound. In fact, polyphenols have a poor absorption and biodistribution, but also a fast metabolism and excretion in the human body. The poor bioavailability of a polyphenol will affect the effective dose delivered to cancer cells. One way to counteract this drawback could be combination treatment with different polyphenols or with polyphenols and other anti-cancer drugs, which can lead to more effective antitumor effects than treatment using only one of the compounds. This report reviews current knowledge on the anticancer effects of combinations of polyphenols or polyphenols and anticancer drugs, with a focus on their ability to modulate multiple signaling transduction pathways involved in cancer. PMID:25918934

  3. Effects of nanoparticle size on antitumor activity of 10-hydroxycamptothecin-conjugated gold nanoparticles: in vitro and in vivo studies

    PubMed Central

    Bao, Hanmei; Zhang, Qing; Xu, Hui; Yan, Zhao

    2016-01-01

    Gold nanoparticles (AuNPs) have emerged as a promising anticancer drug delivery scaffold. However, some controversial points still require further investigation before clinical use. A complete understanding of how animal cells interact with drug-conjugated AuNPs of well-defined sizes remains poorly understood. In this study, we prepared a series of 10-hydroxycamptothecin (HCPT)-AuNP conjugates of different sizes and compared their cytotoxic effect in vitro and antitumor effect in vivo. Transmission electron micrographs showed that the NPs had a round, regular shape with a mean diameter of ~10, 25, and 50 nm. An in vitro drug release study showed that HCPT was continuously released for 120 hours. HCPT-AuNPs showed greater cytotoxic effects on the MDA-MB-231 cell line compared with an equal dose of free HCPT. Notably, HCPT-AuNPs of an average diameter of 50 nm (HCPT-AuNPs-50) had the greatest effect. Furthermore, administration of HCPT-AuNPs-50 showed the most tumor-suppressing activity against MDA-MB-231 tumor in mice among all treatment groups. The results indicate that AuNPs not only act as a carrier but also play an active role in mediating biological effects. This work gives important insights into the design of nanoscale delivery and therapeutic systems. PMID:27022260

  4. Effects of nanoparticle size on antitumor activity of 10-hydroxycamptothecin-conjugated gold nanoparticles: in vitro and in vivo studies.

    PubMed

    Bao, Hanmei; Zhang, Qing; Xu, Hui; Yan, Zhao

    2016-01-01

    Gold nanoparticles (AuNPs) have emerged as a promising anticancer drug delivery scaffold. However, some controversial points still require further investigation before clinical use. A complete understanding of how animal cells interact with drug-conjugated AuNPs of well-defined sizes remains poorly understood. In this study, we prepared a series of 10-hydroxycamptothecin (HCPT)-AuNP conjugates of different sizes and compared their cytotoxic effect in vitro and antitumor effect in vivo. Transmission electron micrographs showed that the NPs had a round, regular shape with a mean diameter of ~10, 25, and 50 nm. An in vitro drug release study showed that HCPT was continuously released for 120 hours. HCPT-AuNPs showed greater cytotoxic effects on the MDA-MB-231 cell line compared with an equal dose of free HCPT. Notably, HCPT-AuNPs of an average diameter of 50 nm (HCPT-AuNPs-50) had the greatest effect. Furthermore, administration of HCPT-AuNPs-50 showed the most tumor-suppressing activity against MDA-MB-231 tumor in mice among all treatment groups. The results indicate that AuNPs not only act as a carrier but also play an active role in mediating biological effects. This work gives important insights into the design of nanoscale delivery and therapeutic systems. PMID:27022260

  5. Preparation and antitumor effects of glaucocalyxin A-γ-cyclodextrin clathrate

    PubMed Central

    Zhang, Chong; Qu, Yan; Jia, Yan-Long; Shang, Xiao-Jun; Bai, Su-Ping

    2015-01-01

    Objective: To improve the water solubility of glaucocalyxin A (GLA) by the preparation of glaucocalyxin A γ-cyclodextrin clathrate (GLA-γ-CD) and to investigate the inhibitory effect of GLA-γ-CD on tumor growth in S180 cell xenografts. Materials and methods: GLA-γ-CD, γ-cyclodextrin (γ-CD) and GLA were combined at a mass ratio of 1:1, dissolved in 60°C water by stirring. GLA completely entrapped by the γ-CD was verified by differential thermal analysis, the GLA content was determined. Phase solubility, solubility, and in vitro dissolution rate experiments were performed. The S180 xenograft mouse model was used to observe the tumor inhibitory effects of GLA-γ-CD and GLA, and the TUNEL assay was used to detect differences in their rates of tumor cell apoptosis induction. Results: After combination with γ-CD, the solubility of GLA-γ-CD was 21.78-fold greater than that of GLA. The in vitro dissolution rate of GLA-γ-CD was significantly greater than that of GLA, and reached more than 90% in 20 min. Furthermore, GLA-γ-CD was more effective than GLA as an inhibitor of S180 tumor cells; the inhibitory rate of the high-dose group reached 57.26%, which was 54.11% greater than the inhibitory rate of the GLA group at the same dose. In addition, GLA-γ-CD induced tumor cell apoptosis more effectively than did GLA. Conclusion: The water solubility of GLA significantly increased in combination with γ-CD resulting in the production of GLA-γ-CD. Furthermore, GLA-γ-CD was more effective than GLA as an inducer of S180 tumor cell apoptosis and an inhibitor of tumor growth. PMID:26550426

  6. Antitumor effect of sinoporphyrin sodium-mediated photodynamic therapy on human esophageal cancer Eca-109 cells.

    PubMed

    Hu, Jianmin; Wang, Xiaobing; Liu, Quanhong; Zhang, Kun; Xiong, Wenli; Xu, Chuanshan; Wang, Pan; Leung, Albert Wingnang

    2014-01-01

    The aim of this study was to evaluate the photodynamic effect of Sinoporphyrin sodium (DVDMS). In this study, Eca-109 cells were treated with DVDMS (5 μg mL(-1)) and subjected to photodynamic therapy (PDT). The uptake and subcellular localization of DVDMS were monitored by flow cytometry and confocal microscopy. The phototoxicity of DVDMS was studied by MTT assay. The morphological changes were observed by scanning electron microscopy (SEM). DNA damage, reactive oxygen species (ROS) generation and mitochondria membrane potential (MMP) changes were analyzed by flow cytometry. Studies demonstrated maximal uptake of DVDMS occurred within 3 h, with a mitochondrial subcellular localization. MTT assays displayed that DVDMS could be effectively activated by light and the phototoxicity was much higher than photofrin under the same conditions. In addition, SEM observation indicated that cells were seriously damaged after PDT treatment. Furthermore, activation of DVDMS resulted in significant increases in ROS production. The generated ROS played an important role in the phototoxicity of DVDMS. DVDMS-mediated PDT (DVDMS-PDT) also induced DNA damage and MMP loss. It is demonstrated that DVDMS-mediated PDT is an effective approach on cell proliferation inhibition of Eca-109 cells. PMID:25142812

  7. The antitumor effects of geraniol: Modulation of cancer hallmark pathways (Review).

    PubMed

    Cho, Minsoo; So, Insuk; Chun, Jung Nyeo; Jeon, Ju-Hong

    2016-05-01

    Geraniol is a dietary monoterpene alcohol that is found in the essential oils of aromatic plants. To date, experimental evidence supports the therapeutic or preventive effects of geraniol on different types of cancer, such as breast, lung, colon, prostate, pancreatic, and hepatic cancer, and has revealed the mechanistic basis for its pharmacological actions. In addition, geraniol sensitizes tumor cells to commonly used chemotherapy agents. Geraniol controls a variety of signaling molecules and pathways that represent tumor hallmarks; these actions of geraniol constrain the ability of tumor cells to acquire adaptive resistance against anticancer drugs. In the present review, we emphasize that geraniol is a promising compound or chemical moiety for the development of a safe and effective multi-targeted anticancer agent. We summarize the current knowledge of the effects of geraniol on target molecules and pathways in cancer cells. Our review provides novel insight into the challenges and perspectives with regard to geraniol research and to its application in future clinical investigation. PMID:26983575

  8. The antitumor effects of geraniol: Modulation of cancer hallmark pathways (Review)

    PubMed Central

    CHO, MINSOO; SO, INSUK; CHUN, JUNG NYEO; JEON, JU-HONG

    2016-01-01

    Geraniol is a dietary monoterpene alcohol that is found in the essential oils of aromatic plants. To date, experimental evidence supports the therapeutic or preventive effects of geraniol on different types of cancer, such as breast, lung, colon, prostate, pancreatic, and hepatic cancer, and has revealed the mechanistic basis for its pharmacological actions. In addition, geraniol sensitizes tumor cells to commonly used chemotherapy agents. Geraniol controls a variety of signaling molecules and pathways that represent tumor hallmarks; these actions of geraniol constrain the ability of tumor cells to acquire adaptive resistance against anticancer drugs. In the present review, we emphasize that geraniol is a promising compound or chemical moiety for the development of a safe and effective multi-targeted anticancer agent. We summarize the current knowledge of the effects of geraniol on target molecules and pathways in cancer cells. Our review provides novel insight into the challenges and perspectives with regard to geraniol research and to its application in future clinical investigation. PMID:26983575

  9. Antioxidant and antitumor activities in vitro of polysaccharides from E. sipunculoides.

    PubMed

    He, Rongjun; Zhao, Yuejun; Zhao, Ruina; Sun, Peilong

    2015-01-01

    Three polysaccharides (SAP30, SAP60 and SAP80) were separated from the body of Edwardsia sipunculoides by tissue homogenate and papain hydrolysis. Total soluble sugar contents, monosaccharide compositions, antioxidant and antitumor activities in vitro of those polysaccharides were investigated, respectively. Results showed that the total soluble sugar contents of SAP composed of Man, GlcN, Rha, GalN, GlcUA, Glc, Gal, Xyl and Fuc were more than 85% estimated by the phenol-sulfuric acid assay. In addition, SAP had potential antioxidant and antitumor activities. SAP30 has the most significant antitumor effect. This study suggested that SAP could be a potential natural antioxidants and antitumor agents. PMID:25834926

  10. Hydrogel-PLGA delivery system prolongs 2-methoxyestradiol-mediated anti-tumor effects in osteosarcoma cells.

    PubMed

    Maran, Avudaiappan; Dadsetan, Mahrokh; Buenz, Colleen M; Shogren, Kristen L; Lu, Lichun; Yaszemski, Michael J

    2013-09-01

    Osteosarcoma is a bone tumor that affects children and young adults. 2-Methoxyestradiol (2-ME), a naturally occurring estrogen metabolite, kills osteosarcoma cells, but does not affect normal osteoblasts. In order to effectively target osteosarcoma and improve the therapeutic index of the drug 2-ME, we have encapsulated 2-ME in a composite of oligo-(polyethylene glycol) fumarate (OPF) hydrogel and poly (lactic-co-glycolic acid) (PLGA) microspheres and investigated the effect of polymer composition on 2-ME release kinetics and osteosarcoma cell survival. The in vitro study shows that 2-ME can be released in a controlled manner over 21-days. The initial burst releases observed on day 1 were 50% and 32% for OPF and OPF/PLGA composites, respectively. The extended release kinetics show that 100% of the encapsulated 2-ME is released by day 12 from OPF, whereas the OPF/PLGA composites showed a release of 85% on day 21. 2-ME released from the polymers was biologically active and blocked osteosarcoma cell proliferation in vitro. Also, comparison of 2-ME delivery in osteosarcoma cells in culture, shows that direct treatment has no effect after 3 days, whereas polymer-mediated delivery produces anti-tumor effects that could be sustained for 21 days. These findings show that the OPF and PLGA polymeric system may prove to be useful in controlled and sustained delivery of 2-ME and could be further explored in the treatment of osteosarcoma. PMID:23355512

  11. Size-dependent effects of gold nanoparticles uptake on maturation and antitumor functions of human dendritic cells in vitro.

    PubMed

    Tomić, Sergej; Ðokić, Jelena; Vasilijić, Saša; Ogrinc, Nina; Rudolf, Rebeka; Pelicon, Primož; Vučević, Dragana; Milosavljević, Petar; Janković, Srđa; Anžel, Ivan; Rajković, Jelena; Rupnik, Marjan Slak; Friedrich, Bernd; Colić, Miodrag

    2014-01-01

    Gold nanoparticles (GNPs) are claimed as outstanding biomedical tools for cancer diagnostics and photo-thermal therapy, but without enough evidence on their potentially adverse immunological effects. Using a model of human dendritic cells (DCs), we showed that 10 nm- and 50 nm-sized GNPs (GNP10 and GNP50, respectively) were internalized predominantly via dynamin-dependent mechanisms, and they both impaired LPS-induced maturation and allostimulatory capacity of DCs, although the effect of GNP10 was more prominent. However, GNP10 inhibited LPS-induced production of IL-12p70 by DCs, and potentiated their Th2 polarization capacity, while GNP50 promoted Th17 polarization. Such effects of GNP10 correlated with a stronger inhibition of LPS-induced changes in Ca2+ oscillations, their higher number per DC, and more frequent extra-endosomal localization, as judged by live-cell imaging, proton, and electron microscopy, respectively. Even when released from heat-killed necrotic HEp-2 cells, GNP10 inhibited the necrotic tumor cell-induced maturation and functions of DCs, potentiated their Th2/Th17 polarization capacity, and thus, impaired the DCs' capacity to induce T cell-mediated anti-tumor cytotoxicity in vitro. Therefore, GNP10 could potentially induce more adverse DC-mediated immunological effects, compared to GNP50. PMID:24802102

  12. The anti-tumor effect of Euchema serra agglutinin on colon cancer cells in vitro and in vivo.

    PubMed

    Fukuda, Yuki; Sugahara, Takuya; Ueno, Masashi; Fukuta, Yusuke; Ochi, Yukari; Akiyama, Koichi; Miyazaki, Tatsuhiko; Masuda, Seizo; Kawakubo, Akihiro; Kato, Keiichi

    2006-09-01

    Eucheuma serra agglutinin (ESA) is a lectin derived from a marine red alga E. serra and binds specifically to mannose-rich sugar chains. Previous reports have indicated that ESA associates with several cancer cells via sugar chains on cell surfaces and induces apoptotic cell death. In this study, we investigated the effect of ESA on Colon26 mouse colon adenocarcinoma cells both in vitro and in vivo. ESA induced cell death against Colon26 cells in vitro, and the expression of caspase-3 and the translocation of phosphatidylserine in ESA-treated Colon26 cells suggested that this cell death was induced through apoptosis. An intravenous injection of ESA significantly inhibited the growth of Colon26 tumors in BALB/c mice; moreover, DNA fragmentation was detected in tumor cells following ESA treatment. These results indicated that ESA is effective as an anti-cancer drug not only in vitro but also in vivo. The side-effects of ESA were not considered to be serious because the decrease in body weight of the mice injected with it was negligible. These observations suggest that ESA has the potential to be an effective anti-tumor drug. PMID:16940804

  13. An aqueous extract of Limoniastrum guyonianum gall induces anti-tumor effects in melanoma-injected mice via modulation of the immune response.

    PubMed

    Krifa, Mounira; Skandrani, Ines; Pizzi, Antonio; Nasr, Nouha; Ghedira, Zied; Mustapha, Nadia; Ghedira, Kamel; Chekir-Ghedira, Leila

    2014-07-01

    The objectives of this study were to evaluate the in vitro and in vivo anti-tumor potential of the aqueous gall extract (G extract) from Limoniastrum guyonianum and to elucidate its immunological mechanisms, in part, by assessing its effects on the growth of transplanted tumors and the immune response in these tumor-bearing mice. Here, mice were inoculated with B16F10 mouse tumor cells and then treated intraperitoneally with G extract at 25 or 50 mg extract/kg BW for 7, 14, or 21 days. At each timepoint, effects of the extract on the tumor growth, splenocytes proliferation, NK cell activity, and CTL activity among splenocytes isolated from the mice were measured. G extract-induced tumor growth inhibition was associated with characteristic apoptotic changes in the tumor cells, like nuclear condensation. In addition, the extract inhibited melanin synthesis and tyrosinase activity among melanoma cells in a concentration-related manner. G extract did not only significantly inhibit the growth of the transplantable tumor, but also remarkably increased splenocytes proliferation and both NK and CTL activities in tumor-bearing mice. The extract was also seen to have promoted lysosomal activity of host macrophages and gave rise to enhanced cellular anti-oxidant activity in several cell types in mice. PMID:24705020

  14. Cytokines and antitumor immunity.

    PubMed

    Müller, Ludmila; Pawelec, Graham

    2003-06-01

    Currently, the notion of immunosurveillance against tumors is enjoying something of a renaissance. Even if we still refuse to accept that tumors arising in the normal host are unable to trigger an immune response because of the lack of initiation ("danger") signals, there is no doubt that the immune system can be manipulated experimentally and by implication therapeutically to exert anti-tumor effects. For this activity to be successful, the appropriate cytokine milieu has to be provided, making cytokine manipulation central to immunotherapy. On the other hand, the major hurdle currently preventing successful immunotherapy is the ability of tumors to evolve resistant variants under the pressure of immune selection. Here, too, the cytokine milieu plays an essential role. The purpose of this brief review is to consider the current status of the application of cytokines in facilitating antitumor immunity, as well their role in inhibiting responses to tumors. Clearly, encouraging the former but preventing the latter will be the key to the effective clinical application of cancer immunotherapy. PMID:12779349

  15. OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models.

    PubMed

    Berenguer-Daizé, Caroline; Astorgues-Xerri, Lucile; Odore, Elodie; Cayol, Mylène; Cvitkovic, Esteban; Noel, Kay; Bekradda, Mohamed; MacKenzie, Sarah; Rezai, Keyvan; Lokiec, François; Riveiro, Maria E; Ouafik, L'Houcine

    2016-11-01

    Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines. OTX015 displayed higher antiproliferative effects compared to its analog JQ1, with GI50 values of approximately 0.2 µM. In addition, C-MYC and CDKN1A mRNA levels increased transiently after 4 h-exposure to OTX015, while BRD2, SESN3, HEXIM-1, HIST2H2BE, and HIST1H2BK were rapidly upregulated and sustained after 24 h. Studies in three additional GBM cell lines supported the antiproliferative effects of OTX015. In U87MG cells, OTX015 showed synergistic to additive activity when administered concomitant to or before SN38, temozolomide or everolimus. Single agent oral OTX015 significantly increased survival in mice bearing orthotopic or heterotopic U87MG xenografts. OTX015 combined simultaneously with temozolomide improved mice survival over either single agent. The passage of OTX015 across the blood-brain barrier was demonstrated with OTX015 tumor levels 7 to 15-fold higher than in normal tissues, along with preferential binding of OTX015 to tumor tissue. The significant antitumor effects seen with OTX015 in GBM xenograft models highlight its therapeutic potential in GBM patients, alone or combined with conventional chemotherapies. PMID:27388964

  16. Effects of psoralens as anti-tumoral agents in breast cancer cells

    PubMed Central

    Panno, Maria Luisa; Giordano, Francesca

    2014-01-01

    This review examines the biological properties of coumarins, widely distributed at the highest levels in the fruit, followed by the roots, stems and leaves, by considering their beneficial effects in the prevention of some diseases and as anti-cancer agents. These compounds are well known photosensitizing drugs which have been used as pharmaceuticals for a broad number of therapeutic applications requiring cell division inhibitors. Despite this, even in the absence of ultraviolet rays they are active. The current paper mainly focuses on the effects of psoralens on human breast cancer as they are able to influence many aspects of cell behavior, such as cell growth, survival and apoptosis. In addition, analytical and pharmacological data have demonstrated that psoralens antagonize some metabolizing enzymes, affect estrogen receptor stability and counteract cell invasiveness as well as cancer drug resistance. The scientific findings summarized highlight the pleiotropic functions of phytochemical drugs, given that recently their target signals and how these are modified in the cells have been identified. The encouraging results in this field suggest that multiple modulating strategies based on coumarin drugs in combination with canonical chemotherapeutic agents or radiotherapy could be a useful approach to address the treatment of many types of cancer. PMID:25114850

  17. Immune-mediated antitumor effect by type 2 diabetes drug, metformin

    PubMed Central

    Eikawa, Shingo; Nishida, Mikako; Mizukami, Shusaku; Yamazaki, Chihiro; Nakayama, Eiichi; Udono, Heiichiro

    2015-01-01

    Metformin, a prescribed drug for type 2 diabetes, has been reported to have anti-cancer effects; however, the underlying mechanism is poorly understood. Here we show that this mechanism may be immune-mediated. Metformin enabled normal but not T-cell–deficient SCID mice to reject solid tumors. In addition, it increased the number of CD8+ tumor-infiltrating lymphocytes (TILs) and protected them from apoptosis and exhaustion characterized by decreased production of IL-2, TNFα, and IFNγ. CD8+ TILs capable of producing multiple cytokines were mainly PD-1−Tim-3+, an effector memory subset responsible for tumor rejection. Combined use of metformin and cancer vaccine improved CD8+ TIL multifunctionality. The adoptive transfer of antigen-specific CD8+ T cells treated with metformin concentrations as low as 10 μM showed efficient migration into tumors while maintaining multifunctionality in a manner sensitive to the AMP-activated protein kinase (AMPK) inhibitor compound C. Therefore, a direct effect of metformin on CD8+ T cells is critical for protection against the inevitable functional exhaustion in the tumor microenvironment. PMID:25624476

  18. Anti-tumor angiogenesis effect of a new compound: B-9-3 through interference with VEGFR2 signaling.

    PubMed

    Ma, Qin; Chen, Wei; Chen, Wen

    2016-05-01

    B-9-3, a derivative of harmine, was first synthesized in our laboratory. We have reported that B-9-3 has an anti-proliferative effect against human lung cancer cells via induction of apoptosis and inhibition of cell migration. In the present study, we first studied that the anti-tumor angiogenesis effect and the molecular mechanism of B-9-3-induced tumor vascular degrade and mortify in lung cancer. In vitro, the results showed that B-9-3 selectively inhibited the proliferation of endothelial cells IC50 = 6.16 μg/ml) and vascular fibroblasts (IC50 = 12.59 μg/ml) and induced regression of tumor cells of the following: Lewis lung carcinoma (LLC), Mouse fore-stomach carcinoma (MFC), Human ovarian cancer (SK-OV-3), and prostate cancer (22RV1). Moreover, B-9-3 could significantly increase the apoptosis rate (80.95 %) of vascular endothelial cells, while inhibiting migration of endothelial cells, capillary tube formation of endothelial cells, neovascularization of the rat thoracic aorta ring, and the angiogenesis of chick chorioallantoic membrane (CAM) predominantly through blocking VEGFR2 signaling pathway. In vivo, we investigated the anti-tumor rate and the signal transduction mechanism of B-9-3 by LCC-bearing C57BL/6 mice. The data showed that the tumor inhibition ratio of high dose (20 mg/kg) of B-9-3 was 72.9 %, and quantification of CD34 marker indicated a marked reduction in the number of neovessels after B-9-3 treatment as compared with control group (66.87 %). Remarkably, using IHC and q-RT-PCR, we found that downregulation of the expression of VEGFR2, VEGF-A, and TGFβ1 in tumor confers enhancement to the angiogenesis effect of B-9-3. These data suggest that the angiogenesis inhibitor B-9-3 selectively induces apoptosis of endothelial cells, in part through disruption of VEGF-A/VEGFR2 signaling. PMID:26611645

  19. Antitumor Effect of IP-10 by Using Two Different Approaches: Live Delivery System and Gene Therapy

    PubMed Central

    Taslimi, Yasaman; Zahedifard, Farnaz; Habibzadeh, Sima; Taheri, Tahereh; Abbaspour, Hossain; Sadeghipour, Alireza

    2016-01-01

    Purpose Immunotherapy is one of the treatment strategies for breast cancer, the most common cancer in women worldwide. In this approach, the patient's immune system is stimulated to attack microscopic tumors and control metastasis. Here, we used interferon γ-induced protein 10 (IP-10), which induces and strengthens antitumor immunity, as an immunotherapeutic agent. We employed Leishmania tarentolae, a nonpathogenic lizard parasite that lacks the ability to persist in mammalian macrophages, was used as a live delivery system for carrying the immunotherapeutic agent. It has been already shown that arginase activity, and consequently, polyamine production, are associated with tumor progression. Methods A live delivery system was constructed by stable transfection of pLEXSY plasmid containing the IP-10-enhanced green fluorescent protein (IP-10-egfp) fusion gene into L. tarentolae. Then, the presence of the IP-10-egfp gene and the accurate integration location into the parasite genome were confirmed. The therapeutic efficacy of IP-10 delivered via L. tarentolae and recombinant pcDNA-(IP-10-egfp) plasmid was compared by determining the arginase activity in a mouse 4T1 breast cancer model. Results The pcDNA-(IP-10-egfp) group showed a significant reduction in tumor weight and growth. Histological evaluation also revealed that only this group demonstrated inhibition of metastasis to the lung tissue. The arginase activity in the tissue of the pcDNA-(IP-10-egfp) mice significantly decreased in comparison with that in normal mice. No significant difference was observed in arginase activity in the sera of mice receiving other therapeutic strategies. Conclusion Our data indicates that IP-10 immunotherapy is a promising strategy for breast cancer treatment, as shown in the 4T1-implanted BALB/c mouse model. However, the L. tarentolae-(IP-10-EGFP) live delivery system requires dose modifications to achieve efficacy in the applied regimen (six injections in 3 weeks). Our results

  20. Interleukin-4 receptor α-based hybrid peptide effectively induces antitumor activity in head and neck squamous cell carcinoma.

    PubMed

    Seto, Kahori; Shoda, Junichi; Horibe, Tomohisa; Warabi, Eiji; Ishige, Kazunori; Yamagata, Kenji; Kohno, Masayuki; Yanagawa, Toru; Bukawa, Hiroki; Kawakami, Koji

    2013-06-01

    Interleukin-4 receptor α (IL-4Rα) is highly expressed on the surface of various human solid tumors including head and neck squamous cell carcinoma (HNSCC). We designed a novel IL-4Rα-lytic hybrid peptide composed of a binding peptide to IL-4Rα and a cell-lytic peptide. In the present study, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular-targeted therapy in HNSCC. Immunoblot analysis revealed that IL-4Rα was expressed in all tested HNSCC cell lines (HSC-2, HSC-3, HSC-4, Ca9-22 and OSC-19), but not in a human normal keratinocyte (HaCaT) cell line. Immunohistochemical expression levels of IL-4Rα in HNSCC tissues were higher compared to those in normal epithelial tissue. The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in all five cancer cell lines with a concentration that killed 50% of all cells (IC50) as low as 10 µM. HaCaT cells were less sensitive to this peptide with an IC50 of >30 µM. In addition, intratumoral administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human HNSCC in vivo. These results indicate that the IL-4Rα-lytic hybrid peptide may serve as a potent agent to provide a novel therapy for patients with HNSCC. PMID:23563734

  1. Ex vivo evaluation of the effect of regulatory T cells on the anti-tumor activity of bortezomib in multiple myeloma.

    PubMed

    Ercetin, Ayse Pinar; Ozcan, Mehmet Ali; Aktas, Safiye; Yuksel, Faize; Solmaz, Serife Medeni; Sevindik, Gokmen Omur; Katgi, Abdullah; Piskin, Ozden; Undar, Bulent

    2016-04-01

    Multiple myeloma (MM) is a hematologic cancer characterized by malignant proliferation of plasma cells and their precursors. Immunosuppressive CD4+CD25+Foxp3+ regulatory T (Treg) cells are increased in the peripheral blood of patients with MM. On the basis of this finding, we sought to evaluate the ex vivo effect of CD4+CD25+Foxp3+ Treg cells on the anti-tumor effect of the proteosome inhibitor bortezomib on MM cells. We collected peripheral blood and bone marrow aspiration samples from 20 patients with newly diagnosed MM and isolated CD4+CD25+Foxp3+ Treg cells from peripheral blood mononuclear cells. The bone marrow mononuclear cells were cultivated in RPMI at 37°C and 5% CO2 for 72 hours. The LD50 doses of bortezomib, isolated Treg cells, and their combination were added. After 24 hours, the viability of CD138+ myeloma cells was evaluated by WST-1. We compared the anti-tumor effect of bortezomib alone and in combination with Treg expansion and statistically analyzed the measured differences with respect to the clinical parameters of the patients. Treg cells had varied effects on bortezomib, increasing, decreasing, or not changing its anti-tumor effect. The increased in vitro anti-tumor effect of bortezomib after Treg cell expansion was correlated in patients who did not develop bortezomib resistance in vivo (p = 0.022). These patients with in vivo non-bortezomib-resistant MM also responded to Treg expansion with decreased cell viability (p = 0.024). Our data indicate that the ex vivo expansion of Treg cells increased the cytotoxic effect of bortezomib in clinically sensitive cases. PMID:26774384

  2. Combined inhibition of the mevalonate pathway with statins and zoledronic acid potentiates their anti-tumor effects in human breast cancer cells.

    PubMed

    Göbel, Andy; Thiele, Stefanie; Browne, Andrew J; Rauner, Martina; Zinna, Valentina M; Hofbauer, Lorenz C; Rachner, Tilman D

    2016-05-28

    Amino-bisphosphonates are antiresorptive drugs for the treatment of osteolytic bone metastases, which are frequently caused by breast and other solid tumors. Like statins, amino-bisphosphonates inhibit the mevalonate pathway. Direct anti-tumor effects of amino-bisphosphonates and statins have been proposed, although high concentrations are required to achieve these effects. Here, we demonstrate that the treatment of different human breast cancer cell lines (MDA-MB-231, MDA-Bone, and MDA-Met) by combined inhibition of the mevalonate pathway using statins and zoledronic acid at the same time significantly reduces the concentrations required to achieve a meaningful anti-tumor effect over a single agent approach (50% reduction of cell vitality and 4-fold increase of apoptosis; p < 0.05). The effects were mediated by suppressed protein geranylation that caused an accumulation of GTP-bound RhoA and CDC42. Importantly, the knockdown of both proteins prior to mevalonate pathway inhibition reduced apoptosis by up to 65% (p < 0.01), indicating the accumulation of the GTP-bound GTPases as the mediator of apoptosis. Our results point to effective anti-tumor effects in breast cancer by the combination of statins and zoledronic acid and warrant further validation in preclinical settings. PMID:26968247

  3. Anti-tumor effects of bemiparin in HepG2 and MIA PaCa-2 cells.

    PubMed

    Alur, İhsan; Dodurga, Yavuz; Seçme, Mücahit; Elmas, Levent; Bağcı, Gülseren; Gökşin, İbrahim; Avcı, Çığır Biray

    2016-07-10

    Recent researches have demonstrated improved survival in oncologic patients treated with low molecular weight heparins (LMWHs) which are anticoagulant drugs. We evaluated "second generation" LMWH bemiparin and its in vitro anti-tumor effects on HepG2 hepatocellular carcinoma and MIA PaCa-2 cancer cells. The aim of the study is to investigate anti-cancer mechanism of bemiparin in HepG2 and Mia-Paca-2 cancer cells. Cytotoxic effects of bemiparin were determined by XTT assay. IC50 dose of bemiparin was found to be 200IU/mL in the 48th hour in the MiaPaCa-2 cell line and 50IU/mL in the 48th hour in the HepG2 cell line. CCND1 (cyclin D1), CDK4, CDK6, p21, p16, p53, caspase-3, caspase-9, caspase-8, Bcl-2, BID, DR4, DR5, FADD, TRADD, Bax, gene mRNA expressions were evaluated by Real-time PCR. Real-time PCR analysis showed that CCND1 expression was reduced in HepG2 dose the group cells when compared with the control group cells and p53, caspase-3, caspase p21, caspase-8 and expressions were increased in the dose group cells when compared with the control group cells. CCND1, CDK4 and CDK6 expressions were reduced in MIA PaCa-2 dose group cells when compared with the control group cells and p53 expression was increased in the dose group cells when compared with the control group cells. Other expressions of genes were found statistically insignificant both of cell lines. It was found that bemiparin in HepG2 and MIA PaCa-2 cells suppressed invasion, migration, and colony formation by using matrigel invasion chamber, and colony formation assay, respectively. In conclusion, it is thought that bemiparin indicates anti-tumor activity by affecting cell cycle arrest, apoptosis, invasion, migration, and colony formation on cancer cells. PMID:27048831

  4. The strong in vivo anti-tumor effect of the UIC2 monoclonal antibody is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity.

    PubMed

    Szalóki, Gábor; Krasznai, Zoárd T; Tóth, Ágnes; Vízkeleti, Laura; Szöllősi, Attila G; Trencsényi, György; Lajtos, Imre; Juhász, István; Krasznai, Zoltán; Márián, Teréz; Balázs, Margit; Szabó, Gábor; Goda, Katalin

    2014-01-01

    P-glycoprotein (Pgp) extrudes a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance (MDR). The UIC2 monoclonal antibody recognizes human Pgp and inhibits its drug transport activity. However, this inhibition is partial, since UIC2 binds only to 10-40% of cell surface Pgps, while the rest becomes accessible to this antibody only in the presence of certain substrates or modulators (e.g. cyclosporine A (CsA)). The combined addition of UIC2 and 10 times lower concentrations of CsA than what is necessary for Pgp inhibition when the modulator is applied alone, decreased the EC50 of doxorubicin (DOX) in KB-V1 (Pgp+) cells in vitro almost to the level of KB-3-1 (Pgp-) cells. At the same time, UIC2 alone did not affect the EC50 value of DOX significantly. In xenotransplanted severe combined immunodeficient (SCID) mice co-treated with DOX, UIC2 and CsA, the average weight of Pgp+ tumors was only ∼10% of the untreated control and in 52% of these animals we could not detect tumors at all, while DOX treatment alone did not decrease the weight of Pgp+ tumors. These data were confirmed by visualizing the tumors in vivo by positron emission tomography (PET) based on their increased 18FDG accumulation. Unexpectedly, UIC2+DOX treatment also decreased the size of tumors compared to the DOX only treated animals, as opposed to the results of our in vitro cytotoxicity assays, suggesting that immunological factors are also involved in the antitumor effect of in vivo UIC2 treatment. Since UIC2 binding itself did not affect the viability of Pgp expressing cells, but it triggered in vitro cell killing by peripheral blood mononuclear cells (PBMCs), it is concluded that the impressive in vivo anti-tumor effect of the DOX-UIC2-CsA treatment is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity (ADCC). PMID:25238617

  5. Active hexose correlated compound potentiates the antitumor effects of low-dose 5-fluorouracil through modulation of immune function in hepatoma 22 tumor-bearing mice

    PubMed Central

    Cao, Zhiyun; Chen, Xuzheng; Lan, Lan; Zhang, Zhideng; Du, Jian

    2015-01-01

    BACKGROUND/OBJECTIVES A variety of immunomodulators can improve the efficacy of low-dose chemotherapeutics. Active hexose correlated compound (AHCC), a mushroom mycelia extract, has been shown to be a strong immunomodulator. Whether AHCC could enhance the antitumor effect of low-dose 5-fluorouracil (5-FU) via regulation of host immunity is unknown. MATERIALS/METHODS In the current study Hepatoma 22 (H22) tumor-bearing mice were treated with PBS, 5-FU (10 mg·kg-1·d-1, i.p), or AHCC (360 mg·kg-1·d-1, i.g) plus 5-FU, respectively, for 5 d. CD3+, CD4+, CD8+, and NK in peripheral blood were detected by flow cytometry. ALT, AST, BUN, and Cr levels were measured by biochemical assay. IL-2 and TNFα in serum were measured using the RIA kit and apoptosis of tumor was detected by TUNEL staining. Bax, Bcl-2, and TS protein levels were measured by immunohistochemical staining and mRNA level was evaluated by RT-PCR. RESULTS Diet consumption and body weight showed that AHCC had no apparent toxicity. AHCC could reverse liver injury and myelosuppression induced by 5-FU (P < 0.05). Compared to mice treated with 5-FU, mice treated with AHCC plus 5-FU had higher thymus index, percentages of CD3+, CD4+, and NK cells (P < 0.01), and ratio of CD4+/CD8+ (P < 0.01) in peripheral blood. Radioimmunoassay showed that mice treated with AHCC plus 5-FU had the highest serum levels of IL-2 and TNFα compared with the vehicle group and 5-FU group. More importantly, the combination of AHCC and 5-FU produced a more potent antitumor effect (P < 0.05) and caused more severe apoptosis in tumor tissue (P < 0.05) compared with the 5-FU group. In addition, the combination of AHCC and 5-FU further up-regulated the expression of Bcl-2 associated X protein (Bax) (P < 0.01), while it down-regulated the expression of B cell lymphoma 2 (Bcl-2) (P < 0.01). CONCLUSIONS These results support the claim that AHCC might be beneficial for cancer patients receiving chemotherapy. PMID:25861418

  6. Antitumor effects of a drug combination targeting glycolysis, glutaminolysis and de novo synthesis of fatty acids.

    PubMed

    Cervantes-Madrid, Diana; Dueñas-González, Alfonso

    2015-09-01

    There is a strong rationale for targeting the metabolic alterations of cancer cells. The most studied of these are the higher rates of glycolysis, glutaminolysis and de novo synthesis of fatty acids (FAs). Despite the availability of pharmacological inhibitors of these pathways, no preclinical studies targeting them simultaneously have been performed. In the present study it was determined whether three key enzymes for glycolysis, glutaminolysis and de novo synthesis of FAs, hexokinase-2, glutaminase and fatty acid synthase, respectively, were overexpressed as compared to primary fibroblasts. In addition, we showed that at clinically relevant concentrations lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat, known inhibitors of the mentioned enzymes, exerted a cell viability inhibitory effect. Genetic downregulation of the three enzymes also reduced cell viability. The three drugs were highly synergistic when administered as a triple combination. Of note, the cytotoxicity of the triple combination was low in primary fibroblasts and was well tolerated when administered into healthy BALB/c mice. The results suggest the feasibility and potential clinical utility of the triple metabolic targeting which merits to be further studied by using either repositioned old drugs or newer, more selective inhibitors. PMID:26134042

  7. Zinc supplementation augments in vivo antitumor effect of chemotherapy by restoring p53 function.

    PubMed

    Margalit, Ofer; Simon, Amos J; Yakubov, Eduard; Puca, Rosa; Yosepovich, Ady; Avivi, Camila; Jacob-Hirsch, Jasmine; Gelernter, Ilana; Harmelin, Alon; Barshack, Iris; Rechavi, Gideon; D'Orazi, Gabriella; Givol, David; Amariglio, Ninette

    2012-08-15

    Activated p53 is necessary for tumor suppression. Homeodomain-interacting protein kinase-2 (HIPK2) is a positive regulator of functional p53. HIPK2 modulates wild-type p53 activity toward proapoptotic transcription and tumor suppression by the phosphorylation of serine 46. Knock-down of HIPK2 interferes with tumor suppression and sensitivity to chemotherapy. Combined administration of adriamycin and zinc restores activity of misfolded p53 and enables the induction of its proapoptotic and tumor suppressor functions in vitro and in vivo. We therefore looked for a cancer model where HIPK2 expression is low. MMTV-neu transgenic mice overexpressing HER2/neu, develop mammary tumors at puberty with a long latency, showing very low expression of HIPK2. Here we show that whereas these tumors are resistant to adriamycin treatment, a combination of adriamycin and zinc suppresses tumor growth in vivo in these mice, an effect evidenced by the histological features of the mammary tumors. The combined treatment of adriamycin and zinc also restores wild-type p53 conformation and induces proapoptotic transcription activity. These findings may open up new possibilities for the treatment of human cancers via the combination of zinc with chemotherapeutic agents, for a selected group of patients expressing low levels of HIPK2, with an intact p53. In addition, HIPK2 may serve as a new biomarker for tumor aggressiveness. PMID:21932419

  8. Antitumor Effects and Mechanism of Novel Emodin Rhamnoside Derivatives against Human Cancer Cells In Vitro

    PubMed Central

    Deng, Jun-peng; Jiang, Ling-zhi; Xiong, Ping; Yang, Bin-jie; Liu, Shan-shan

    2015-01-01

    A series of novel anthracene L-rhamnopyranosides compounds were designed and synthesized and their anti-proliferative activities on cancer cell lines were investigated. We found that one derivative S-8 (EM-d-Rha) strongly inhibited cell proliferation of a panel of different human cancer cell lines including A549, HepG2, OVCAR-3, HeLa and K562 and SGC-790 cell lines, and displayed IC50 values in low micro-molar ranges, which are ten folds more effective than emodin. In addition, we found EM-d-Rha (3-(2”,3”-Di-O-acetyl-α-L-rhamnopyranosyl-(1→4)-2’,3’-di-O-acetyl-α-L-rhamnopyranosyl)-emodin) substantially induced cellular apoptosis of HepG2 and OVCAR-3 cells in the early growth stage. Furthermore, EM-d-Rha led to the decrease of mitochondrial transmembrane potential, and up-regulated the express of cells apoptosis factors in a concentration- and time-dependent manner. The results indicated the EM-d-Rha may inhibit the growth and proliferation of HepG2 cells through the pathway of apoptosis induction, and the possible molecular mechanism may due to the activation of intrinsic apoptotic signal pathway. PMID:26682731

  9. A novel combination of TRAIL and doxorubicin enhances antitumor effect based on passive tumor-targeting of liposomes

    NASA Astrophysics Data System (ADS)

    Guo, Liangran; Fan, Li; Ren, Jinfeng; Pang, Zhiqing; Ren, Yulong; Li, Jingwei; Wen, Ziyi; Jiang, Xinguo

    2011-07-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel anticancer agent for non-small cell lung cancer (NSCLC). However, approximately half of NSCLC cell lines are highly resistant to TRAIL. Doxorubicin (DOX) can sensitize NSCLC cells to TRAIL-induced apoptosis, indicating the possibility of combination therapy. Unfortunately, the therapeutic effect of a DOX and TRAIL combination is limited by multiple factors including the short serum half-life of TRAIL, poor compliance and application difficulty in the clinic, chronic DOX-induced cardiac toxicity, and the multidrug resistance (MDR) property of NSCLC cells. To solve such problems, we developed the combination of TRAIL liposomes (TRAIL-LP) and DOX liposomes (DOX-LP). An in vitro cytotoxicity study indicated that DOX-LP sensitized the NSCLC cell line A-549 to TRAIL-LP-induced apoptosis. Furthermore, this combination therapy of TRAIL-LP and DOX-LP displayed a stronger antitumor effect on NSCLC in xenografted mice when compared with free drugs or liposomal drugs alone. Therefore, the TRAIL-LP and DOX-LP combination therapy has excellent potential to become a new therapeutic approach for patients with advanced NSCLC.

  10. Iron oxide @ polypyrrole nanoparticles as a multifunctional drug carrier for remotely controlled cancer therapy with synergistic antitumor effect.

    PubMed

    Wang, Chao; Xu, Huan; Liang, Chao; Liu, Yumeng; Li, Zhiwei; Yang, Guangbao; Cheng, Liang; Li, Yonggang; Liu, Zhuang

    2013-08-27

    Multifunctional nanoplatforms that are safe and have multiple therapeutic functions together with imaging capabilities are highly demanded in the development of new cancer theranostic approaches. A number of near-infrared (NIR)-absorbing inorganic nanomaterials, although having shown great promise not only to photothermally ablate tumors but also to enhance the efficacy of other types of therapies, are not biodegradable and would be retained in the body for a long time. Herein, we develop a multifunctional nanocomposite by coating magnetic iron oxide nanoclusters with a near-infrared light-absorbing polymer polypyrrole (PPy), obtaining Fe3O4@PPy core-shell nanoparticles, which after functionalization with polyethylene glycol could be used for imaging-guided, remotely controlled cancer combination therapy. In this system, the Fe3O4 core, which could be gradually decomposed in physiological environments, is useful for magnetically controlled drug delivery as well as a magnetic resonance imaging contrast. The PPy shell, as an organic polymer, is able to load therapeutic molecules with aromatic structures and also exhibits a strong photothermal effect, which can be used to enhance the chemotherapeutic efficacy, showing an outstanding in vivo synergistic antitumor effect. Our work encourages further exploration of light-absorbing polymer-based nanocomposites for cancer combination therapy under remote physical controls. PMID:23822176

  11. In Vivo and In Vitro Antitumor Effects of Platycodin D, a Saponin Purified from Platycodi Radix on the H520 Lung Cancer Cell

    PubMed Central

    Park, Jae Chan; Choi, Hae Yun; Shin, Yong Kook; Kim, Jong Dae; Ku, Sae Kwang

    2014-01-01

    Platycodin D is a major pharmacological constituent of Platycodi radix and has showed various pharmacological activities through oxidative stress defense mechanisms. Here, possible antitumor, anticachexia, and immunomodulatory activities of platycodin D were observed on the H520 tumor cell-bearing athymic nude mice after confirming the in vitro cytotoxicity. Platycodin D was orally administered at dose levels of 200, 100, and 50 mg/kg, once a day for 35 days from 15 days after implantation. The results were compared with gemcitabine 160 mg/kg intraperitoneally treated mice (7-day intervals). Platycodin D showed favorable cytotoxic effects on the H520 cells, and also dose-dependently decreased the tumor volumes and weights with increases of apoptotic cells (caspase-3 and PARP immunopositive cells), iNOS and TNF-α immunoreactivities, decreases of COX-2 immunoreactivities in tumor masses. Platycodin D also showed dose-dependent immunostimulatory and anticachexia effects. Gemcitabine showed favorable cytotoxity against H520 tumor cell and related in vivo antitumor effects but aggravated the cancer related cachexia and immunosuppress in H520 tumor cell-bearing athymic nude mice. Taken together, it is considered that oral treatment of platycodin D has potent antitumor activities on H520 cells through direct cytotoxic effects, increases of apoptosis in tumor cells, and immunostimulatory effects and can be control cancer related cachexia. PMID:25477992

  12. In vivo and in vitro antitumor effects of platycodin d, a saponin purified from platycodi radix on the h520 lung cancer cell.

    PubMed

    Park, Jae Chan; Lee, Young Joon; Choi, Hae Yun; Shin, Yong Kook; Kim, Jong Dae; Ku, Sae Kwang

    2014-01-01

    Platycodin D is a major pharmacological constituent of Platycodi radix and has showed various pharmacological activities through oxidative stress defense mechanisms. Here, possible antitumor, anticachexia, and immunomodulatory activities of platycodin D were observed on the H520 tumor cell-bearing athymic nude mice after confirming the in vitro cytotoxicity. Platycodin D was orally administered at dose levels of 200, 100, and 50 mg/kg, once a day for 35 days from 15 days after implantation. The results were compared with gemcitabine 160 mg/kg intraperitoneally treated mice (7-day intervals). Platycodin D showed favorable cytotoxic effects on the H520 cells, and also dose-dependently decreased the tumor volumes and weights with increases of apoptotic cells (caspase-3 and PARP immunopositive cells), iNOS and TNF-α immunoreactivities, decreases of COX-2 immunoreactivities in tumor masses. Platycodin D also showed dose-dependent immunostimulatory and anticachexia effects. Gemcitabine showed favorable cytotoxity against H520 tumor cell and related in vivo antitumor effects but aggravated the cancer related cachexia and immunosuppress in H520 tumor cell-bearing athymic nude mice. Taken together, it is considered that oral treatment of platycodin D has potent antitumor activities on H520 cells through direct cytotoxic effects, increases of apoptosis in tumor cells, and immunostimulatory effects and can be control cancer related cachexia. PMID:25477992

  13. Interleukin-2 gene transfer potentiates the alpha-galactosylceramide-stimulated antitumor effect by the induction of TRAIL in NKT and NK cells in mouse models of subcutaneous and metastatic carcinoma.

    PubMed

    Nishihori, Yoshiki; Kato, Kazunori; Tanaka, Maki; Okamoto, Tetsuro; Hagiwara, Seiya; Araki, Naoko; Kogawa, Katsuhisa; Kuribayashi, Kageaki; Nakamura, Kiminori; Niitsu, Yoshiro

    2009-09-01

    Alpha-Galactosylceramide (alpha-GalCer) is a potent CD1d ligand that activates natural killer like T-cells (NKT), leading to the production of helper T (Th) 1 and Th2 cytokines that mediate various immunemodulatory and antitumor effects. Here, we determined whether the administration of adenovirus-vector-encoding mouse interleukin-2 (AdmIL-2) can augment the antitumor effect of alpha-GalCer on subcutaneous and metastatic tumors in mice. Mice were intraperitoneally injected with alpha-GalCer on days 7, 10 and 13 after tumor inoculation, with or without intratumoral injection of AdmIL-2 on day 7. alpha-GalCer treatment increased the serum levels of interferon-gamma, while intratumoral injection of AdmIL-2 elevated serum IL-2 levels. A combination of alpha-GalCer and AdmIL-2 (alpha-GalCer/AdmIL-2) inhibited the in vivo tumor growth and improved the survival of tumor-bearing mice, as compared to the use of a single agent. Experiments on spontaneous metastasis models revealed that alpha-GalCer/AdmIL-2 reduced lung metastasis and prolonged survival, as compared to control groups. In addition, the splenic and liver mononuclear cells from mice treated with alpha-GalCer/AdmIL-2 showed enhanced cytolytic activity against NK-sensitive YAC-1 and NK-resistant 3LL tumors. Moreover, alpha-GalCer/AdmIL-2 treatment expanded the absolute numbers of lung and liver NK, NKT and T-cells as well as the TNF-related apoptosis-inducing ligand (TRAIL) expression of these cells. This study shows the efficacy of alpha-GalCer/AdmIL-2 immunomodulatory therapy, and provides a cellular mechanism on how it exerts the antitumor effects. PMID:19901518

  14. Blocking the interleukin 2 (IL2)-induced systemic autophagic syndrome promotes profound antitumor effects and limits toxicity.

    PubMed

    Lotze, Michael T; Buchser, William J; Liang, Xiaoyan

    2012-08-01

    Cancer is the leading cause of death in the United States in those dying under the age of 85. Although cancer is increasingly controlled as a chronic disease, true cures of patients with metastatic epithelial malignancies have rarely been obtained with currently available systemic therapies. For example, administration of high-dose recombinant interleukin 2 (IL2), enhancing cytolytic immune cell proliferation and delivery, promotes complete antitumor responses in < 10% of treated individuals. Means to reduce the toxicity, attributed to a cytokine storm and an associated "systemic autophagic syndrome" as well as enhance efficacy and increase the potential set of malignancies in which it is applied (currently patients with renal cancer and melanoma) would be of great interest. IL2 promotes both T-cell and NK cell induction of immune cell-mediated autophagy (iC-MA) in tumor targets. We have demonstrated that HMGB1 is detected at high levels in the serum of IL2-treated mice with translocation to the cytoplasm from the nucleus in the liver, consistent with HMGB1's release in response to stress, and ability to sustain autophagy. Limiting autophagy in mice with coadministration of chloroquine (CQ) diminishes serum levels of HMGB1, cytokines (IFNG and IL6 but not IL18), and autophagic flux, attenuating weight gain, enhancing DC, T-cell and NK cell numbers, and promoting long-term tumor control in a murine hepatic metastases model. Autophagy (programmed cell survival) is a metabolic process associated with promotion of late cancer growth. In tumor cell lines, CQ treatment limits ATP production through inhibition of oxidative phosphorylation and promotion of apoptosis. CQ increases autophagic vacuoles and LC3-II levels in tumor cells, associated with increased annexin V(+)/PI(-) cells, cleaved-PARP, cleaved-CASP3, and cytochrome c release from mitochondria. These observations, limiting toxicity and prolonging antitumor effects, with a combination of IL2 and autophagy

  15. Pifithrin-μ, an Inhibitor of Heat-Shock Protein 70, Can Increase the Antitumor Effects of Hyperthermia Against Human Prostate Cancer Cells

    PubMed Central

    Sekihara, Kazumasa; Harashima, Nanae; Tongu, Miki; Tamaki, Yukihisa; Uchida, Nobue; Inomata, Taisuke; Harada, Mamoru

    2013-01-01

    Hyperthermia (HT) improves the efficacy of anti-cancer radiotherapy and chemotherapy. However, HT also inevitably evokes stress responses and increases the expression of heat-shock proteins (HSPs) in cancer cells. Among the HSPs, HSP70 is known as a pro-survival protein. In this study, we investigated the sensitizing effect of pifithrin (PFT)-μ, a small molecule inhibitor of HSP70, when three human prostate cancer cell lines (LNCaP, PC-3, and DU-145) were treated with HT (43°C for 2 h). All cell lines constitutively expressed HSP70, and HT further increased its expression in LNCaP and DU-145. Knockdown of HSP70 with RNA interference decreased the viability and colony-forming ability of cancer cells. PFT-μ decreased the viabilities of all cell lines at one-tenth the dose of Quercetin, a well-known HSP inhibitor. The combination therapy with suboptimal doses of PFT-μ and HT decreased the viability of cancer cells most effectively when PFT-μ was added immediately before HT, and this combination effect was abolished by pre-knockdown of HSP70, suggesting that the effect was mediated via HSP70 inhibition. The combination therapy induced cell death, partially caspase-dependent, and decreased proliferating cancer cells, with decreased expression of c-Myc and cyclin D1 and increased expression of p21WAF1/Cip, indicating arrest of cell growth. Additionally, the combination therapy significantly decreased the colony-forming ability of cancer cells compared to therapy with either alone. Furthermore, in a xenograft mouse model, the combination therapy significantly inhibited PC-3 tumor growth. These findings suggest that PFT-μ can effectively enhance HT-induced antitumor effects via HSP70 inhibition by inducing cell death and arrest of cell growth, and that PFT-μ is a promising agent for use in combination with HT to treat prostate cancer. PMID:24244355

  16. Pifithrin-μ, an inhibitor of heat-shock protein 70, can increase the antitumor effects of hyperthermia against human prostate cancer cells.

    PubMed

    Sekihara, Kazumasa; Harashima, Nanae; Tongu, Miki; Tamaki, Yukihisa; Uchida, Nobue; Inomata, Taisuke; Harada, Mamoru

    2013-01-01

    Hyperthermia (HT) improves the efficacy of anti-cancer radiotherapy and chemotherapy. However, HT also inevitably evokes stress responses and increases the expression of heat-shock proteins (HSPs) in cancer cells. Among the HSPs, HSP70 is known as a pro-survival protein. In this study, we investigated the sensitizing effect of pifithrin (PFT)-μ, a small molecule inhibitor of HSP70, when three human prostate cancer cell lines (LNCaP, PC-3, and DU-145) were treated with HT (43°C for 2 h). All cell lines constitutively expressed HSP70, and HT further increased its expression in LNCaP and DU-145. Knockdown of HSP70 with RNA interference decreased the viability and colony-forming ability of cancer cells. PFT-μ decreased the viabilities of all cell lines at one-tenth the dose of Quercetin, a well-known HSP inhibitor. The combination therapy with suboptimal doses of PFT-μ and HT decreased the viability of cancer cells most effectively when PFT-μ was added immediately before HT, and this combination effect was abolished by pre-knockdown of HSP70, suggesting that the effect was mediated via HSP70 inhibition. The combination therapy induced cell death, partially caspase-dependent, and decreased proliferating cancer cells, with decreased expression of c-Myc and cyclin D1 and increased expression of p21(WAF1/Cip), indicating arrest of cell growth. Additionally, the combination therapy significantly decreased the colony-forming ability of cancer cells compared to therapy with either alone. Furthermore, in a xenograft mouse model, the combination therapy significantly inhibited PC-3 tumor growth. These findings suggest that PFT-μ can effectively enhance HT-induced antitumor effects via HSP70 inhibition by inducing cell death and arrest of cell growth, and that PFT-μ is a promising agent for use in combination with HT to treat prostate cancer. PMID:24244355

  17. Intravaginal HPV DNA vaccination with electroporation induces local CD8+ T-cell immune responses and antitumor effects against cervicovaginal tumors

    PubMed Central

    Sun, Y; Peng, S; Qiu, J; Miao, J; Yang, B; Jeang, J; Hung, C-F; Wu, T-C

    2015-01-01

    Therapeutic human papillomavirus (HPV) vaccines have the potential to inhibit the progression of an established HPV infection to precancer and cancer lesions by targeting HPV oncoproteins. We have previously developed a therapeutic DNA vaccine encoding calreticulin (CRT) linked to E7, CRT/E7 DNA vaccine, for use in the treatment of HPV-associated lesions. Since the transfection efficiency of DNA vaccines administered in vivo is typically low, we examined the use of electroporation as well as different routes of administration to enhance antigen-specific tumor control. We tested the effects of the CRT/E7 DNA vaccine administered intramuscularly or intravaginally, with or without electroporation, on the generation of CD8+ T-cell immunity and therapeutic antitumor effects in HPV16 E7-expressing cervicovaginal tumor-bearing mice. We found that intravaginal vaccination of CRT/E7 DNA followed by electroporation-induced potent E7-specific CD8+ T-cell responses in the cervicovaginal tract, compared with intramuscular injection followed by electroporation. Furthermore, tumor-bearing mice vaccinated intravaginally followed by electroporation had an enhanced survival, antitumor effects and local production of IFN-γ+CD8+ T cells compared with those vaccinated intramuscularly with electroporation. Thus, we show that intravaginal CRT/E7 DNA vaccination followed by electroporation generates the most potent therapeutic antitumor effects against an orthotopic E7-expressing tumor model. The current study will have significant clinical implications once a clinically applicable electroporation device for intravaginal use becomes available. PMID:25786869

  18. Selenium Induces an Anti-tumor Effect Via Inhibiting Intratumoral Angiogenesis in a Mouse Model of Transplanted Canine Mammary Tumor Cells.

    PubMed

    Li, Wenyu; Guo, Mengyao; Liu, Yuzhu; Mu, Weiwei; Deng, Ganzhen; Li, Chengye; Qiu, Changwei

    2016-06-01

    Selenium (Se) has been widely reported to possess anti-tumor effects. Angiogenesis is the formation of new blood vessels and is required to supply oxygen, nutrients, and growth factors for tumor growth, progression, and metastasis. To explore whether the anti-tumor effect of Se was associated with angiogenesis in vivo, we studied the effects of sodium selenite (Sel) and methylseleninic acid (MSA) on tumors induced by canine mammary tumor cells (CMT1211) in mice; cyclophosphamide (CTX) served as a positive control. The results showed that the Se content was significantly increased in the Sel and MSA groups. Se significantly inhibited the tumor weights and volumes. Large necrotic areas and scattered and abnormal small necrotic areas were observed in the Se treatment group. Immunofluorescence double staining showed a reduction in the microvessel density (MVD) and increment in the vessel maturation index (VMI) compared with the untreated control group. As expected, the protein and mRNA levels of the angiogenesis factors angiopoietin-2 (Ang-2), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) were decreased in the Se-treated tumors by IHC, as shown by western blotting and RT-QPCR. We also found that organic Se MSA provided stronger inhibition of tumor growth compared with inorganic sodium selenite (Sel). Altogether, our results indicated that Se exerted anti-tumor effects in vivo at least partially by inhibiting angiogenic factors. PMID:26507439

  19. Role of cysteinyl leukotriene receptor-1 antagonists in treatment of experimentally induced mammary tumor: does montelukast modulate antitumor and immunosuppressant effects of doxorubicin?

    PubMed

    El-Sisi, Alaa El-Din E; Sokar, Samia S; Salem, Tarek A; Abu Risha, Sally E

    2015-11-01

    It has been reported that a leukotriene (LT)-D4 receptor (i.e. cysteinyl LT1 receptor; CysLT1R) has an important role in carcinogenesis. The current study was carried out to assess the possible antitumor effects of montelukast (MON), a CysLT1R antagonist, in a mouse mammary carcinoma model, that is, a solid Ehrlich carcinoma (SEC). Effects of MON on tumor-induced immune dysfunction and the possibility that MON may modulate the antitumor and immunomodulatory effects of doxorubicin (DOX) were also studied. The effects in tumor-bearing hosts of several dosings with MON (10 mg/kg, per os), with and without the added presence of DOX (2 mg/kg, intraperitoneal), were investigated in vivo; end points evaluated included assessment of tumor volume, splenic lymphocyte profiles/functionality, tumor necrosis factor-α content, as well as apoptosis and expression of nuclear factor-κB (NF-κB) among the tumor cells. The data indicate that MON induced significant antitumor activity against the SEC. MON treatments also significantly mitigated both tumor- and DOX-induced declines in immune parameters assessed here. Moreover, MON led to decreased NF-κB nuclear expression and, in doing so, appeared to chemosensitize these tumor cells to DOX-induced apoptosis. PMID:26499992

  20. Antitumor effect of dehydroxymethylepoxyquinomicin, a small molecule inhibitor of nuclear factor-κB, on glioblastoma

    PubMed Central

    Fukushima, Tsuyoshi; Kawaguchi, Makiko; Yorita, Kenji; Tanaka, Hiroyuki; Takeshima, Hideo; Umezawa, Kazuo; Kataoka, Hiroaki

    2012-01-01

    Glioblastoma is the most malignant type of brain tumor. Despite recent advances in therapeutic modalities, the prognosis of glioblastoma remains very poor. Recent studies have indicated that RelA/nuclear factor (NF)-κB is consistently activated in human glioblastoma. In this study, we searched for a new treatment modality for glioblastoma, by examining the effects of dehydroxymethylepoxyquinomicin (DHMEQ), a unique small molecule inhibitor of NF-κB. Addition of DHMEQ to cultured human glioblastoma cells inhibited the nuclear translocation of RelA. It also reduced the growth rate of human glioblastoma cells significantly in 6 cell lines and modestly in 3 among 10 cell lines examined. Then, we performed further analyses using 3 sensitive cell lines (U87, U251, and YKG-1). The growth retardation was accompanied by G2/M arrest in vitro. Increased apoptosis was observed in U87 and YKG-1, but not U251 cells after DHMEQ treatment. Then, we tested the efficacy of DHMEQ in chemoprevention through the use of a nude mouse model. Subcutaneous tumors formed by U87 or U251 cells were reduced by ∼40% in size by intraperitoneal administration of DHMEQ started immediately after implantation of the cells. DHMEQ treatment achieved statistically significant improvements in survival curves of mice intracranially implanted with U87 or U251 cells. Histological analysis revealed increased areas of necrosis, increased numbers of collapsed microvessels, decreased nuclear immunoreactivity of RelA, and decreased immunoreactivity of urokinase-type plasminogen activator in the DHMEQ-treated U87 tumor tissues. These results suggest that the targeting of NF-κB by DHMEQ may serve as a promising treatment modality in glioblastoma. PMID:21968049

  1. Antitumor effectiveness of different amounts of electrical charge in Ehrlich and fibrosarcoma Sa-37 tumors

    PubMed Central

    Ciria, HC; Quevedo, MS; Cabrales, LB; Bruzón, RP; Salas, MF; Pena, OG; González, TR; López, DS; Flores, JM

    2004-01-01

    Background In vivo studies were conducted to quantify the effectiveness of low-level direct electric current for different amounts of electrical charge and the survival rate in fibrosarcoma Sa-37 and Ehrlich tumors, also the effect of direct electric in Ehrlich tumor was evaluate through the measurements of tumor volume and the peritumoral and tumoral findings. Methods BALB/c male mice, 7–8 week old and 20–22 g weight were used. Ehrlich and fibrosarcoma Sa-37 cell lines, growing in BALB/c mice. Solid and subcutaneous Ehrlich and fibrosarcoma Sa-37 tumors, located dorsolaterally in animals, were initiated by the inoculation of 5 × 106 and 1 × 105 viable tumor cells, respectively. For each type of tumor four groups (one control group and three treated groups) consisting of 10 mice randomly divided were formed. When the tumors reached approximately 0.5 cm3, four platinum electrodes were inserted into their bases. The electric charge delivered to the tumors was varied in the range of 5.5 to 110 C/cm3 for a constant time of 45 minutes. An additional experiment was performed in BALB/c male mice bearing Ehrlich tumor to examine from a histolological point of view the effects of direct electric current. A control group and a treated group with 77 C/cm3 (27.0 C in 0.35 cm3) and 10 mA for 45 min were formed. In this experiment when the tumor volumes reached 0.35 cm3, two anodes and two cathodes were inserted into the base perpendicular to the tumor long axis. Results Significant tumor growth delay and survival rate were achieved after electrotherapy and both were dependent on direct electric current intensity, being more marked in fibrosarcoma Sa-37 tumor. Complete regressions for fibrosarcoma Sa-37 and Ehrlich tumors were observed for electrical charges of 80 and 92 C/cm3, respectively. Histopathological and peritumoral findings in Ehrlich tumor revealed in the treated group marked tumor necrosis, vascular congestion, peritumoral neutrophil infiltration, an acute

  2. Antitumor Effect of Folate-Targeted Liposomal Doxorubicin in KB Tumor-Bearing Mice after Intravenous Administration

    PubMed Central

    Riviere, Kareen; Huang, Zhaohua; Jerger, Katherine; Macaraeg, Nichole; Szoka, Francis C.

    2010-01-01

    The effect of folate-targeted liposomal doxorubicin (FTL-Dox) has been well characterized in folate receptor (FR) over-expressing tumors in vitro, particularly in KB human carcinoma cells. However, there are few studies evaluating the in vivo efficacy of FTL-Dox in KB murine xenograft models. In this study, we investigated the antitumor activity of FTL-Dox injected intravenously in mice bearing KB tumors. Folate ligands comprising of folate-polyethyleneglycol-distearoylphosphatidylethanolamine (FA-PEG-DSPE) were synthesized with different MW PEG. To design an optimum FTL-Dox formulation for therapeutic studies, we prepared various FTLs and characterized their in vitro targeting and in vivo tissue biodistribution. Mice were administered a single intravenous injection of free Dox, non-targeted PEGylated liposomal Dox (PL-Dox), or FTL-Dox. FTLs and PLs accumulated similarly in tumor tissue, despite FTLs’ faster clearance from circulation. Mice treated with FTL-Dox 20 mg/kg had a slightly greater tumor growth inhibition and almost a 50% increase in life span than mice receiving PL-Dox 20 mg/kg (P = 0.0121; log-rank test). We conclude that FTLs administered systemically have the potential to enhance the delivery of anticancer drugs in vivo; however, their removal by FR expressing normal tissues may have to be blocked if the benefits of tumor targeting are to be realized. PMID:20353291

  3. Enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA on human brain metastatic breast cancer

    PubMed Central

    Fu, Bo; Long, Wei; Zhang, Ying; Zhang, Aifeng; Miao, Fengqin; Shen, Yuqing; Pan, Ning; Gan, Guangming; Nie, Fang; He, Youji; Zhang, Jianqiong; Teng, Gaojun

    2015-01-01

    Novel molecularly targeted agents that block the development and metastasis of human brain metastatic breast cancer hold great promise for their translational value. In this study, we constructed a novel targeting composite peptide BRBP1-TAT-KLA comprising of three elements: a brain metastatic breast carcinoma cell (231-BR)-binding peptide BRBP1, a cell penetrating peptide TAT, and a proapoptotic peptide KLA. This composite peptide efficiently internalized in 231-BR cells and consequently induced mitochondrial damage and cellular apoptosis. Exposure of 231-BR cells to BRBP1-TAT-KLA significantly decreased cell viability and increased apoptosis compared with the cells treated with the control peptides. In vivo relevance of these findings was further corroborated in the 231-BR tumor-bearing mice that demonstrated significantly delayed tumor development and metastasis following administration of BRBP1-TAT-KLA compared with those treated with TAT-KLA alone. Interestingly, BRBP1-TAT-KLA inhibited the formation of both large and micro-metastases, while TAT-KLA alone failed to significantly reduce micro-metastases in the breast cancer brain metastasis mice. BRBP1-TAT-KLA selectively homed to the tumors in vivo where it induced cellular apoptosis without significant toxicity on non-tumor tissues. Our findings therefore demonstrated the enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA, providing insights toward development of a potential therapeutic strategy for brain metastatic breast cancer. PMID:25619721

  4. Statistical optimization of culture medium for production of exopolysaccharide from endophytic fungus Bionectria ochroleuca and its antitumor effect in vitro

    PubMed Central

    Li, Yun; Guo, Shoujun; Zhu, Hui

    2016-01-01

    Endophytic fungi have been recognized as possible useful sources of bioactive metabolites. However, exopolysaccharide (EPS) production from endophytic fungi and its antitumor activity have been less explored. In the present study, endophtic fungus Bionectria ochroleuca M21 was exploited for the production of EPS in submerged culture. Among tested medium components, glucose, yeast extract, MgSO4 and Tween80 were found to be effective and significant on EPS production. Response surface methodology (RSM) was employed to optimize medium composition. The results showed that the significant factors were glucose, yeast extract and Tween80. The optimal medium was observed at the composition of glucose 55.7 g/L, yeast extract 6.04 g/L, MgSO4 0.25g/L and Tween80 0.1 % (v/v). Using the optimized medium, EPS production was achieve at 2.65 ± 0.16 g/L after 4 days fermentation in a 5L bioreactor. Examination of cytotoxicity showed that the EPS from B. ochroleuca M21 did not have cytotoxic activity on human liver HL-7702 cells at concentration 0.025-1.6 mg/mL. In contrast, the EPS exhibited antiproliferative activities against cell lines of liver cancer (HepG2), gastric cancer (SGC-7901) and colon cancer (HT29) in a dose- and time-dependent manner in the concentration ranges of 0.1-0.45 mg/mL. PMID:27330527

  5. Targeted expression of BikDD combined with metronomic doxorubicin induces synergistic antitumor effect through Bax activation in hepatocellular carcinoma.

    PubMed

    Dai, Huei-Yue; Chen, Hui-Yu; Lai, Wei-Chen; Hung, Mien-Chie; Li, Long-Yuan

    2015-09-15

    Conventional chemotherapy is commonly used to treat advanced non-resectable hepatocellular carcinoma (HCC) but this treatment modality has not demonstrated convincing survival benefit in HCC patients. Our previous studies indicated that targeted expression of therapeutic BikDD driven by a liver cancer-specific α-fetoprotein promoter/enhancer (eAFP) in the VISA backbone (eAFP-VISA-BikDD) significantly and specifically kills HCC cells in multiple orthotopic animal models. To enhance its therapeutic efficacy, we combined eAFP-VISA-BikDD with chemotherapeutic agents and found that eAFP-VISA-BikDD plus doxorubicin (Dox) or 5-fluorouracil (5-FU) demonstrated synergistic cytotoxicity in HCC cells. Specifically, the combination of eAFP-VISA-BikDD plus Dox markedly induced apoptosis via increased Bax mitochondrial translocation and cytoplasmic cytochrome c release. Compared with either agent alone, a low dose of Dox combined with eAFP-VISA-BikDD induced better antitumor effect and prolonged longer survival of mice in two orthotopic liver cancer xenograft models. Our findings provide strong preclinical support for evaluating the combined therapy of eAFP-VISA-BikDD and Dox in a clinical setting as a treatment option for HCC. PMID:26247632

  6. Survivin promoter-regulated oncolytic adenovirus with Hsp70 gene exerts effective antitumor efficacy in gastric cancer immunotherapy

    PubMed Central

    Wang, Weiguo; Ji, Weidan; Hu, Huanzhang; Ma, Juming; Li, Xiaoya; Mei, Weiqun; Xu, Yang; Hu, Huizhen; Yan, Yan; Song, Qizhe; Li, Zhigang; Su, Changqing

    2014-01-01

    Gene therapy is a promising adjuvant therapeutic strategy for cancer treatment. To overcome the limitations of current gene therapy, such as poor transfection efficiency of vectors, low levels of transgene expression and lack of tumor targeting, the Survivin promoter was used to regulate the selective replication of oncolytic adenovirus in tumor cells, and the heat shock protein 70 (Hsp70) gene was loaded as the anticancer transgene to generate an AdSurp-Hsp70 viral therapy system. The efficacy of this targeted immunotherapy was examined in gastric cancer. The experiments showed that the oncolytic adenovirus can selectively replicate in and lyse the Survivin-positive gastric cancer cells, without significant toxicity to normal cells. AdSurp-Hsp70 reduced viability of cancer cells and inhibited tumor growth of gastric cancer xenografts in immuno-deficient and immuno-reconstruction mouse models. AdSurp-Hsp70 produced dual antitumor effects due to viral replication and high Hsp70 expression. This therapeutic system used the Survivin promoter-regulated oncolytic adenovirus vector to mediate targeted expression of the Hsp70 gene and ensure safety and efficacy for subsequent gene therapy programs against a variety of cancers. PMID:24473833

  7. Docetaxel Loaded PEG-PLGA Nanoparticles: Optimized Drug Loading, In-vitro Cytotoxicity and In-vivo Antitumor Effect

    PubMed Central

    Noori Koopaei, Mona; Khoshayand, Mohammad Reza; Mostafavi, Seyed Hossein; Amini, Mohsen; Khorramizadeh, Mohammad Reza; Jeddi Tehrani, Mahmood; Atyabi, Fatemeh; Dinarvand, Rassoul

    2014-01-01

    In this study a 3-factor, 3-level Box-Behnken design was used to prepare optimized docetaxel (DTX) loaded pegylated poly lactide-co-glycolide (PEG-PLGA) Nanoparticles (NPs) with polymer concentration (X1), drug concentration (X2) and ratio of the organic to aqueous solvent (X3) as the independent variables and particle size (Y1), poly dispersity index (PDI) (Y2) and drug loading (Y3) as the responses. The cytotoxicity of optimized DTX loaded PEG-PLGA NPs was studied in SKOV3 tumor cell lines by standard MTT assay. The in-vivo antitumor efficacy of DTX loaded PLGA-PEG NPs was assessed in tumor bearing female BALB/c mice. The optimum level of Y1, Y2 and Y3 predicted by the model were 188 nm, 0.16 and 9% respectively with perfect agreement with the experimental data. The in-vitro release profile of optimum formulation showed a burst release of approximately 20% (w/w) followed by a sustained release profile of the loaded drug over 288 h. The DTX loaded optimized nanoparticles showed a greater cytotoxicity against SKOV3 cancer cells than free DTX. Enhanced tumor-suppression effects were achieved with DTX-loaded PEG-PLGA NPs. These results demonstrated that optimized NPs could be a potentially useful delivery system for DTX as an anticancer agent. PMID:25276182

  8. Violacein inhibits matrix metalloproteinase mediated CXCR4 expression: potential anti-tumor effect in cancer invasion and metastasis.

    PubMed

    Platt, Derek; Amara, Suneetha; Mehta, Toral; Vercuyssee, Koen; Myles, Elbert L; Johnson, Terrance; Tiriveedhi, Venkataswarup

    2014-12-01

    Matrix metalloproteinases (MMP-2 and -9) play an important role in the tumor metastasis through cleavage of proinflammatory cytokines. Violacein a small molecule produced by Chromobacterium violaceum and has been implicated with anti-cancer effects. In this study we investigated the molecular basis of violacein mediated downregulation of CXCL12/CXCR4, chemokine-receptor ligand interaction. Zymography analysis demonstrated that violacein significantly inhibited the cytokine (TNFα and TGFβ) mediated MMP-2 activation in MCF-7 breast cancer cell line. MMP-2 plays a critical role in the secretion of inflammatory chemokine, CXCL12, involved in cell migration and cancer metastasis. ELISA analysis demonstrated that violacein inhibited the secretion of CXCL12 from the activated MCF-7 cells. Further, we show that MMP-2/-9 act synergistically at two distinct steps towards the membrane expression of the tumor metastasis chemokine receptor, CXCR4. Violacein efficiently downregulated the CXCR4 membrane expression through MMP-9 inhibition. Taken together, these studies demonstrate a unique anti-tumor mechanism of action of violacein through reduction of CXCL12/CXCR4 interaction. These studies could offer a novel venue for violacein in cancer therapy. PMID:25450700

  9. Interaction of Di-2-pyridylketone 2-pyridine Carboxylic Acid Hydrazone and Its Copper Complex with BSA: Effect on Antitumor Activity as Revealed by Spectroscopic Studies.

    PubMed

    Li, Cuiping; Huang, Tengfei; Fu, Yun; Liu, Youxun; Zhou, Sufeng; Qi, Zhangyang; Li, Changzheng

    2016-01-01

    The drug, di-2-pyridylketone-2-pyridine carboxylic acid hydrazone (DPPCAH) and its copper complex (DPPCAH-Cu) exhibit significant antitumor activity. However, the mechanism of their pharmacological interaction with the biological molecule bovine serum albumin (BSA) remains poorly understood. The present study elucidates the interactions between the drug and BSA through MTT assays, spectroscopic methods and molecular docking analysis. Our results indicate that BSA could attenuate effect on the cytotoxicity of DPPCAH, but not DPPCAH-Cu. Data from fluorescence quenching measurements demonstrated that both DPPCAH and DPPCAH-Cu could bind to BSA, with a reversed effect on the environment of tryptophan residues in polarity. CD spectra revealed that the DPPCAH-Cu exerted a slightly stronger effect on the secondary structure of BSA than DPPCAH. The association constant of DPPCAH with BSA was greater than that of DPPCAH-Cu. Docking studies indicated that the binding of DPPCAH to BSA involved a greater number of hydrogen bonds compared to DPPCAH-Cu. The calculated distances between bound ligands and tryptophans in BSA were in agreement with fluorescence resonance energy transfer results. Thus, the binding affinity of the drug (DPPCAH or DPPCAH-Cu) with BSA partially contributes to its antitumor activity; the greater the drug affinity is to BSA, the less is its antitumor activity. PMID:27136517

  10. Lovastatin and tumor necrosis factor-alpha exhibit potentiated antitumor effects against Ha-ras-transformed murine tumor via inhibition of tumor-induced angiogenesis.

    PubMed

    Feleszko, W; Bałkowiec, E Z; Sieberth, E; Marczak, M; Dabrowska, A; Giermasz, A; Czajka, A; Jakóbisiak, M

    1999-05-17

    Lovastatin, a drug commonly used in the treatment of hypercholesterolemia, has previously been reported to exert potentiated antitumor activity when combined with either tumor necrosis factor-alpha (TNF-alpha), cisplatin or doxorubicin in a melanoma model in mice. Since lovastatin interferes with the function of ras oncogene-encoded (Ras) proteins, we have investigated the antitumor activity of lovastatin and TNF-alpha using a Ha-ras-transformed murine tumor model. In in vitro studies, lovastatin inhibited the growth of cells transformed with Ha-ras oncogene (Ras-3T3 and HBL100-ras cells) more effectively than control NIH-3T3 and HBL100-neo cells. In in vivo experiments, the Ras-3T3 tumor demonstrated significantly increased sensitivity to combined treatment with both lovastatin (50 mg/kg) and TNF-alpha (1 microg/day) compared with either agent alone. Combined treatment with both agents also resulted in greater inhibition of blood-vessel formation. Ras-3T3 tumor cells produced increased amounts of vascular endothelial growth factor (VEGF) and lovastatin effectively suppressed VEGF production by these cells. Our results suggest that lovastatin increases antitumor activity of TNF-alpha against tumor cells transformed with v-Ha-ras oncogene via inhibition of tumor-induced blood-vessel formation. PMID:10225445

  11. Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines

    PubMed Central

    2012-01-01

    Background TAK733 is a novel allosteric, non-ATP-binding, inhibitor of the BRAF substrates MEK-1/2. Methods The growth inhibitory effects of TAK733 were assessed in a panel of 27 cutaneous and five uveal melanoma cell lines genotyped for driver oncogenic mutations. Flow cytometry, Western blots and metabolic tracer uptake assays were used to characterize the changes induced by exposure to TAK733. Results Fourteen cutaneous melanoma cell lines with different driver mutations were sensitive to the antiproliferative effects of TAK733, with a higher proportion of BRAFV600E mutant cell lines being highly sensitive with IC50s below 1 nM. The five uveal melanoma cell lines had GNAQ or GNA11 mutations and were either moderately or highly sensitive to TAK733. The tested cell lines wild type for NRAS, BRAF, GNAQ and GNA11 driver mutations were moderately to highly resistant to TAK733. TAK733 led to a decrease in pERK and G1 arrest in most of these melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733. MEK inhibition resulted in increase in pMEK more prominently in NRASQ61L mutant and GNAQ mutant cell lines than in BRAFV600E mutant cell lines. Uptake of the metabolic tracers FDG and FLT was inhibited by TAK733 in a manner that closely paralleled the in vitro sensitivity assays. Conclusions The MEK inhibitor TAK733 has antitumor properties in melanoma cell lines with different oncogenic mutations and these effects could be detectable by differential metabolic tracer uptake. PMID:22515704

  12. Anti-tumor effect via passive anti-angiogenesis of PEGylated liposomes encapsulating doxorubicin in drug resistant tumors.

    PubMed

    Kibria, Golam; Hatakeyama, Hiroto; Sato, Yusuke; Harashima, Hideyoshi

    2016-07-25

    The PEGylated liposomal (PEG-LP) Doxorubicin, PEG-LP (DOX), with a diameter of around 100nm, accumulates in tumors via the enhanced permeability and retention (EPR) effect, and is used clinically for the treatment of several types of cancer. However, there are a number of tumor types that are resistant to DOX. We report herein on a unique anti-tumor effect of PEG-LP (DOX) in a DOX-resistant tumor xenograft model. PEG-LP (DOX) failed to suppress the growth of the DOX-resistant tumors (ex. non-small cell lung cancer, H69AR; renal cell carcinoma, OSRC-2) as observed in the xenograft model. Unexpectedly, tumor growth was suppressed in a DOX-resistant breast cancer (MDA-MB-231) xenograft model. We investigated the mechanism by which PEG-LP (DOX) responses differ in different drug resistant tumors. In hyperpermeable OSRC-2 tumors, PEG-LP was distributed to deep tumor tissues, where it delivers DOX to drug-resistant tumor cells. In contrast, extracellular matrix (ECM) molecules such as collagen, pericytes, cancer-associated fibroblasts render MDA-MB-231 tumors hypopermeable, which limits the extent of the penetration and distribution of PEG-LP, thereby enhancing the delivery of DOX to the vicinity of the tumor vasculature. Therefore, a remarkable anti-angiogenic effect with a preferential suppression in tumor growth is achieved. Based on the above findings, it appears that the response of PEG-LP (DOX) to drug-resistant tumors results from differences in the tumor microenvironment. PMID:27234700

  13. Anti-tumoral effect of arsenic compound, sodium metaarsenite (KML001), in non-Hodgkin's lymphoma: an in vitro and in vivo study.

    PubMed

    Yoon, Jin Sun; Hwang, Deok Won; Kim, Eun Shil; Kim, Jung Soon; Kim, Sujong; Chung, Hwa Jin; Lee, Sang Kook; Yi, Jun Ho; Uhm, Jieun; Won, Young Woong; Park, Byeong Bae; Choi, Jung Hye; Lee, Young Yiul

    2016-02-01

    Arsenic compounds have been used in traditional medicine for several centuries. KML001 (sodium metaarsenite; NaAsO2) is an orally bio-available arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in lymphoid neoplasms. The aim of this study is to evaluate the anti-proliferative effect of KML001 in non-Hodgkin's lymphoma and to compare its efficacy with As2O3. KML001 inhibited cellular proliferation in all tested lymphoma cell lines as well as JurkatR cells (adriamycin-resistant Jurkat cells) in a dose-dependent manner, while As2O3 was not effective. Cell cycle regulatory protein studies have suggested that KML001 induces G1 arrest via p27-induced inhibition of the kinase activities of CDK2, 4, and 6. Treatment of KML001 induced apoptosis in Jurkat and JurkatR cells. The apoptotic process was associated with down-regulation of Bcl-2 (antiapoptotic molecule), up-regulation of Bax (proapoptotic molecule), and inhibition of caspase-3, -8, and -9. In addition, cell signaling including the STAT, PI3K/Akt, MAPK, and NF-κB signal pathways were inhibited in KML001-treated Jurkat and JurkatR cells. Furthermore, targeting the telomere by KML001 was observed in the Jurkat and JurkatR cells. The In vivo anti-tumoral activity of KML001 was confirmed in a xenograft murine model. Interestingly, partial responses were seen in two lymphoma patients treated with 10 mg/day (follicular lymphoma for 16 weeks and mantle cell lymphoma for 24 weeks) without severe toxicities. These findings suggest that KML001 may be a candidate agent for the treatment of de novo, refractory, and relapsed non-Hodgkin's lymphoma patients. PMID:26581399

  14. Boswellic acid exerts antitumor effects in colorectal cancer cells by modulating expression of the let-7 and miR-200 microRNA family

    PubMed Central

    Goel, Ajay

    2012-01-01

    Colorectal cancer (CRC) is a complex disease with genetic and epigenetic alterations in many key oncogenes and tumor suppressor genes. The active principle of a gum resin from Boswellia serrata, 3-acetyl-11-keto-β-boswellic acid (AKBA), has recently gained attention as a chemopreventive compound due to its ability to target key oncogenic proteins such as 5-lipoxygenase and nuclear factor-kappaB. AKBA has been shown to inhibit the growth of CRC cells; however, the precise molecular mechanisms underlying its anticancer activities in CRC remain unclear. We hypothesized that boswellic acids may achieve their chemopreventive effects by modulating specific microRNA (miRNA) pathways. We found that AKBA significantly up-regulated expression of the let-7 and miR-200 families in various CRC cell lines. Both let-7 and miR-200 are putative tumor-suppressive miRNAs. AKBA modulated the expression of several downstream targets of the let-7 and miR-200 families, such as CDK6, vimentin and E-cadherin. These data were further strengthened by miRNA knockdown studies, which revealed that inhibition of let-7i facilitated enhanced cancer cell proliferation, migration and invasion. In addition, AKBA also induced similar modulation of the let-7 and miR-200 downstream genes in CRC tumors orthotopically implanted in nude mice. These results indicate that AKBA-induced antitumor effects in CRC occur, at least partly through the up-regulation of specific miRNA pathways. Our data provide novel evidence that anticancer effects of boswellic acids are due in part to their ability to regulate cellular epigenetic machinery and further highlight the promise for this phytochemical in the preventative and therapeutic applications of CRC. PMID:22983985

  15. Proteasome inhibition potentiates antitumor effects of photodynamic therapy in mice through induction of ER stress and unfolded protein response

    PubMed Central

    Szokalska, Angelika; Makowski, Marcin; Nowis, Dominika; Wilczyński, Grzegorz M.; Kujawa, Marek; Wójcik, Cezary; Młynarczuk-Biały, Izabela; Salwa, Pawel; Bil, Jacek; Janowska, Sylwia; Agostinis, Patrizia; Verfaillie, Tom; Bugajski, Marek; Gietka, Jan; Issat, Tadeusz; Głodkowska, Eliza; Mrówka, Piotr; Stoklosa, Tomasz; Hamblin, Michael R; Mróz, Paweł; Jakóbisiak, Marek; Golab, Jakub

    2009-01-01

    Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity towards tumor cells by inducing production of reactive oxygen species such as singlet oxygen. PDT leads to oxidative damage of cellular macromolecules, including numerous proteins that undergo multiple modifications such as fragmentation, cross-linking and carbonylation that result in protein unfolding and aggregation. Since the major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in endoplasmatic reticulum (ER), aggravated ER stress and potentiated cytotoxicity towards tumor cells. Indeed, we observed that Photofrin-mediated PDT leads to robust carbonylation of cellular proteins and induction of unfolded protein response (UPR). Pre-treatment of tumor cells with three different proteasome inhibitors, including bortezomib, MG132 and PSI gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells of murine (EMT6 and C-26) as well as human (HeLa) origin to PDT-mediated cytotoxicity. Significant retardation of tumor growth with 60-100% complete responses was observed in vivo in two different murine tumor models (EMT6 and C-26) when PDT was combined with either bortezomib or PSI. Altogether these observations indicate that combination of PDT with proteasome inhibitors leads to potentiated antitumor effects. The results of these studies are of immediate clinical application as bortezomib is a clinically approved drug that undergoes extensive clinical evaluations for the treatment of solid tumors. PMID:19435917

  16. Yiqi Formula Enhances the Antitumor Effects of Erlotinib for Treatment of Triple-Negative Breast Cancer Xenografts

    PubMed Central

    Liao, Ming-juan; Ye, Mei-na; Zhou, Rui-juan; Sheng, Jia-yu; Chen, Hong-feng

    2014-01-01

    Yiqi formula (YF), a traditional herbal prescription, has long been used to treat triple-negative breast cancer (TNBC) patients. The present study aims to investigate the effects and the related mechanism of YF for treatment of TNBC xenografts. MDA-MB-231 (human TNBC) cells were subcutaneously injected into the second mammary fat pad of 40 female nude mice, which were divided into four groups: control, erlotinib (an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor), YF, and combination (YF plus erlotinib). All treatments were administered orally for 30 days. Inhibition rate of tumor weight by erlotinib, YF, and the combination was 26.47%, 17.24%, and 39.15%, respectively. Western blotting showed that YF, erlotinib, and the combination downregulated p-EGFR (P < 0.01) and p-Akt1 (pT308) (P < 0.05) and upregulated PTEN compared with control, and the combination was more efficacious than erlotinib alone (P < 0.05). Similar results were detected by immunohistochemistry. Real-time quantitative PCR showed that YF, erlotinib, and the combination increased PTEN mRNA (P < 0.05, P < 0.01) compared with control, and the combination was more efficacious than erlotinib alone (P < 0.05). In conclusion, YF can regulate the main components of the PI3K/Akt pathway in TNBC xenografts. When YF was used in combination with erlotinib, it enhanced the antitumor effects of erlotinib on TNBC xenografts. These findings suggest that YF is suitable to use for the treatment of TNBC patients. PMID:25389442

  17. Enhanced Antitumor Effect of Tirapazamine Delivered Intraperitoneally to VX2 Liver Tumor-Bearing Rabbits Subjected to Transarterial Hepatic Embolization

    SciTech Connect

    Sonoda, Akinaga Nitta, Norihisa Ohta, Shinich Nitta-Seko, Ayumi Nagatani, Yukihiro Takahashi, Masashi Murata, Kiyoshi

    2011-12-15

    Purpose: We evaluated the effects of the combination of Tirapazamine (TPZ), activated preferentially under hypoxic conditions, and gelatin microspheres (GMS) on the tumor growth ratio in rabbits. Methods: We assigned 20 liver tumor-bearing Japanese white rabbits to 4 equal groups. Group 1 received 1 ml of saline intra-arterially (i.a.) and 20 ml of saline intraperitoneally (i.p.; saline group). Group 2 was injected with GMS i.a. and 20 ml saline i.p. (GMS group). Group 3 received 1 ml of saline i.a. and 300 mg/m{sup 2} of TPZ i.p. (TPZ group), and group 4 was treated with GMS i.a. and 300 mg/m{sup 2} of TPZ i.p. (GMS + TPZ group). The infusion of GMS was stopped when the blood flow stagnated. Before and 7 days after treatment, the liver tumor volumes were measured as the total number of pixels on 0.3Tesla (T) magnetic resonance imaging (MRI) scans. Results: The tumor growth ratio (mean {+-} standard deviation) of the saline, GMS, TPZ, and GMS + TPZ groups was 519.15 {+-} 93.78, 279.24 {+-} 91.83, 369.78 {+-} 95.73, and 119.87 {+-} 17.62, respectively. The difference between the GMS + TPZ group and the other groups was statistically significant (P < 0.05). Conclusions: Our results show that the combination of TPZ i.p. and GMS i.a. enhanced the antitumor effect of TPZ. This procedure may represent a new alternative treatment for patients with hepatic cell carcinoma.

  18. Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation

    SciTech Connect

    Zeitlin, Benjamin D.; Spalding, Aaron C.; Campos, Marcia S.; Ashimori, Naoki; Dong Zhihong; Wang Shaomeng; Lawrence, Theodore S.; Noer, Jacques E.

    2010-11-01

    Purpose: To investigate the effect of a metronomic (low-dose, high-frequency) small-molecule inhibitor of Bcl-2 (TW-37) in combination with radiotherapy on microvascular endothelial cells in vitro and in tumor angiogenesis in vivo. Methods and Materials: Primary human dermal microvascular endothelial cells were exposed to ionizing radiation and/or TW-37 and colony formation, as well as capillary sprouting in three-dimensional collagen matrices, was evaluated. Xenografts vascularized with human blood vessels were engineered by cotransplantation of human squamous cell carcinoma cells (OSCC3) and human dermal microvascular endothelial cells seeded in highly porous biodegradable scaffolds into the subcutaneous space of immunodeficient mice. Mice were treated with metronomic TW-37 and/or radiation, and tumor growth was evaluated. Results: Low-dose TW-37 sensitized primary endothelial cells to radiation-induced inhibition of colony formation. Low-dose TW-37 or radiation partially inhibited endothelial cell sprout formation, and in combination, these therapies abrogated new sprouting. Combination of metronomic TW-37 and low-dose radiation inhibited tumor growth and resulted in significant increase in time to failure compared with controls, whereas single agents did not. Notably, histopathologic analysis revealed that tumors treated with TW-37 (with or without radiation) are more differentiated and showed more cohesive invasive fronts, which is consistent with less aggressive phenotype. Conclusions: These results demonstrate that metronomic TW-37 potentiates the antitumor effects of radiotherapy and suggest that patients with head and neck cancer might benefit from the combination of small molecule inhibitor of Bcl-2 and radiation therapy.

  19. Antitumor effects of nano-bubble hydrogen-dissolved water are enhanced by coexistent platinum colloid and the combined hyperthermia with apoptosis-like cell death.

    PubMed

    Asada, Ryoko; Kageyama, Katsuhiro; Tanaka, Hiroshi; Matsui, Hisakazu; Kimura, Masatsugu; Saitoh, Yasukazu; Miwa, Nobuhiko

    2010-12-01

    In order to erase reactive oxygen species (ROS) related with the proliferation of tumor cells by reducing activity of hydrogen, we developed functional water containing nano-bubbles (diameters: <900 nm for 71%/population) hydrogen of 1.1-1.5 ppm (the theoretical maximum: 1.6 ppm) with a reducing ability (an oxidation-reduction potential -650 mV, normal water: +100-200 mV) using a microporous-filter hydrogen-jetting device. We showed that hydrogen water erased ROS indispensable for tumor cell growth by ESR/spin trap, the redox indicator CDCFH-DA assay, and was cytotoxic to Ehrlich ascites tumor cells as assessed by WST-8 assay, crystal violet dye stain and scanning electron microscopy, after 24-h or 48-h incubation sequent to warming at 37°C or 42°C. Hydrogen water supplemented with platinum colloid (0.3 ppm Pt in 4% polyvinylpyrrolidone) had more antitumor activity than hydrogen water alone, mineral water alone (15.6%), hydrogen water plus mineral water, or platinum colloid alone as observed by decreased cell numbers, cell shrinkage and pycnosis (nuclear condensation)/karyorrhexis (nuclear fragmentation) indicative of apoptosis, together with cell deformation and disappearance of microvilli on the membrane surface. These antitumor effects were promoted by combination with hyperthermia at 42°C. Thus, the nano-bubble hydrogen water with platinum colloid is potent as an anti-tumor agent. PMID:21042740

  20. Antitumor and anti-cachectic effects of shark liver oil and fish oil: comparison between independent or associative chronic supplementation in Walker 256 tumor-bearing rats

    PubMed Central

    2013-01-01

    Background Shark liver oil (SLOil) and fish oil (FOil), which are respectively rich in alkylglycerols (AKGs) and n-3 polyunsaturated fatty acids (PUFAs), are able to reduce the growth of some tumors and the burden of cachexia. It is known that FOil is able to reduce proliferation rate and increase apoptotic cells and lipid peroxidation of tumor cells efficiently. However, there are few reports revealing the influence of SLOil on these parameters. In the current study, effects of FOil chronic supplementation on tumor growth and cachexia were taken as reference to compare the results obtained with SLOil supplementation. Also, we evaluated if the association of SLOil and FOil was able to promote additive effects. Methods Weanling male Wistar rats were divided into 4 groups: fed regular chow (C), supplemented (1 g/kg body weight) with SLOil (CSLO), FOil (CFO) and both (CSLO + FO). After 8 weeks half of each group was inoculated with Walker 256 cells originating new groups (W, WSLO, WFO and WSLO + FO). Biochemical parameters of cachexia, tumor weight, hydroperoxide content, proliferation rate and percentage of apoptotic tumor cells were analysed. Fatty acids and AKG composition of tumor and oils were obtained by high performance liquid chromatography and gas chromatography – mass spectrometry, respectively. Statistical analysis was performed by unpaired t-test and one-way ANOVA followed by a post hoc Tukey test. Results Fourteen days after inoculation, SLOil was able to restore cachexia parameters to control levels, similarly to FOil. WSLO rats presented significantly lower tumor weight (40%), greater tumor cell apoptosis (~3-fold), decreased tumor cell proliferation (35%), and higher tumor content of lipid hydroperoxides (40%) than observed in W rats, but FOil showed more potent effects. Supplementation with SLOil + FOil did not promote additive effects. Additionally, chromatographic results suggested a potential incorporation competition between the n

  1. [The Molecular Aspect of the Antitumor Effect of Oxaliplatin in Combination with 5-FU].

    PubMed

    Kitao, Hiroyuki; Kiyonari, Shinichi; Iimori, Makoto; Niimi, Shinichiro; Kataoka, Yuki; Akiyama, Shingo; Edahiro, Keitaro; Nakanishi, Ryota; Tokunaga, Eriko; Saeki, Hiroshi; Oki, Eiji; Kanaji, Shingo; Kakeji, Yoshihiro; Maehara, Yoshihiko

    2016-06-01

    Platinum-based chemotherapeutic drugs as a component of combination chemotherapy are widely used in the treatment of cancer. In particular, oxaliplatin(L-OHP), one such platinum-based chemotherapeutic drug, has a synergistic effect in combination with 5-FU and Leucovorin for the treatment of advanced colorectal cancer. However, the underlying molecular mechanism of this synergistic effect has not been fully clarified yet. In this review, we summarize several updates about the in vitro action of oxaliplatin in human tumor cells and discuss the underlying mechanism of its synergistic effect with 5-FU. PMID:27306806

  2. Examples of adjuvant treatment enhancing the antitumor effect of photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Cecic, Ivana; Sun, Jinghai; Chaplin, David J.

    1999-07-01

    Strategies for improving the clinical efficacy of photodynamic therapy (PDT) in treatment of solid cancers include applications of different types of adjuvant treatments in addition to this modality that may result in superior therapeutic outcome. Examples of such an approach investigated using mouse tumor models are presented in this report. It is shown that the cures of PDT treated subcutaneous tumors can be substantially improved by adjuvant therapy with: metoclopramide (enhancement of cancer cell apoptosis), combretastatin A-4 (selective destruction of tumor neovasculature), Roussin's Black Salt (light activated tumor localized release of nitric oxide), or dendritic cell-based adoptive immunotherapy (immune rejection of treated tumor).

  3. Study on in-vivo anti-tumor activity of Verbena officinalis extract.

    PubMed

    Kou, Wei-Zheng; Yang, Jun; Yang, Qing-Hui; Wang, Ying; Wang, Zhi-Fen; Xu, Su-Ling; Liu, Jing

    2013-01-01

    We investigated the anti-tumor effects of Verbena officinalis extract on H22 tumor-bearing mice and its effect on immune function. Mice model of H22 solid tumor was established, the mice were divided into five groups and administered the extract, later, tumors were removed and inhibition rates were calculated; spleens were removed and spleen indices were calculated, and the sheep red blood cell-delayed-type hypersensitivity (SRBC-DTH) and the serum hemolysin level were determined. The Verbena officinalis extract had anti-tumor effect, with the inhibition rate reaching 38.78%, it also increased the spleen index to a certain extent, in addition, the changes in DTA and HA were not obvious compared with the model group. The Verbena officinalis extract had in vivo anti-tumor effect, while causing no damage on the immune function. PMID:24146482

  4. Data for comparative proteomics analysis of the antitumor effect of CIGB-552 peptide in HT-29 colon adenocarcinoma cells.

    PubMed

    Núñez de Villavicencio-Díaz, Teresa; Ramos Gómez, Yassel; Oliva Argüelles, Brizaida; Fernández Masso, Julio R; Rodríguez-Ulloa, Arielis; Cruz García, Yiliam; Guirola-Cruz, Osmany; Perez-Riverol, Yasset; Javier González, Luis; Tiscornia, Inés; Victoria, Sabina; Bollati-Fogolín, Mariela; Besada Pérez, Vladimir; Guerra Vallespi, Maribel

    2015-09-01

    CIGB-552 is a second generation antitumor peptide that displays potent cytotoxicity in lung and colon cancer cells. The nuclear subproteome of HT-29 colon adenocarcinoma cells treated with CIGB-552 peptide was identified and analyzed [1]. This data article provides supporting evidence for the above analysis. PMID:26306321

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

    PubMed

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

    2015-09-20

    Our previous studies demonstrated that SIP-S had anti-metastatic activity and inhibited the growth of metastatic foci. Here we report the anti-tumor and immunoregulatory potential of SIP-S. SIP-S could significantly inhibit tumor growth in S180-bearing mice, and the inhibition rates was 43.7% at 30 mg/kg d. Besides, SIP-S could improve the thymus and spleen indices of S180-bearing mice and the mice treated with CTX. The combination of SIP-S (15 mg/kg d) with CTX (12.5 mg/kg d) showed higher anti-tumor potency than CTX (25 mg/kg d) alone. These results indicated that SIP-S had immunoenhancing and anticancer activity, and the immunoenhancing activity might be one mechanism for its anti-tumor activity. Flow cytometry results showed that SIP-S could induce tumor cells apoptosis. Western blot analysis indicated that SIP-S could upregulate the expression of pro-apoptotic proteins, caspase-3, -8, -9 and Bax, and downregulate the expression of anti-apoptotic protein PARP-1 in tumor cells in a dose-dependent manner. In summary, SIP-S has anti-tumor activity, which may be associated with its immunostimulating and pro-apoptotic activity. PMID:26050887

  6. Effects of Anti-Tumor Necrosis Factor α (anti-TNF) agents on Bone

    PubMed Central

    Kawai, Vivian K.; Stein, C. Michael; Perrien, Daniel S.; Griffin, Marie R.

    2013-01-01

    Purpose of the review TNF inhibitors are effective for achieving disease control in several inflammatory diseases. Although anti-TNF agents can inhibit bone loss in vitro, their role in the prevention of clinically relevant outcomes such as osteoporosis and fractures has not been clearly established. Recent findings There are many studies of the effects of TNF inhibitors on markers of bone turnover; however few have measured bone mineral density (BMD) or fractures. Most of these studies have small sample sizes and a minority had a placebo control group. Overall these studies suggest that the anti-resorptive effects of anti-TNF therapy are related to control of disease activity. Summary The antiresorptive effects of TNF inhibitors are likely related to their anti-inflammatory properties. Studies to date have not demonstrated any advantages of TNF inhibitors over traditional non biologic therapies in the prevention of bone loss and fractures. PMID:22810364

  7. Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells.

    PubMed

    Bongiorno-Borbone, Lucilla; Giacobbe, Arianna; Compagnone, Mirco; Eramo, Adriana; De Maria, Ruggero; Peschiaroli, Angelo; Melino, Gerry

    2015-07-10

    Lung cancer is the most feared of all cancers because of its heterogeneity and resistance to available treatments. Cancer stem cells (CSCs) are the cell population responsible for lung cancer chemoresistance and are a very good model for testing new targeted therapies. Clomipramine is an FDA-approved antidepressant drug, able to inhibit in vitro the E3 ubiquitin ligase Itch and potentiate the pro-apoptotic effects of DNA damaging induced agents in several cancer cell lines. Here, we investigated the potential therapeutic effect of desmethylclomipramine (DCMI), the active metabolite of Clomipramine, on the CSCs homeostasis. We show that DCMI inhibits lung CSCs growth, decreases their stemness potential and increases the cytotoxic effect of conventional chemotherapeutic drugs. Being DCMI an inhibitor of the E3 ubiquitin ligase Itch, we also verified the effect of Itch deregulation on CSCs survival. We found that the siRNA-mediated depletion of Itch induces similar anti-proliferative effects on lung CSCs, suggesting that DCMI might exert its effect, at least in part, by inhibiting Itch. Notably, Itch expression is a negative prognostic factor in two primary lung tumors datasets, supporting the potential clinical relevance of Itch inhibition to circumvent drug resistance in the treatment of lung cancer. PMID:26219257

  8. Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells

    PubMed Central

    Bongiorno-Borbone, Lucilla; Giacobbe, Arianna; Compagnone, Mirco; Eramo, Adriana; De Maria, Ruggero; Peschiaroli, Angelo; Melino, Gerry

    2015-01-01

    Lung cancer is the most feared of all cancers because of its heterogeneity and resistance to available treatments. Cancer stem cells (CSCs) are the cell population responsible for lung cancer chemoresistance and are a very good model for testing new targeted therapies. Clomipramine is an FDA-approved antidepressant drug, able to inhibit in vitro the E3 ubiquitin ligase Itch and potentiate the pro-apoptotic effects of DNA damaging induced agents in several cancer cell lines. Here, we investigated the potential therapeutic effect of desmethylclomipramine (DCMI), the active metabolite of Clomipramine, on the CSCs homeostasis. We show that DCMI inhibits lung CSCs growth, decreases their stemness potential and increases the cytotoxic effect of conventional chemotherapeutic drugs. Being DCMI an inhibitor of the E3 ubiquitin ligase Itch, we also verified the effect of Itch deregulation on CSCs survival. We found that the siRNA-mediated depletion of Itch induces similar anti-proliferative effects on lung CSCs, suggesting that DCMI might exert its effect, at least in part, by inhibiting Itch. Notably, Itch expression is a negative prognostic factor in two primary lung tumors datasets, supporting the potential clinical relevance of Itch inhibition to circumvent drug resistance in the treatment of lung cancer. PMID:26219257

  9. Fasting protects against the side effects of irinotecan but preserves its anti-tumor effect in Apc15lox mutant mice

    PubMed Central

    Huisman, Sander A; Bijman-Lagcher, Wendy; IJzermans, Jan NM; Smits, Ron; de Bruin, Ron WF

    2015-01-01

    Irinotecan is a widely used topoisomerase-I-inhibitor with a very narrow therapeutic window because of its severe toxicity. In the current study we have examined the effects of fasting prior to irinotecan treatment on toxicity and anti-tumor activity. FabplCre;Apc15lox/+ mice, which spontaneously develop intestinal tumors, of 27 weeks of age were randomized into 3-day fasted and ad libitum fed groups, followed by treatment with a flat-fixed high dose of irinotecan or vehicle. Side-effects were recorded until 11 days after the start of the experiment. Tumor size, and markers for cell-cycle activity, proliferation, angiogenesis, and senescence were measured. Fasted mice were protected against the side-effects of irinotecan treatment. Ad libitum fed mice developed visible signs of discomfort including weight loss, lower activity, ruffled coat, hunched-back posture, diarrhea, and leukopenia. Irinotecan reduced tumor size in fasted and ad libitum fed groups similarly compared to untreated controls (2.4 ± 0.67 mm and 2.4 ± 0.82 mm versus 3.0 ± 1.05 mm and 2.8 ± 1.08 mm respectively, P < 0.001). Immunohistochemical analysis showed reduced proliferation, a reduced number of vascular endothelial cells, and increased levels of senescence in tumors of both irinotecan treated groups. In conclusion, 3 days of fasting protects against the toxic side-effects of irinotecan in a clinically relevant mouse model of spontaneously developing colorectal cancer without affecting its anti-tumor activity. These results support fasting as a powerful way to improve treatment of colorectal carcinoma patients. PMID:25955194

  10. Combined gene therapy of endostatin and interleukin 12 with polyvinylpyrrolidone induces a potent antitumor effect on hepatoma

    PubMed Central

    Li, Pei-Yuan; Lin, Ju-Sheng; Feng, Zuo-Hua; He, Yu-Fei; Zhou, He-Jun; Ma, Xin; Cai, Xiao-Kun; Tian, De-An

    2004-01-01

    AIM: To study the antitumor effect of combined gene therapy of endostatin and interleukin 12 (IL-12) with polyvinylpyrrolidone (PVP) on mouse transplanted hepatoma. METHODS: Mouse endostatin eukaryotic plasmid (pSecES) with a mouse Igκ signal sequence inside and mouse IL-12 eukaryotic plasmid (pmIL-12) were transfected into BHK-21 cells respectively. Endostatin and IL-12 were assayed by ELISA from the supernant and used to culture endothelial cells and spleen lymphocytes individually. Proliferation of the latter was evaluated by MTT. H22 cells were inoculated into the leg muscle of mouse, which was injected intratumorally with pSecES/PVP, pmIL-12/PVP or pSecES + pmIL-12/PVP repeatedly. Tumor weight, serum endostatin and serum IL-12 were assayed. Tumor infiltrating lymphocytes, tumor microvessel density and apoptosis of tumor cells were also displayed by HE staining, CD31 staining and TUNEL. RESULTS: Endostatin and IL-12 were secreted after transfection, which could inhibit the proliferation of endothelial cells or promote the proliferation of spleen lymphocytes. Tumor growth was highly inhibited by 91.8% after injection of pSecES + pmIL-12/PVP accompanied by higher serum endostatin and IL-12, more infiltrating lymphocytes, fewer tumor vessels and more apoptosis cells compared with injection of pSecES/PVP, pmIL-12/PVP or vector/PVP. CONCLUSION: Mouse endostatin gene and IL-12 gene can be expressed after intratumoral injection with PVP. Angiogenesis of hepatoma can be inhibited synergisticly, lymphocytes can be activated to infiltrate, and tumor cells are induced to apoptosis. Hepatoma can be highly inhibited or eradiated. PMID:15259064

  11. Anti-Tumoral Effects of Anti-Progestins in a Patient-Derived Breast Cancer Xenograft Model.

    PubMed

    Esber, Nathalie; Cherbonnier, Clément; Resche-Rigon, Michèle; Hamze, Abdallah; Alami, Mouad; Fagart, Jérôme; Loosfelt, Hugues; Lombès, Marc; Chabbert-Buffet, Nathalie

    2016-04-01

    Breast cancer is a hormone-dependent disease in which estrogen signaling targeting drugs fail in about 10 % due to resistance. Strong evidences highlighted the mitogen role of progesterone, its ligands, and the corresponding progesterone receptor (PR) isoforms in mammary carcinoma. Several PR antagonists have been synthesized; however, some of them are non-selective and led to side or toxic effects. Herein, we evaluated the anti-tumor activity of a commercially available PR modulator, ulipristal acetate (UPA), and a new selective and passive PR antagonist "APR19" in a novel preclinical approach based on patient-derived breast tumor (HBCx-34) xenografted in nude mice. As opposed to P4 that slightly reduces tumor volume, UPA and APR19 treatment for 42 days led to a significant 30 % reduction in tumor weight, accompanied by a significant 40 % retardation in tumor growth upon UPA exposure while a 1.5-fold increase in necrotic areas was observed in APR19-treated tumors. Interestingly, PR expression was upregulated by a 2.5-fold factor in UPA-treated tumors while APR19 significantly reduced expression of both PR and estrogen receptor α, indicating a potential distinct molecular mechanism among PR antagonists. Cell proliferation was clearly reduced in UPA group compared to vehicle conditions, as revealed by the significant reduction in Ki-67, Cyclin D1, and proliferating cell nuclear antigen (PCNA) expression. Likewise, an increase in activated, cleaved poly(ADP-ribose) polymerase (PARP) expression was also demonstrated upon UPA exposure. Collectively, our findings provide direct in vivo evidence for anti-progestin-mediated control of human breast cancer growth, given their anti-proliferative and pro-apoptotic activities, supporting a potential role in breast cancer therapy. PMID:26941094

  12. The anti-tumor effects of cordycepin-loaded liposomes on the growth of hepatoma 22 tumors in mice and human hepatoma BEL-7402 cells in culture.

    PubMed

    Wu, Peng-Kai; Tao, Zhi; Ouyang, Zhao; Cao, Jiang-Ye; Geng, Di; Liu, Jin; Wang, Chun-Mei

    2016-09-01

    Liposomes have successfully been used for decades to encapsulate and protect drugs that are prone to deactivation in the body. The present study aimed to demonstrate the use of liposomes to encapsulate cordycepin, an adenosine analog that quickly loses its activity in vivo. The cordycepin-loaded liposomes were prepared by the ammonium sulfate gradient approach, and its in vitro and in vivo antitumour activities were evaluated using BEL-7402 cells and hepatocellular carcinoma H22 transplanted tumors, respectively. An MTT assay was used to observe the cytotoxicity of cells treated with cordycepin and cordycepin-loaded liposomes in vitro. High-content screening (HSC) was carried out using Hoechst 33342 to detect apoptotic cells and the ratio of cells in different cell cycle stages. The data demonstrated that both the cordycepin and the cordycepin-loaded liposomes resulted in clear cytotoxicity with IC50 values of 18.97 and 29.39 μg/mL, respectively. The latter showed significantly strong inhibitory effects on H22 tumor growth in mice, while the former did not show any inhibitory effects on tumor growth. In addition, the HSC assay showed that the cordycepin-loaded liposomes resulted in a higher rate of apoptosis than the cordycepin alone in BEL-7402 cells. Further data analysis revealed that the cells treated with cordycepin-loaded liposomes were predominately arrested at the G2/M phase (p < 0.05), while those treated with cordycepin alone were arrested in the G0/G1 phase (p < 0.05). In conclusion, these results suggest that liposomes can enhance and maintain the in vivo anti-tumor activity of cordycepin. PMID:26984179

  13. Antitumor drug effect of betulinic acid mediated by polyethylene glycol modified liposomes.

    PubMed

    Liu, Yanping; Gao, Dawei; Zhang, Xuwu; Liu, Zhiwei; Dai, Kun; Ji, Bingshuo; Wang, Qianqian; Luo, Liyao

    2016-07-01

    Betulinic acid (BA), as a natural pentacyclic lupine-type triterpene, principally derives from bark of white birch, due to its potent pharmacological properties and low side-effect, which has been demonstrated a prominent efficiency on cancer therapy. However, the poor solubility and low bioavailability limit its pharmaceutical effect. Herein, we reported the rapid efficient synthesis of the polyethylene glycol modified (PEGylated) BA liposomes using ethanol injection technique for the first time. In the study, hydrophobic BA was encapsulated in the lipid bilayer of liposomes, meanwhile hydrophilic PEG layer covered the surface of liposomes. The mean diameter of PEGylated BA liposomes was 142nm, which can effectively accumulate in the tumor tissues. In vitro drug release study showed that the PEGylated BA liposomes had a better sustained drug release effect than BA liposomes. The PEGylated BA liposomes also exhibited a better tumor inhibitory effect compared with those of free BA or BA liposomes in vitro and in vivo experiments. Therefore, the PEGylated BA liposomes could serve as a better alternative for the cancer therapy in future. PMID:27127036

  14. Differences in antitumor effects of various statins on human pancreatic cancer.

    PubMed

    Gbelcová, Helena; Lenícek, Martin; Zelenka, Jaroslav; Knejzlík, Zdenek; Dvoráková, Gabriela; Zadinová, Marie; Poucková, Pavla; Kudla, Michal; Balaz, Peter; Ruml, Tomás; Vítek, Libor

    2008-03-15

    Statins are widely used for the treatment of hypercholesterolemia. However, their inhibitory action on HMG-CoA reductase also results in the depletion of intermediate biosynthetic products, which importantly contribute to cell proliferation. The aim of the present study was to compare the effects of the individual commercially available statins on experimental pancreatic cancer. The in vitro effects of individual statins (pravastatin, atorvastatin, simvastatin, lovastatin, cerivastatin, rosuvastatin and fluvastatin) on the viability of human pancreatic cancer were evaluated in CAPAN-2, BxPc-3 and MiaPaCa-2 cell lines. The in vivo experiments were performed on nude mice xenotransplanted with CAPAN-2 cells. The mice received oral treatments either with a placebo, or with the statins mentioned earlier in a daily dose corresponding to a hypocholesterolemic dose in humans. The effect of these statins on the intracellular Ras protein, trafficking in MiaPaCa-2 transfected cells, was also investigated. Substantial differences in the tumor-suppressive effects of all statins were detected in both in vitro and in vivo experiments. While simvastatin exerted the highest tumor-suppressive effects in vitro, rosuvastatin (p = 0.002), cerivastatin (p = 0.002) and fluvastatin (p = 0.009) were the most potent compounds in an animal model. All statins (except pravastatin) inhibited intracellular Ras protein translocation. In summary, substantial tumor-suppressive effects of various statins on the progression of experimental pancreatic adenocarcinoma were demonstrated, with marked differences among individual statins. These results support greatly the potential of statins for the chemoadjuvant treatment of pancreatic cancer. PMID:18027870

  15. Special antitumor immune effects of laser immunotherapy with SWNT-GC

    NASA Astrophysics Data System (ADS)

    Zhou, Feifan; Song, Sheng; Chen, Wei R.

    2014-02-01

    In our previous work, we constructed a multifunction nano system SWNT-GC, which can synergize photothermal and immunological effects. To further improve the application of this system, we study the cytotoxicity of SWNT-GC and investigate the effects on malignant tumor therapy. Here, we selected the optimal concentration of GC and SWNTs for the stable SWNT-GC construction. No cytotoxicity was observed under the dose used in the experiments. Using mouse melanoma tumor model, Laser+SWNT-GC treatment resulted in a significant mice survival rate, there were no long-term survivors under other treatment. It is providing a promising treatment modality for the malignancy.

  16. Implementation of Complexity Analyzing Based on Additional Effect

    NASA Astrophysics Data System (ADS)

    Zhang, Peng; Li, Na; Liang, Yanhong; Liu, Fang

    According to the Complexity Theory, there is complexity in the system when the functional requirement is not be satisfied. There are several study performances for Complexity Theory based on Axiomatic Design. However, they focus on reducing the complexity in their study and no one focus on method of analyzing the complexity in the system. Therefore, this paper put forth a method of analyzing the complexity which is sought to make up the deficiency of the researches. In order to discussing the method of analyzing the complexity based on additional effect, this paper put forth two concepts which are ideal effect and additional effect. The method of analyzing complexity based on additional effect combines Complexity Theory with Theory of Inventive Problem Solving (TRIZ). It is helpful for designers to analyze the complexity by using additional effect. A case study shows the application of the process.

  17. Antitumor effects of combining tumor radiation with the antivascular action of ultrasound stimulated microbubbles

    PubMed Central

    Ji, Yanlei; Han, Zhen; Shao, Limei; Zhao, Yuehuan

    2015-01-01

    Objective: More and more evidence indicates tumor vasculature plays an important role in tumor radiation response. In this study, we investigated ultrasound stimulated microbubbles to enhance the effects of radiation. Methods: Human bladder cancer HT-1376 xenografts in severe combined immuno-deficient mice were used. High-frequency (25 MHz) ultrasound was used to image tumor responses caused by ultrasound-stimulated microbubbles in combination with radiation. Human bladder xenografts grown in severe combined immunodeficiency (SCID) mice were treated using microbubbles stimulated with ultrasound at 250, 570, or 750 kPa, and exposed to 0, 2, or 8 Gy of radiation. Tumors were imaged prior to treatment and 24 hours after treatment. Spectral analysis of images acquired from treated tumors revealed overall increases in ultrasound backscatter intensity and the spectral intercept parameter. Results: There existed a synergistic effect in vivo with combined single treatments of ultrasound-stimulated microbubble vascular perturbation and radiation inducing an over 10-fold greater cell kill with combined treatments. We further demonstrate that induction of ceramide-related endothelial cell apoptosis, leading to vascular disruption, is a causative mechanism. In vivo experiments with ultrasound and bubbles permit radiation doses to be decreased significantly for comparable effect. Conclusion: We envisage this unique combined ultrasound-based vascular perturbation and radiation treatment method being used to enhance the effects of radiation in a tumor, leading to greater tumor eradication. PMID:26617705

  18. Wogonin potentiates the antitumor action of etoposide and ameliorates its adverse effects.

    PubMed

    Enomoto, Riyo; Koshiba, Chika; Suzuki, Chie; Lee, Eibai

    2011-05-01

    Wogonin, a flavone in the roots of Scutellaria baicalensis, reduced etoposide-induced apoptotic cell death in normal cells, such as bone marrow cells and thymocytes. On the other hand, wogonin potentiated the proapoptotic or cytotoxic action of etoposide in tumor cells, such as Jurkat, HL-60, A549, and NCI-H226. These contradictory actions of wogonin on apoptosis are distinguished by normal or cancer cell types. Wogonin had no effect on apoptosis induced by other anticancer agents in the tumor cells. Thus, the potentiation effect of wogonin was observed only in etoposide-induced apoptosis in tumor cells. In a functional assay for P-glycoprotein (P-gp), wogonin suppressed excretion of calcein, a substrate for P-gp, in these tumor cells. Moreover, wogonin decreased the excretion of radiolabeled etoposide and accordingly increased intracellular content of this agent in the cells. P-gp inhibitors showed a similar potentiation effect on etoposide-induced apoptosis in these tumor cells. Thus, wogonin is likely to potentiate the anticancer action of etoposide due to P-gp inhibition and accumulation of this agent. These findings suggest that wogonin may be a useful chemotherapeutic adjuvant to potentiate the pharmacological action of etoposide and ameliorate its adverse effects. PMID:20658136

  19. Antitumoral Effect of Hibiscus sabdariffa on Human Squamous Cell Carcinoma and Multiple Myeloma Cells.

    PubMed

    Malacrida, Alessio; Maggioni, Daniele; Cassetti, Arianna; Nicolini, Gabriella; Cavaletti, Guido; Miloso, Mariarosaria

    2016-10-01

    Cancer is a leading cause of death worldwide. Despite therapeutic improvements, some cancers are still untreatable. Recently there has been an increasing interest in the use of natural substances for cancer prevention and treatment. Hibiscus sabdariffa (HS) is a plant, belonging to Malvaceae family, widespread in South Asia and Central Africa. HS extract (HSE) used in folk medicine, gained researchers' interest thanks to its antioxidant, anti-inflammatory, and chemopreventive properties. In the present study, we initially assessed HSE effect on a panel of human tumor cell lines. Then we focused our study on the following that are most sensitive to HSE action cell lines: Multiple Myeloma (MM) cells (RPMI 8226) and Oral Squamous Cell Carcinoma (OSCC) cells (SCC-25). In both RPMI 8226 and SCC-25 cells, HSE impaired cell growth, exerted a reversible cytostatic effect, and reduced cell motility and invasiveness. We evaluated the involvement of MAPKs ERK1/2 and p38 in HSE effects by using specific inhibitors, U0126 and SB203580, respectively. For both SCC-25 and RPMI 8226, HSE cytostatic effect depends on p38 activation, whereas ERK1/2 modulation is crucial for cell motility and invasiveness. Our results suggest that HSE may be a potential therapeutic agent against MM and OSCC. PMID:27618152

  20. Antitumor Effects of Flavopiridol on Human Uterine Leiomyoma In Vitro and in a Xenograft Model

    PubMed Central

    Lee, Hyun-Gyo; Baek, Jong-Woo; Shin, So-Jin; Kwon, Sang-Hoon; Cha, Soon-Do; Park, Won-Jin; Chung, Rosa; Choi, Eun-Som; Lee, Gun-Ho

    2014-01-01

    Dysregulated cyclin-dependent kinases (CDKs) are considered a potential target for cancer therapy. Flavopiridol is a potent CDK inhibitor. In this study, the antiproliferative effect of the flavonoid compound flavopiridol and its mechanism in human uterine leiomyoma cells were investigated. The present study focused on the effect of flavopiridol in cell proliferation and cell cycle progression in primary cultured human uterine leiomyoma cells. Cell viability and cell proliferation assays were conducted. Flow cytometry was performed to determine the effect of flavopiridol on cell cycle. The expression of cell cycle regulatory-related proteins was evaluated by Western blotting. Cell viability and proliferation of uterine leiomyoma cells were significantly reduced by flavopiridol treatment in a dose-dependent manner. Flow cytometry results showed that flavopiridol induced G1 phase arrest. Flavopiridol-induced growth inhibition in uterine leiomyoma cells was associated with increased expression of p21cip/wafl and p27kip1 in a dose-dependent manner. Downregulation of CDK2/4 and Cyclin A with a concomitant increase in dephosphorylation of retinoblastoma was observed. This study demonstrates that flavopiridol inhibits cell proliferation by initiating G1 cell cycle arrest in human uterine leiomyoma. We also found that flavopiridol is effective in inhibiting xenografted human uterine leiomyoma growth. These results indicate that flavopiridol could prove to be a promising chemopreventive and therapeutic agent for human uterine leiomyoma. PMID:24572052

  1. The Antitumor Effect of Metformin Is Mediated by miR-26a in Breast Cancer.

    PubMed

    Cabello, Paula; Pineda, Begoña; Tormo, Eduardo; Lluch, Ana; Eroles, Pilar

    2016-01-01

    Metformin, a drug approved for diabetes type II treatment, has been associated with a reduction in the incidence of breast cancer and metastasis and increased survival in diabetic breast cancer patients. High levels of miR-26a expression have been proposed as one of the possible mechanisms for this effect; likewise, this miRNA has also been associated with survival/apoptosis processes in breast cancer. Our aim was to evaluate if miR-26a and some of its targets could mediate the effect of metformin in breast cancer. The viability of MDA-MB-231, MDA-MB-468, and MCF-7 breast cancer cell lines was evaluated with an MTT assay after ectopic overexpression and/or downregulation of miR-26a. Similarly, the expression levels of the miR-26a targets CASP3, CCNE2, ABL2, APAF1, XIAP, BCL-2, PTEN, p53, E2F3, CDC25A, BCL2L1, MCL-1, EZH2, and MTDH were assessed by quantitative polymerase chain reaction (PCR). The effect of metformin treatment on breast cancer cell viability and miR-26a, BCL-2, PTEN, MCL-1, EZH2, and MTDH modulation were evaluated. Wound healing experiments were performed to analyze the effect of miR-26a and metformin treatment on cell migration. MiR-26a overexpression resulted in a reduction in cell viability that was partially recovered by inhibiting it. E2F3, MCL-1, EZH2, MTDH, and PTEN were downregulated by miR-26a and the PTEN (phosphatase and tensin homolog) protein was also reduced after miR-26a overexpression. Metformin treatment reduced breast cancer cell viability, increased miR-26a expression, and led to a reduction in BCL-2, EZH2, and PTEN expression. miR-26a inhibition partly prevents the metformin viability effect and the PTEN and EZH2 expression reduction. Our results indicate that metformin effectively reduces breast cancer cell viability and suggests that the effects of the drug are mediated by an increase in miR-26a expression and a reduction of its targets, PTEN and EHZ2 Thus, the use of metformin in breast cancer treatment constitutes a promising

  2. The Antitumor Effect of Metformin Is Mediated by miR-26a in Breast Cancer

    PubMed Central

    Cabello, Paula; Pineda, Begoña; Tormo, Eduardo; Lluch, Ana; Eroles, Pilar

    2016-01-01

    Metformin, a drug approved for diabetes type II treatment, has been associated with a reduction in the incidence of breast cancer and metastasis and increased survival in diabetic breast cancer patients. High levels of miR-26a expression have been proposed as one of the possible mechanisms for this effect; likewise, this miRNA has also been associated with survival/apoptosis processes in breast cancer. Our aim was to evaluate if miR-26a and some of its targets could mediate the effect of metformin in breast cancer. The viability of MDA-MB-231, MDA-MB-468, and MCF-7 breast cancer cell lines was evaluated with an MTT assay after ectopic overexpression and/or downregulation of miR-26a. Similarly, the expression levels of the miR-26a targets CASP3, CCNE2, ABL2, APAF1, XIAP, BCL-2, PTEN, p53, E2F3, CDC25A, BCL2L1, MCL-1, EZH2, and MTDH were assessed by quantitative polymerase chain reaction (PCR). The effect of metformin treatment on breast cancer cell viability and miR-26a, BCL-2, PTEN, MCL-1, EZH2, and MTDH modulation were evaluated. Wound healing experiments were performed to analyze the effect of miR-26a and metformin treatment on cell migration. MiR-26a overexpression resulted in a reduction in cell viability that was partially recovered by inhibiting it. E2F3, MCL-1, EZH2, MTDH, and PTEN were downregulated by miR-26a and the PTEN (phosphatase and tensin homolog) protein was also reduced after miR-26a overexpression. Metformin treatment reduced breast cancer cell viability, increased miR-26a expression, and led to a reduction in BCL-2, EZH2, and PTEN expression. miR-26a inhibition partly prevents the metformin viability effect and the PTEN and EZH2 expression reduction. Our results indicate that metformin effectively reduces breast cancer cell viability and suggests that the effects of the drug are mediated by an increase in miR-26a expression and a reduction of its targets, PTEN and EHZ2 Thus, the use of metformin in breast cancer treatment constitutes a promising

  3. Effects of fuel and additives on combustion chamber deposits

    SciTech Connect

    Jackson, M.M.; Pocinki, S.B.

    1994-10-01

    The effects of gasoline composition, as represented in typical regular and premium unleaded gasolines and fuel additives, on Combustion Chamber Deposits (CCD) were investigated in BMW and Ford tests. In addition, the influences of engine lubricant oil and ethanol oxygenate on CCD were examined in Ford 2.3L engine dynamometer tests. Also, additive effects of packages based on mineral oil fluidizers versus synthetic fluidizers were studied in several different engines for CCD. Finally, a new method for evaluating the effect of fluidizers on valve sticking is introduced. 6 refs., 16 figs., 14 tabs.

  4. Effect of additives on the purification of urease

    NASA Astrophysics Data System (ADS)

    Yu, X.; Wang, J.; Ulrich, J.

    2015-12-01

    The effect of additives on the purification of proteins was investigated. The target protein studied here is the enzyme urease. Studies on the purification of urease from jack bean meal were carried out. 32% (v/v) acetone was utilized to extract urease from the jack bean meal. Further purification by crystallization with the addition of 2-mercaptoethanol and EDTA disodium salt dehydrate was carried out. It was found out that the presence of additives can affect the selectivity of the crystallization. Increases in both purity and yield of the urease after crystallization were observed in the presence of additives, which were proven using both SDS-PAGE and activity. Urease crystals with a yield of 69.9% and a purity of 85.1% were obtained in one crystallization step in the presence of additives. Furthermore, the effect of additives on the thermodynamics and kinetics of urease crystallization was studied.

  5. AntiTumor and Immunoregulatory Effects of Fermented Papaya Preparation (FPP: SAIDOPS501).

    PubMed

    Murakami, Shinki; Eikawa, Shingo; Kaya, Savas; Imao, Mitsuko; Aji, Toshiki

    2016-01-01

    Various beneficial effects have been described for fermented papaya preparation (FPP: SAIDOPS501) based on its antioxidative and antiinflammatory functions. The present study was designed to determine the effects of FPP on carcinogenesis in vivo, and immunomodulatory function in vitro. Mice were injected with RL male 1 cells subcutaneously or 3methylcholantherene (MCA) intravenously to induce cancer and orally or intraperitoneally treated with FPP solution. Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers and patients with atopic dermatitis, treated with FPP, and subjected to measurement of cytokine production and changes in Foxp3expressing regulatory T cell (Treg) stimulated with phytohemagglutinin (PHA). Administration of FPP suppressed tumor size and the incidence of malignancy. In vitro, treatment of PBMC with FPP induced IL1?, TNFα and IFNγ production. Moreover, FPP suppressed proliferation of PHAstimulated Foxp3expressing Treg. These results suggest that FPP has chemotherapeutic properties. PMID:27509932

  6. Anti-tumor effect of SLPI on mammary but not colon tumor growth.

    PubMed

    Amiano, Nicolás O; Costa, María J; Reiteri, R Macarena; Payés, Cristian; Guerrieri, Diego; Tateosian, Nancy L; Sánchez, Mercedes L; Maffia, Paulo C; Diament, Miriam; Karas, Romina; Orqueda, Andrés; Rizzo, Miguel; Alaniz, Laura; Mazzolini, Guillermo; Klein, Slobodanka; Sallenave, Jean-Michel; Chuluyan, H Eduardo

    2013-02-01

    Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor that was related to cancer development and metastasis dissemination on several types of tumors. However, it is not known the effect of SLPI on mammary and colon tumors. The aim of this study was to examine the effect of SLPI on mammary and colon tumor growth. The effect of SLPI was tested on in vitro cell apoptosis and in vivo tumor growth experiments. SLPI over-expressing human and murine mammary and colon tumor cells were generated by gene transfection. The administration of murine mammary tumor cells over-expressing high levels of SLPI did not develop tumors in mice. On the contrary, the administration of murine colon tumor cells over-expressing SLPI, developed faster tumors than control cells. Intratumoral, but not intraperitoneal administration of SLPI, delayed the growth of tumors and increased the survival of mammary but not colon tumor bearing mice. In vitro culture of mammary tumor cell lines treated with SLPI, and SLPI producer clones were more prone to apoptosis than control cells, mainly under serum deprivation culture conditions. Herein we demonstrated that SLPI induces the apoptosis of mammary tumor cells in vitro and decreases the mammary but not colon tumor growth in vivo. Therefore, SLPI may be a new potential therapeutic tool for certain tumors, such as mammary tumors. PMID:22767220

  7. Potent anti-tumor effects of EGFR-targeted hybrid peptide on mice bearing liver metastases.

    PubMed

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

    2016-01-01

    In this study, we investigated the therapeutic efficacy of EGFR2R-lytic hybrid peptide for the treatment of liver metastasis from colon carcinoma. The cytotoxic activity of the hybrid peptide against luciferase-expressing human colon cancer (HCT-116-luc) cells was determined by the WST-8 assay. The experimental mouse model of liver metastases was generated by splenic injection of HCT-116-luc cells. The hybrid peptide was intravenously injected into mice the day after cell implantation at a dose of 5 mg/kg and this was repeated on alternate days for a total of 7 doses. Saline-treated mice were used as controls. Tumor growth and therapeutic responses were monitored by an IVIS imaging system. It was shown that the hybrid peptide exhibited potent cytotoxic activity against HCT-116-luc cells and the liver metastases were significantly reduced after intravenous injections of hybrid peptide compared with controls. Furthermore, Kaplan–Meier analysis showed that hybrid peptide-treated mice had significantly longer survival than controls. In addition, bright-field and ex vivo imaging of liver tissue revealed that mice treated with the hybrid peptide had significantly fewer tumors compared with controls. These results demonstrated that the EGFR2R-lytic hybrid peptide is a potential treatment option for patients with colorectal cancer metastases in the liver. PMID:26467564

  8. 5-Hydroxy-3,6,7,8,3',4'-hexamethoxyflavone, a polymethoxyflavone, exerts antitumor effect on PI3K/Akt signaling pathway in human gastric cancer cell BGC-7901.

    PubMed

    Wang, Xinjian; Xia, Min

    2016-10-01

    5-Hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5HHMF), a polymethoxyflavone (PMF) mainly found in citrus plants, exhibits excellent physiological functions. In this study, we aimed to investigate the anticancer activity of 5HHMF against human gastric cancer cell BGC-7901 both in vitro and in vivo and illustrate the potential mechanisms. The proliferation of BGC-7901 cells was assessed by MTT assay. Reactive oxygen species (ROS) level was determined by ELISA kit. The protein expression was determined by western blot analysis. Antitumor activity of 5HHMF in vivo was evaluated in BALB/c nude mice. The results showed that treatment with 5HHMF significantly suppressed BGC-7901 cells proliferation, increased ROS generation, and upregulated cytochrome c release from the mitochondria to the cytosol. Western blot analysis demonstrated that 5HHMF significantly downregulated the expression of procaspase-3, procaspase-9, and PARP and upregulated cleaved caspase-3, cleaved caspase-9, cleaved PARP, and Bax/Bcl-2 ratio. Meanwhile, 5HHMF treatment markedly decreased the expression of PI3K and p-Akt. In addition, 5HHMF effectively inhibited tumor growth in xenograft models in BALB/c nude mice without major side action. In summary, 5HHMF-induced apoptosis via targeting PI3K/Akt, indicating 5HHMF is a potential antitumor agent for gastric cancer. PMID:26671739

  9. Polymer Photooxidation: An Experiment to Demonstrate the Effect of Additives.

    ERIC Educational Resources Information Center

    Allen, Norman S.; McKellar, John F.

    1979-01-01

    This undergraduate experiment shows that the inclusion of an appropriate additive can have a very marked effect on the physical properties of a polymer. The polymer used is polypropylene and the additives are 2-hydroxy-4-octyloxy-benzophenone and benzophenone. (BB)

  10. Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia.

    PubMed

    Sharabani, Hagar; Izumchenko, Eugene; Wang, Qing; Kreinin, Rita; Steiner, Michael; Barvish, Zeev; Kafka, Michael; Sharoni, Yoav; Levy, Joseph; Uskokovic, Milan; Studzinski, George P; Danilenko, Michael

    2006-06-15

    1alpha,25-dihydroxyvitamin D(3) (1,25D(3)) is a powerful differentiation agent, which has potential for treatment of myeloid leukemias and other types of cancer, but the calcemia produced by pharmacologically active doses precludes the use of this agent in the clinic. We have shown that carnosic acid, the major rosemary polyphenol, enhances the differentiating and antiproliferative effects of low concentrations of 1,25D(3) in human myeloid leukemia cell lines (HL60, U937). Here we translated these findings to in vivo conditions using a syngeneic mouse leukemia tumor model. To this end, we first demonstrated that as in HL60 cells, differentiation of WEHI-3B D(-) murine myelomonocytic leukemia cells induced by 1 nM 1,25D(3) or its low-calcemic analog, 1,25-dihydroxy-16-ene-5,6-trans-cholecalciferol (Ro25-4020), can be synergistically potentiated by carnosic acid (10 microM) or the carnosic acid-rich ethanolic extract of rosemary leaves. This effect was accompanied by cell cycle arrest in G0 + G1 phase and a marked inhibition of cell growth. In the in vivo studies, i.p. injections of 2 microg Ro25-4020 in Balb/c mice bearing WEHI-3B D(-) tumors produced a significant delay in tumor appearance and reduction in tumor size, without significant toxicity. Another analog, 1,25-dihydroxy-16,23Z-diene-20-epi-26,27-hexafluoro-19-nor-cholecalciferol (Ro26-3884) administered at the same dose was less effective than Ro25-4020 and profoundly toxic. Importantly, combined treatment with 1% dry rosemary extract (mixed with food) and 1 microg Ro25-4020 resulted in a strong cooperative antitumor effect, without inducing hypercalcemia. These results indicate for the first time that a plant polyphenolic preparation and a vitamin D derivative can cooperate not only in inducing leukemia cell differentiation in vitro, but also in the antileukemic activity in vivo. These data may suggest novel protocols for chemoprevention or differentiation therapy of myeloid leukemia. PMID:16395705

  11. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells

    PubMed Central

    Muniyan, Sakthivel; D’Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G.; Bu, Xiu R.; Batra, Surinder K.; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents. PMID:26121643

  12. Unraveling Additive from Nonadditive Effects Using Genomic Relationship Matrices

    PubMed Central

    Muñoz, Patricio R.; Resende, Marcio F. R.; Gezan, Salvador A.; Resende, Marcos Deon Vilela; de los Campos, Gustavo; Kirst, Matias; Huber, Dudley; Peter, Gary F.

    2014-01-01

    The application of quantitative genetics in plant and animal breeding has largely focused on additive models, which may also capture dominance and epistatic effects. Partitioning genetic variance into its additive and nonadditive components using pedigree-based models (P-genomic best linear unbiased predictor) (P-BLUP) is difficult with most commonly available family structures. However, the availability of dense panels of molecular markers makes possible the use of additive- and dominance-realized genomic relationships for the estimation of variance components and the prediction of genetic values (G-BLUP). We evaluated height data from a multifamily population of the tree species Pinus taeda with a systematic series of models accounting for additive, dominance, and first-order epistatic interactions (additive by additive, dominance by dominance, and additive by dominance), using either pedigree- or marker-based information. We show that, compared with the pedigree, use of realized genomic relationships in marker-based models yields a substantially more precise separation of additive and nonadditive components of genetic variance. We conclude that the marker-based relationship matrices in a model including additive and nonadditive effects performed better, improving breeding value prediction. Moreover, our results suggest that, for tree height in this population, the additive and nonadditive components of genetic variance are similar in magnitude. This novel result improves our current understanding of the genetic control and architecture of a quantitative trait and should be considered when developing breeding strategies. PMID:25324160

  13. Mathematics Anxiety Effects in Simple and Complex Addition.

    ERIC Educational Resources Information Center

    Faust, Michael W.; And Others

    1996-01-01

    Reports three experiments that show that anxiety effects were prominent in two-column addition problems, especially those involving carrying. Elaborates a theory of mathematics anxiety. Contains 50 references. (SKS)

  14. Antitumor effect of Kanglaite® injection in human pancreatic cancer xenografts

    PubMed Central

    2014-01-01

    Background Kanglaite® injection (KLT), with a main ingredient of Coix seed oil (a traditional Chinese medicine), has been widely used for cancer treatment in China. KLT has an inhibitory effect on many kinds of tumors and PI3K/Akt/mTOR signaling promotes cell survival, proliferation, and progression in cancer cells. Therefore, targeting this pathway may lead to the development of novel therapeutic approaches for human cancers. Methods Here, we examined the effects of KLT on the PI3K/Akt/mTOR pathway in pancreatic cancer xenografts in mice, and assessed its therapeutic potential. Growth and apoptosis of tumor xenografts were examined, and the expression levels of genes and proteins involved in the PI3K/Akt/mTOR pathway were measured by RT-PCR and western blotting, respectively. Results Our results revealed that KLT dramatically inhibited the growth of pancreatic cancer xenografts and induced apoptosis simultaneously. Furthermore, it downregulated the expression of phospho-Akt and phospho-mTOR. Conclusions These results suggest that KLT can suppress growth and induce apoptosis of pancreatic cancer xenografts. Moreover, KLT can downregulate the expression of phospho-Akt and phospho-mTOR to modulate the PI3K/Akt/mTOR signaling pathway. PMID:25005526

  15. A Chinese herbal Formula, Chang-Wei-Qin, Synergistically Enhances Antitumor Effect of Oxaliplatin.

    PubMed

    Zhang, Yong; Zhang, Qiang; Fan, Zhongze; Sun, Jue; Liu, Xulin; Cheng, Lingling; Li, Ao; Xu, Jianhua

    2015-04-01

    Chang-Wei-Qing (CWQ), a Chinese herbal formula, has long been employed clinically to treat cancers. In this study, we investigated the synergistic effect of CWQ with oxaliplatin (OXA) on the tumor growth inhibition of orthotopic transplanted colon cancer and explored the underlying mechanism. By generating the orthotopic transplanted nude mouse model of human colon carcinoma, we found that (1) CWQ enhanced OXA-mediated tumor suppression by 4.25-fold. (2) The body weights of nude mice in CWQ group and combination group were increased. (3) The survival time of tumor-bearing nude mice was dramatically improved in CWQ and CWQ/OXA group. (4) CWQ could restore OXA-mediated deregulation of copper transporter genes, hCTR1, ATP7A and ATP7B. (5) OXA-induced drug resistance index for OXA, 5-FU, HCPT and THP were 7.59, 4.28, 5.78 and 4.50 respectively, while the reversal index by combined CWQ treatment were 6.57, 2.61, 4.97 and 3.10, respectively. Our study demonstrates that the repeated intraperitoneal injection of OXA can induce multi-drug resistance of orthotopic transplanted nude mouse model of human colon carcinoma. The CWQ treatment can alleviate OXA-triggered side effects and reverse platinum drug resistance via up-regulation of hCTR1 expression and down-regulation of ATP7A and ATP7B levels. PMID:25103530

  16. Willow Leaves' Extracts Contain Anti-Tumor Agents Effective against Three Cell Types

    PubMed Central

    El-Shemy, Hany A.; Aboul-Enein, Ahmed M.; Aboul-Enein, Khalid Mostafa; Fujita, Kounosuke

    2007-01-01

    Many higher plants contain novel metabolites with antimicrobial, antifungal and antiviral properties. However, in the developed world almost all clinically used chemotherapeutics have been produced by in vitro chemical synthesis. Exceptions, like taxol and vincristine, were structurally complex metabolites that were difficult to synthesize in vitro. Many non-natural, synthetic drugs cause severe side effects that were not acceptable except as treatments of last resort for terminal diseases such as cancer. The metabolites discovered in medicinal plants may avoid the side effect of synthetic drugs, because they must accumulate within living cells. The aim here was to test an aqueous extract from the young developing leaves of willow (Salix safsaf, Salicaceae) trees for activity against human carcinoma cells in vivo and in vitro. In vivo Ehrlich Ascites Carcinoma Cells (EACC) were injected into the intraperitoneal cavity of mice. The willow extract was fed via stomach tube. The (EACC) derived tumor growth was reduced by the willow extract and death was delayed (for 35 days). In vitro the willow extract could kill the majority (75%–80%) of abnormal cells among primary cells harvested from seven patients with acute lymphoblastic leukemia (ALL) and 13 with AML (acute myeloid leukemia). DNA fragmentation patterns within treated cells inferred targeted cell death by apoptosis had occurred. The metabolites within the willow extract may act as tumor inhibitors that promote apoptosis, cause DNA damage, and affect cell membranes and/or denature proteins. PMID:17264881

  17. Antioxidant and antitumor effects of polysaccharides from the fungus Pleurotus abalonus.

    PubMed

    Ren, Daoyuan; Jiao, Yadong; Yang, Xingbin; Yuan, Li; Guo, Jianjun; Zhao, Yan

    2015-07-25

    Dietary supplement of edible Pleurotus abalonus (P. abalonus) rich in fungal polysaccharides is associated with anticancer health benefit. We here isolated the polysaccharides (PAP) from the fruiting bodies of P. abalonus, and evaluated the antiproliferative activity of the polysaccharides in human colorectal carcinoma LoVo cells. HPLC analysis showed that PAP consisted of D-mannose, D-ribose, l-rhamnose, D-glucuronic acid, D-glucose and D-galactose, and their corresponding mole percentages were 3.4%, 1.1%, 1.9%, 1.4%, 87.9% and 4.4%, respectively. PAP was shown to exert a high antioxidant activity in vitro and a dose-dependent antiproliferative effect against LoVo cancer cells. Flow cytometry analysis demonstrated that PAP exhibited a stimulatory effect on apoptosis of LoVo cells, and induced the cell-cycle arrest at the S phase. We also found that PAP could increase the generation of intracellular ROS which was a critical mediator in PAP-induced cell growth inhibition. These findings suggest that PAP may serve as a potential novel dietary agent for human colon cancer chemoprevention. PMID:26091901

  18. Antitumor effects of total alkaloids isolated from Solanum nigrum in vitro and in vivo.

    PubMed

    Li, Jian; Li, Qing-Wang; Gao, Da-Wei; Han, Zeng-Sheng; Li, Kun

    2008-07-01

    This study demonstrated that the total alkaloids isolated from the traditional Chinese medicinal herb Solanum nigrum Linne (SNL-A) inhibited the growth of human cervical cancer HeLa cells in culture medium with much lower toxicity to human normal lymphocytes. By means of HE staining and TUNEL assay, our results further revealed that SNL-A induced cell death by apoptosis. An immunohistochemical assay showed down-regulation of the bcl-2 and p53 genes and no obvious change of bax gene in the SNL-A treated cells. Subcutaneous injection of HeLa cells induced tumor formation in nude mice, and SNL-A showed a significant inhibitory effect on tumor formation. These results suggested that SNL-A may be a potential, natural apoptosis-inducing agent for cervical cancer. PMID:18717490

  19. Antitumoral effect of IL-12 gene transfected via liposomes into B16F0 cells.

    PubMed

    Speroni, Lucía; Gasparri, Julieta; de los A Bustuoabad, Victoria; Chiaramoni, Nadia S; Smagur, Andrzej; Szala, Stanisław; Taira, María C; del V Alonso, Silvia

    2009-01-01

    Murine melanoma B16F0 cells were transfected with SA:DPPC:DOPE (2:1:1 molar ratio) liposomes associated with a plasmid encoding murine IL-12. Stearylamine, a cationic lipid, showed a greater transfection efficiency compared to DOTAP-containing liposomes. The lipid:DNA ratio was 2:1 (w/w). Control groups were mock transfected or transfected with an empty plasmid (pNeo). pNeo or IL-12 transfected cells and controls were inoculated intradermically into the dorsal region of the foot or the lateral flank of C57BL6 mice. Results showed that IL-12 expression had a marked effect on in vivo growth of B16 melanoma tumors developed in both anatomic sites, significantly retarding their growth and prolonging host survival. PMID:19421429

  20. Effects of various additives on sintering of aluminum nitride

    NASA Technical Reports Server (NTRS)

    Komeya, K.; Inoue, H.; Tsuge, A.

    1982-01-01

    Effects of thirty additives on sintering A/N were investigated. The addition of alkali earth oxides and rare earth oxides gave fully densified aluminum nitride. This is due to the formation of nitrogen-containing aluminate liquid in the system aluminum nitride-alkali earth oxides or rare earth oxides. Microstructural studies of the sintered specimens with the above two types of additives suggested that the densification was due to the liquid phase sintering. Additions of silicon compounds resulted in poor densification by the formation of highly refractory compounds such as A/N polytypes.

  1. Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors

    PubMed Central

    Du, Yi; Yamaguchi, Hirohito; Wei, Yongkun; Hsu, Jennifer L.; Wang, Hung-Ling; Hsu, Yi-Hsin; Lin, Wan-Chi; Yu, Wen-Hsuan; Leonard, Paul G.; Lee, Gilbert R.; Chen, Mei-Kuang; Nakai, Katsuya; Hsu, Ming-Chuan; Chen, Chun-Te; Sun, Ye; Wu, Yun; Chang, Wei-Chao; Huang, Wen-Chien; Liu, Chien-Liang; Chang, Yuan-Ching; Chen, Chung-Hsuan; Park, Morag; Jones, Philip; Hortobagyi, Gabriel N.; Hung, Mien-Chie

    2016-01-01

    Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials1. One PARP inhibitor, olaparib (Lynparza™, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with BRCA mutations. BRCA1 and BRCA2 play essential roles in repairing DNA double strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition2,3. Here we show that receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907. Phosphorylation of PARP1 Tyr907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. Combining c-Met and PARP1 inhibitors synergized to suppress growth of breast cancer cells in vitro and xenograft tumor models. Similar synergistic effects were observed in a lung cancer xenograft tumor model. These results suggest that PARP1 pTyr907 abundance may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients bearing tumors with high c-Met expression who do not respond to PARP inhibition alone. PMID:26779812

  2. Anti-tumor effect of RGD modified PTX loaded liposome on prostatic cancer

    PubMed Central

    Cao, Yunjie; Zhou, Yaojun; Zhuang, Qianfeng; Cui, Li; Xu, Xianlin; Xu, Renfang; He, Xiaozhou

    2015-01-01

    In this study, we report an active targeting liposomal formulation directed by a novel peptide (RGD) that specifically binds to the integrins receptors overexpressed on prostatic cancer cells. The objectives of this study were to evaluate the in vitro and in vivo tumor drug targeting delivery of RGD modified liposomes on PC-3 cells and DU145 cells. The uptake efficiency of RGD-LP was 5.2 times higher than that of LP on PC-3 cells. The uptake efficiency of RGD-LP was 3.2 times higher than that of LP on DU145 cells. The anti-proliferative activity of RGD-LP-PTX against PC-3 cells and DU145 cells were much stronger compared to that of LP-PTX and free PTX, respectively. The tumor spheroids experiment revealed that RGD-LP-PTX was more efficaciously internalized into tumor spheroids than LP in both PC-3 cells and DU145 cells. Compared to LP-PTX and free PTX, RGD-LP-PTX showed the greatest tumor growth inhibitory effect in vivo. In brief, the RGD-LP may be an efficient targeting drug delivery system for prostatic cancer. PMID:26550128

  3. Exploring the anti-tumoral effects of tick saliva and derived components.

    PubMed

    Sousa, Ana Carolina Prado; Szabó, Matias Pablo Juan; Oliveira, Carlo Jose Freire; Silva, Marcelo José Barbosa

    2015-08-01

    Ticks are blood-feeding arthropods with an outstanding ability to remain attached to its host for considerable periods while blood-feeding and remaining unnoticed. Their success results from the ability to modulate hemostatic and host immune responses. The ability to "bypass" a host's defenses, prevent blood clotting and wound healing makes ticks utterly interesting animals for the development of new drugs. Studies worldwide on various tick species have shown that tick saliva possesses a wide array of lipidic and proteic biomolecules with useful properties. These include not only immunomodulatory, anti-inflammatory, anti-platelet and anti-clotting properties, but also cytotoxic and cytolitic properties that act against various cell types, and anti-angiogenic properties, which have gained increasing prominence. We searched PubMed, Science Direct, Elsevier and other sites for publications regarding tick saliva and its effects on cancer cells and angiogenesis. Our aim was to compile a list of molecules with potential for host adaptation and for the development of new cancer treatment drugs. PMID:26079950

  4. Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors.

    PubMed

    Du, Yi; Yamaguchi, Hirohito; Wei, Yongkun; Hsu, Jennifer L; Wang, Hung-Ling; Hsu, Yi-Hsin; Lin, Wan-Chi; Yu, Wen-Hsuan; Leonard, Paul G; Lee, Gilbert R; Chen, Mei-Kuang; Nakai, Katsuya; Hsu, Ming-Chuan; Chen, Chun-Te; Sun, Ye; Wu, Yun; Chang, Wei-Chao; Huang, Wen-Chien; Liu, Chien-Liang; Chang, Yuan-Ching; Chen, Chung-Hsuan; Park, Morag; Jones, Philip; Hortobagyi, Gabriel N; Hung, Mien-Chie

    2016-02-01

    Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907). PARP1 pY907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. The combination of c-Met and PARP1 inhibitors synergized to suppress the growth of breast cancer cells in vitro and xenograft tumor models, and we observed similar synergistic effects in a lung cancer xenograft tumor model. These results suggest that the abundance of PARP1 pY907 may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients whose tumors show high c-Met expression and who do not respond to PARP inhibition alone. PMID:26779812

  5. Effects of some polymeric additives on the cocrystallization of caffeine

    NASA Astrophysics Data System (ADS)

    Chung, Jihae; Kim, Il Won

    2011-11-01

    Effects of polymeric additives on the model cocrystallization were examined. The model cocrystal was made from caffeine and oxalic acid, and poly(ethylene glycol) (PEG), poly( L-lactide) (PLLA), poly(ɛ-caprolactone) (PCL), and poly(acrylic acid) (PAA) were the additives. The cocrystals were formed as millimeter-sized crystals without additives, and they became microcrystals with PLLA and PCL, and nanocrystals with PAA. XRD and IR revealed that the cocrystal structure was unchanged despite the strong effects of the additives on the crystal morphology, although some decrease in crystallinity was observed with PAA as confirmed by DSC. The DSC study also showed that the cocrystal melted and recrystallized to form α-caffeine upon heating. The present study verified that the polymeric additives can be utilized to modulate the size and morphology of the cocrystals without interfering the intermolecular interactions essential to the integrity of the cocrystal structures.

  6. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms.

    PubMed

    King, Constance; Diaz, H Bruce; McNeely, Samuel; Barnard, Darlene; Dempsey, Jack; Blosser, Wayne; Beckmann, Richard; Barda, David; Marshall, Mark S

    2015-09-01

    CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe. PMID:26141948

  7. The Relationship between the Antitumor Effect of the IL-12 Gene Therapy and the Expression of Th1 Cytokines in an HPV16-Positive Murine Tumor Model

    PubMed Central

    García Paz, Flor; Madrid Marina, Vicente; Morales Ortega, Ausencio; Santander González, Abimelec; Peralta Zaragoza, Oscar; Burguete García, Ana; Torres Poveda, Kirvis; Moreno, José; Alcocer González, Juan; Hernandez Marquez, Eva; Bermúdez Morales, Victor

    2014-01-01

    Objective. The goal of the present study was to investigate the effect of IL-12 expressed in plasmid on the Th1 cytokine profile in an experimental HPV16-positive murine tumor model and the association with the IL-12's antitumor effect. Methods. Mice were injected with BMK-16/myc cells to establish HPV16-positive tumor and then pNGVL3-mIL-12 plasmid; pcDNA3 plasmid or PBS was injected directly into tumor site. The antitumor effect of the treatment was evaluated and the cytokines expression profile in each tumor tissue was analyzed. Results. Treatment with pNGVL3-mIL-12 plasmid had a significant antitumor effect, and a Th2-Th3-type cytokines prolife was detected in the murine tumor model with expression of the cytokines IL-10, IL-4, and TGF-β1. However, after the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine profile associated with Th1 with expression of IL-2, IL-12, and IFN-γ cytokines and reduced expression of IL-10, IL-4, and TGF-β1. Conclusions. The treatment with the IL-12 gene in the experimental HPV16-positive tumor model promoted the activation of the cellular immune response via expression of a Th1-type cytokine profile and was associated with the inhibition of tumor growth. Thus, IL-12 treatment represents a novel approach for gene therapy against cervical cancer. PMID:24808638

  8. Additive effects on the toughening of unsaturated polyester resins

    SciTech Connect

    Suspene, L.; Yang, Y.S.; Pascault, J.P.

    1993-12-31

    An elastomer additive, carboxy-terminated acrylonitrile-butadiene copolymer, was used for toughening in the free radical cross-linking copolymerization of unsaturated polyester (UP) resins. For molded parts, Charpy impact behavior was generally enhanced and the number of catastrophic failures was reduced. The miscibility and interfacial properties of additive and resin blends play important roles in the toughening process. Phase-diagram studies showed that the elastomer additive is immiscible with the UP resin and is phase-separated from the resin matrix during curing. This phase-separation phenomenon is similar to that in the low-profile mechanism of UP resins. Additive-resin system miscibility greatly influences curing morphology. Microvoids occurred in the additive phase of cured resin because of shrinkage stress. The intrinsic inhomogeneity of the polyester network and the existence of microvoids in the final product limit the toughening effect of additives on unsaturated polyester resins. 49 refs., 13 figs., 3 tabs.

  9. The effect of additives on lime dissolution rates. Final report

    SciTech Connect

    Khang, S.J.

    1996-07-31

    Based on the previous years` studies concerning the efficiency of SO{sub 2} removal by spray dryers with high sulfur coal flue gas, the work for year five included investigations of lime dissolution rates at different slaking conditions and with the effect of additives. The prominent additives that have significant effects on lime dissolution rates were tested with the mini pilot spray drying absorber to see their effects on spray drying desulfurization applications. The mechanisms of these additive effects along with the properties of hygroscopic additives have been discussed and incorporated into the spray drying desulfurization model ``SPRAYMOD-M.`` Slaking conditions are very important factors in producing high quality lime slurry in spray drying desulfurization processes. At optimal slaking conditions, the slaked lime particles are very fine (3-5{mu}m) and the slaked lime has high BET surface areas which are beneficial to the desulfurization. The slaked lime dissolution rate experiments in our study are designed to determine how much lime can dissolve in a unit time if the initial lime surface area is kept constant. The purpose of the dissolution rate study for different additives is to find those effective additives that can enhance lime dissolution rates and to investigate the mechanisms of the dissolution rate enhancement properties for these additives. The applications of these additives on spray drying desulfurization are to further verify the theory that dissolution rate is a rate limiting step in the whole spray drying desulfurization process as well as to test the feasibility of these additives on enhancing SO{sub 2} removal in spray dryers.

  10. Antitumoral Effect of Sunitinib-eluting Beads in the Rabbit VX2 Tumor Model.

    PubMed

    Bize, Pierre; Duran, Rafael; Fuchs, Katrin; Dormond, Olivier; Namur, Julien; Decosterd, Laurent A; Jordan, Olivier; Doelker, Eric; Denys, Alban

    2016-08-01

    Purpose To measure plasmatic sunitinib concentration (PSC) and intratumoral sunitinib concentration (ITSC) after transcatheter arterial chemoembolization (TACE) with two different sizes of sunitinib-eluting beads (SEBs) in rabbits with VX2 hepatic allografts and to investigate treatment effects on vascular endothelial growth factor receptor type 2 (VEGFR2) phosphorylation, tumor volume, and histopathologic changes. Materials and Methods The protocol was approved by the French Ethics Committee for Animal Experiments (Comité d'Ethique en Expérimentation Animale du Centre INRA de Jouy-en-Josas et AgroParisTech, or COMETHEA, approval no. 11/028). Two experiments were performed. In the first, seven animals received 0.05 mL of 100-300-μm SEBs (1.5 mg of sunitinib) in the hepatic artery, and six animals received saline injections. In the second, eight animals received 0.05 mL of 70-150-μm SEBs (1.5 mg of sunitinib), seven received 0.05 mL of 70-150-μm unloaded beads, and seven received oral sunitinib (6 mg every day). Tumor size was monitored with ultrasonography. PSC, ITSC, and phosphorylation of VEGFR2 were assessed on days 1 and 14. After the animals were sacrificed, histopathologic analysis was performed. The Kruskal-Wallis test, Mann-Whitney U test, and Fisher exact test were used to look for statistically significant differences between groups. Results Maximum PSC after TACE with 100-300-μm SEBs was 0.002 μg/mL on day 1. ITSC was 17.8 μg/g on day 1 and 0.16 μg/g on day 14. After TACE with 70-150-μm SEBs, ITSC was 40.4 μg/g on day 1 and 27.4 μg/g on day 14. Phosphorylation of VEGFR2 was inhibited until day 14 after TACE with both sizes of SEBs. The size of VX2 tumors treated with 70-150-μm SEB TACE increased less (-2%) than that of tumors treated with unloaded beads (+42%) and oral sunitinib (6 mg every day; +1853%; P = .044). Conclusion SEB TACE resulted in minimal PSC, high ITSC, and sustained VEGFR2 phosphorylation inhibition until day 14. (©) RSNA

  11. POEM: Identifying Joint Additive Effects on Regulatory Circuits

    PubMed Central

    Botzman, Maya; Nachshon, Aharon; Brodt, Avital; Gat-Viks, Irit

    2016-01-01

    Motivation: Expression Quantitative Trait Locus (eQTL) mapping tackles the problem of identifying variation in DNA sequence that have an effect on the transcriptional regulatory network. Major computational efforts are aimed at characterizing the joint effects of several eQTLs acting in concert to govern the expression of the same genes. Yet, progress toward a comprehensive prediction of such joint effects is limited. For example, existing eQTL methods commonly discover interacting loci affecting the expression levels of a module of co-regulated genes. Such “modularization” approaches, however, are focused on epistatic relations and thus have limited utility for the case of additive (non-epistatic) effects. Results: Here we present POEM (Pairwise effect On Expression Modules), a methodology for identifying pairwise eQTL effects on gene modules. POEM is specifically designed to achieve high performance in the case of additive joint effects. We applied POEM to transcription profiles measured in bone marrow-derived dendritic cells across a population of genotyped mice. Our study reveals widespread additive, trans-acting pairwise effects on gene modules, characterizes their organizational principles, and highlights high-order interconnections between modules within the immune signaling network. These analyses elucidate the central role of additive pairwise effect in regulatory circuits, and provide computational tools for future investigations into the interplay between eQTLs. Availability: The software described in this article is available at csgi.tau.ac.il/POEM/. PMID:27148351

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

    PubMed Central

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

    2016-01-01

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

  13. Separation and purification of an anti-tumor peptide from rapeseed (Brassica campestris L.) and the effect on cell apoptosis.

    PubMed

    Wang, Lifeng; Zhang, Jing; Yuan, Qiang; Xie, Huihui; Shi, Jiayi; Ju, Xingrong

    2016-05-18

    Rapeseed peptides were prepared by means of the combined methods of the laboratory bacteria enzyme synergy and the solid-state fermentation of rapeseed meal. The rapeseed peptides were separated and purified with the tumor cell in vitro anti-proliferative activity as an index. Moreover, a kind of rapeseed peptide component RSP-4-3-3 (rapeseed anti-tumor peptide RSP-4-3-3) with high activity was selected. Furthermore, by using reversed-phase high performance liquid chromatography (RP-HPLC) coupled with electrospray ionization mass spectrometry (ESI-MS/MS), the analysis result of its possible amino acid sequence showed that it was Trp-Thr-Pro (408.2 Da). Inverted microscope observation technology and western blot experiments were applied to explore the antitumor impact of the rapeseed peptide RSP-4-3-3 on tumor cells. The results showed that the rapeseed antitumor peptide RSP-4-3-3 could significantly change the morphological features of the HepG2 cells in vitro and cause apoptosis, thus inhibiting the proliferation of the HepG2 cells. PMID:27116475

  14. An oncolytic adenovirus enhances antiangiogenic and antitumoral effects of a replication-deficient adenovirus encoding endostatin by rescuing its selective replication in nasopharyngeal carcinoma cells

    SciTech Connect

    Liu, Ran-yi; Zhou, Ling; Zhang, Yan-ling; Huang, Bi-jun; Ke, Miao-la; Chen, Jie-min; Li, Li-xia; Fu, Xiang; Wu, Jiang-xue; Huang, Wenlin

    2013-12-13

    Highlights: •H101 promotes endostatin expression by Ad-Endo via rescuing Ad-Endo replication. •H101 rescued Ad-Endo replication by supplying E1A and E1B19k proteins. •Ad-Endo enhanced the cytotoxicity of H101 in NPC cells. •Ad-Endo and oncolytic Ad H101 have synergistic antitumor effects on NPC. -- Abstract: A replication-deficient adenovirus (Ad) encoding secreted human endostatin (Ad-Endo) has been demonstrated to have promising antiangiogenic and antitumoral effects. The E1B55k-deleted Ad H101 can selectively lyse cancer cells. In this study, we explored the antitumor effects and cross-interactions of Ad-Endo and H101 on nasopharyngeal carcinoma (NPC). The results showed that H101 dramatically promoted endostatin expression by Ad-Endo via rescuing Ad-Endo replication in NPC cells, and the expressed endostatin proteins significantly inhibited the proliferation of human umbilical vein endothelial cells. E1A and E1B19k products are required for the rescuing of H101 to Ad-Endo replication in CNE-1 and CNE-2 cells, but not in C666-1 cells. On the other hand, Ad-Endo enhanced the cytotoxicity of H101 by enhancing Ad replication in NPC cells. The combination of H101 and Ad-Endo significantly inhibited CNE-2 xenografts growth through the increased endostatin expression and Ad replication. These findings indicate that the combination of Ad-Endo gene therapy and oncolytic Ad therapeutics could be promising in comprehensive treatment of NPC.

  15. Antitumor and immunomodulatory activity of polysaccharide isolated from Trametes orientalis.

    PubMed

    Zheng, Yi; Wang, Wei-dong; Li, Yong

    2015-10-20

    A water-soluble polysaccharide (TOP-2) was isolated from Trametes orientalis, consisting of galactose, glucose, mannose, and arabinose with the molar ratios of 5.79:5.77:3.45:1, having an average molecular weight of 63kDa. The antitumor and immunomodulatory activity of TOP-2 were determined in Lewis lung carcinoma (LLC) tumor-bearing mice. The results revealed that TOP-2 not only could efficaciously restrain the growth of LLC in mice, but also effectively increase the body weight and relative spleen/thymus weight. In addition, TOP-2 remarkably enhanced splenocyte proliferation, notably stimulated phagocytotic function of macrophages, and strikingly promoted the expression of serum cytokines. These findings indicate that TOP-2 exert antitumor activity in vivo potentially by improving immune function. TOP-2 could be empoldered as a potential supplementary agent for cancer treatment. PMID:26256182

  16. Optimization of T-cell Reactivity by Exploiting TCR Chain Centricity for the Purpose of Safe and Effective Antitumor TCR Gene Therapy.

    PubMed

    Ochi, Toshiki; Nakatsugawa, Munehide; Chamoto, Kenji; Tanaka, Shinya; Yamashita, Yuki; Guo, Tingxi; Fujiwara, Hiroshi; Yasukawa, Masaki; Butler, Marcus O; Hirano, Naoto

    2015-09-01

    Adoptive transfer of T cells redirected by a high-affinity antitumor T-cell receptor (TCR) is a promising treatment modality for cancer patients. Safety and efficacy depend on the selection of a TCR that induces minimal toxicity and elicits sufficient antitumor reactivity. Many, if not all, TCRs possess cross-reactivity to unrelated MHC molecules in addition to reactivity to target self-MHC/peptide complexes. Some TCRs display chain centricity, in which recognition of MHC/peptide complexes is dominated by one of the TCR hemi-chains. In this study, we comprehensively studied how TCR chain centricity affects reactivity to target self-MHC/peptide complexes and alloreactivity using the TCR, clone TAK1, which is specific for human leukocyte antigen-A*24:02/Wilms tumor 1(235-243) (A24/WT1(235)) and cross-reactive with B*57:01 (B57). The TAK1β, but not the TAK1α, hemi-chain possessed chain centricity. When paired with multiple clonotypic TCRα counter-chains encoding TRAV12-2, 20, 36, or 38-2, the de novo TAK1β-containing TCRs showed enhanced, weakened, or absent reactivity to A24/WT1(235) and/or to B57. T cells reconstituted with these TCRα genes along with TAK1β possessed a very broad range (>3 log orders) of functional and structural avidities. These results suggest that TCR chain centricity can be exploited to enhance desired antitumor TCR reactivity and eliminate unwanted TCR cross-reactivity. TCR reactivity to target MHC/peptide complexes and cross-reactivity to unrelated MHC molecules are not inextricably linked and are separable at the TCR sequence level. However, it is still mandatory to carefully monitor for possible harmful toxicities caused by adoptive transfer of T cells redirected by thymically unselected TCRs. PMID:25943533

  17. Optimization of T-cell reactivity by exploiting TCR chain centricity for the purpose of safe and effective antitumor TCR gene therapy

    PubMed Central

    Ochi, Toshiki; Nakatsugawa, Munehide; Chamoto, Kenji; Tanaka, Shinya; Yamashita, Yuki; Guo, Tingxi; Fujiwara, Hiroshi; Yasukawa, Masaki; Butler, Marcus O.; Hirano, Naoto

    2015-01-01

    Adoptive transfer of T cells redirected by a high affinity antitumor T-cell receptor (TCR) is a promising treatment modality for cancer patients. Safety and efficacy depend on the selection of a TCR that induces minimal toxicity and elicits sufficient antitumor reactivity. Many, if not all, TCRs possess cross-reactivity to unrelated MHC molecules in addition to reactivity to target self-MHC/peptide complexes. Some TCRs display chain centricity, in which recognition of MHC/peptide complexes is dominated by one of the TCR hemi-chains. In this study, we comprehensively studied how TCR chain centricity impacts reactivity to target self-MHC/peptide complexes and alloreactivity using the TCR, clone TAK1, which is specific for human leukocyte antigen-A*24:02/Wilms tumor 1235–243 (A24/WT1235) and cross-reactive with B*57:01 (B57). The TAK1β, but not the TAK1α, hemi-chain possessed chain centricity. When paired with multiple clonotypic TCRα counter-chains encoding TRAV12-2, 20, 36, or 38-2, the de novo TAK1β-containing TCRs showed enhanced, weakened, or absent reactivity to A24/WT1235 and/or to B57. T cells reconstituted with these TCRα genes along with TAK1β possessed a very broad range (>3 log orders) of functional and structural avidities. These results suggest that TCR chain centricity can be exploited to enhance desired antitumor TCR reactivity and eliminate unwanted TCR cross-reactivity. TCR reactivity to target MHC/peptide complexes and cross-reactivity to unrelated MHC molecules are not inextricably linked and are separable at the TCR sequence level. However, it is still mandatory to carefully monitor for possible harmful toxicities caused by adoptive transfer of T cells redirected by thymically-unselected TCRs. PMID:25943533

  18. The effect of lubricant additives on fretting wear

    NASA Astrophysics Data System (ADS)

    Qiu, Y.; Roylance, B. J.

    1992-10-01

    The effect of lubricant additives on fretting wear has been investigated using a ball-on-plate machine. The test results confirm that the antiwear additives, e.g. phospho-sulphurized terpene, sulphurized esters and sulphurized paraffins, are effective in reducing friction and wear. Examination of worn surfaces by optical and electron microscope inspection indicated the presence of thin films which had been deposited under fretting action when using oils containing these additives. Unlubricated fretting wear occurred in the scuffing region. In contrast, the lubricated fretting wear with the lubricating oils containing the antiwear additives took place in the mixed lubrication region. In lubricated fretting wear, the size of the wear particles was smaller than with dry fretting wear.

  19. The effect of chemical additives on the synthesis of ethanol

    SciTech Connect

    Chuang, S.S.C.

    1990-07-01

    The objective of this research is to elucidate the role of various chemical additives on ethanol synthesis over Rh- and Ni-based catalysts. Chemical additives used for this study will include S, P, Ag, Cu, Mn, and Na which have different electronegativities. The effect of additives on the surface state of the catalysts, heat of adsorption of reactant molecules, reaction intermediates, reaction pathways, reaction kinetics, and product distributions is/will be investigated by a series of experimental studies of NO adsorption, reaction probing, study state rate measurement, and transient kinetic study. A better understanding of the role of additive on the synthesis reaction may allow us to sue chemical additives to manipulate the catalytic properties of Rh- and Ni-based catalysts for producing high yields of ethanol from syngas. (VC)

  20. The effect of chemical additives on the synthesis of ethanol

    SciTech Connect

    Chuang, S.S.C.

    1990-07-01

    The objective of this research is to elucidate the role of various chemical additives on ethanol synthesis over Rh- and Ni-based catalysts. Chemical additives used for this study will include S, P, Ag, Cu, Mn, and Na which have different electronegativities. The effect of additives on the surface state of the catalysts, heat of adsorption of reactant molecules, reaction intermediates, reaction pathways, reaction kinetics, and product distributions is/will be investigated by a series of experimental studies of NO adsorption, reaction probing, study state rate measurement, and transient kinetic study. A better understanding of the role of additive on the synthesis reaction may allow us to use chemical additives to manipulate the catalytic properties of Rh- and Ni-based catalysts for producing high yields of ethanol from syngas.

  1. The effect of chemical additives on the synthesis of ethanol

    SciTech Connect

    Chuang, S.S.C.

    1988-11-14

    The objective of this research is to elucidate the role of various chemical additives on ethanol synthesis over Rh- and Ni-based catalysts. Chemical additives used for this study will include S, P, Ag, Cu, Mn, and Na which have different electronegativities. The effect of additives on the surface state of the catalysts, heat of adsorption of reactant molecules, reaction intermediates, reaction pathways, reaction kinetics, and product distributions is/will be investigated by a series of experimental studies including temperature programmed desorption, infrared study of NO adsorption, reactive probing, steady state rate measurement, and transient kinetic study. A better understanding of the role of additive on the synthesis reaction may allow us to use chemical additives to manipulate the catalytic properties of Rh- and Ni-based catalysts for producing high yields of ethanol from syngas.

  2. The effect of chemical additives on the synthesis of ethanol

    SciTech Connect

    Chuang, S.S.C.

    1990-11-01

    The objective of this research is to elucidate the role of additives on the ethanol synthesis over Rh- and Ni-based catalysts. Chemical additives used for this study will include S, P, Ag, Cu, Mn, and Na which have different electronegativities. The effect of additives on the surface state of the catalysts, heat of adsorption of reactant molecules, reaction intermediates, reaction pathways, reaction kinetics, and product distributions is/will be investigated by a series of experimental studies of NO adsorption, reaction probing, study state rate measurement, and transient kinetic study. A better understanding of the role of additive on the synthesis reaction may allow them to use chemical additives to manipulate the catalytic properties of Rh- and Ni-based catalysts for producing high yields of ethanol from syngas. 49 refs., 6 figs., 3 tabs.

  3. The effect of chemical additives on the synthesis of ethanol

    SciTech Connect

    Chuang, S.S.C.; Balakos, M.W.

    1991-09-20

    The objective of this research is to elucidate the role of various chemical additives on ethanol synthesis over Rh- and Ni-based catalysts. Chemical additives used for this study will include S, P, Ag, Cu, Mn, and Na which have different electronegativities. The effect of additives on the surface state of the catalysts, heat of adsorption of reactant molecules, reaction intermediates, reaction pathways, reaction kinetics, and product distributions is/will be investigated by a series of experimental studies of NO adsorption, reaction probing, study state rate measurement, and transient kinetic study. A better understanding of the role of additives on the synthesis reaction may allow us to use chemical additives to manipulate the catalytic properties of Rh- and Ni-based catalysts for producing high yields of ethanol from syngas. 27 refs. 7 figs., 2 tabs.

  4. Evaluation of innate and adaptive immunity contributing to the antitumor effects of PD1 blockade in an orthotopic murine model of pancreatic cancer.

    PubMed

    D'Alincourt Salazar, Marcela; Manuel, Edwin R; Tsai, Weimin; D'Apuzzo, Massimo; Goldstein, Leanne; Blazar, Bruce R; Diamond, Don J

    2016-06-01

    Despite the clinical success of anti-PD1 antibody (α-PD1) therapy, the immune mechanisms contributing to the antineoplastic response remain unclear. Here, we describe novel aspects of the immune response involved in α-PD1-induced antitumor effects using an orthotopic Kras (G12D)/p53(R172H)/Pdx1-Cre (KPC) model of pancreatic ductal adenocarcinoma (PDA). We found that positive therapeutic outcome involved both the innate and adaptive arms of the immune system. Adoptive transfer of total splenocytes after short-term (3 d) but not long-term (28 d) PD1 blockade significantly extended survival of non-treated tumor-bearing recipient mice. This protective effect appeared to be mostly mediated by T cells, as adoptive transfer of purified natural killer (NK) cells and/or granulocyte receptor 1 (Gr1)(+) cells or splenocytes depleted of Gr1(+) cells and NK cells did not exhibit transferrable antitumor activity following short-term PD1 blockade. Nevertheless, splenic and tumor-derived CD11b(+)Gr1(+) cells and NK cells showed significant persistence of α-PD1 bound to these cells in the treated primary recipient mice. We observed that short-term inhibition of PD1 signaling modulated the profiles of multifunctional cytokines in the tumor immune-infiltrate, including downregulation of vascular endothelial growth factor A (VEGF-A). Altogether, the data suggest that systemic blockade of PD1 results in rapid modulation of antitumor immunity that differs in the tumor microenvironment (TME) when compared to the spleen. These results demonstrate a key role for early immune-mediated events in controlling tumor progression in response to α-PD1 treatment and warrant further investigation into the mechanisms governing responses to the therapy at the innate-adaptive immune interface. PMID:27471630

  5. Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and antitumor effects.

    PubMed

    Osada, Takuya; Berglund, Peter; Morse, Michael A; Hubby, Bolyn; Lewis, Whitney; Niedzwiecki, Donna; Yang, Xiao Yi; Hobeika, Amy; Burnett, Bruce; Devi, Gayathri R; Clay, Timothy M; Smith, Jonathan; Kim Lyerly, H

    2012-11-01

    We recently demonstrated that Venezuelan equine encephalitis virus-based replicon particle (VRPs) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP-expressing interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and antitumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)), and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12, and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP-IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing antitumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than that of VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted. PMID:22488274

  6. In vitro and in vivo antitumor effects of doxorubicin loaded with bacterial magnetosomes (DBMs) on H22 cells: the magnetic bio-nanoparticles as drug carriers.

    PubMed

    Sun, Jian-Bo; Duan, Jin-Hong; Dai, Shun-Ling; Ren, Jun; Zhang, Yan-Dong; Tian, Jie-Sheng; Li, Ying

    2007-12-01

    Hepatocellular carcinoma (HCC) is the most common form of cancer although effective therapeutic strategy especially targeted therapy is lacking. We recently employed bacterial magnetosomes (BMs) as the magnetic-targeted drug carrier and found an antitumor effect of doxorubicin (DOX)-loaded BMs (DBMs) in EMT-6 and HL60 cell lines. The aim of this study was to evaluate the in vitro and in vivo anti-neoplastic effects of DBMs on hepatic cancer. DBMs, DOX and BMs displayed tumor suppression rates of 86.8%, 78.6% and 4.3%, respectively, in H22 cell-bearing mice. The mortality rates following administration of DBMs, DOX and BMs were 20%, 80% and 0%, respectively. Pathological examination of hearts and tumors revealed that both DBMs and DOX effectively inhibited tumor growth although DBMs displayed a much lower cardiac toxicity compared with DOX. The DBMs were cytotoxic to H22 cells manifested as inhibition of cell proliferation and c-myc expression, consistent with DOX. The IC(50) of DOX, DBMs and BMs in target cells were 5.309 +/- 0.010, 4.652 +/- 0.256 and 22.106 +/- 3.330 microg/ml, respectively. Our data revealed both in vitro and in vivo antitumor property of DBMs similar to that of DOX. More importantly, the adverse cardiac toxicity was significantly reduced in DBMs compared with DOX. Collectively, our study suggests the therapeutic potential of DBMs in target-therapy against liver cancer. PMID:17920762

  7. Integrating individual functional moieties of CXCL10 and CXCL11 into a novel chimeric chemokine leads to synergistic antitumor effects: a strategy for chemokine-based multi-target-directed cancer therapy.

    PubMed

    Wang, Ping; Yang, Xiuli; Xu, Wei; Li, Kang; Chu, Yiwei; Xiong, Sidong

    2010-11-01

    The complexity of tumor biology necessitates a multimodality approach that targets different aspects of tumor environment in order to generate the greatest benefit. IFN-inducible T cell alpha chemoattractant (ITAC)/CXCL11 and IFN-inducible protein 10 (IP10)/CXCL10 could exert antitumor effects with functional specificity and thus emerge as attractive candidates for combinatorial strategy. Disappointedly, a synergistic antitumor effect could not be observed when CXCL10 and CXCL11 were pooled together. In this regard, we seek to improve antitumor efficacy by integrating their individual functional moieties into a chemokine chimeric molecule, designated ITIP, which was engineered by substituting the N-terminal and N-loop region of CXCL10 with those of CXCL11. The functional properties of ITIP were determined by chemotaxis and angiogenesis assays. The antitumor efficacy was tested in murine CT26 colon carcinoma, 4T1 mammary carcinoma and 3LL lung carcinoma. Here we showed that ITIP not only exhibited respective functional superiority but strikingly promoted regression of established tumors and remarkably prolonged survival of mice compared with its parent chemokines, either alone or in combination. The chemokine chimera induced an augmented anti-tumor immunity and a marked decrease in tumor vasculature. Antibody neutralization studies indicated that CXCL10 and CXCL11 moieties of ITIP were responsible for anti-angiogenesis and chemotaxis in antitumor response, respectively. These results indicated that integrating individual functional moieties of CXCL10 and CXCL11 into a chimeric chemokine could lead to a synergistic antitumor effect. Thus, this integration strategy holds promise for chemokine-based multiple targeted therapy of cancer. PMID:20706716

  8. Peripheral Opioid Antagonist Enhances the Effect of Anti-Tumor Drug by Blocking a Cell Growth-Suppressive Pathway In Vivo

    PubMed Central

    Sawada, Yumi; Ashikawa, Maho; Aoyagi, Kazuhiko; Fujita, Takeshi; Yanagihara, Kazuyoshi; Komatsu, Masayuki; Narita, Minoru; Suzuki, Tsutomu; Nagase, Hiroshi; Kushima, Ryoji; Sakamoto, Hiromi; Fukagawa, Takeo; Katai, Hitoshi; Nakagama, Hitoshi; Yoshida, Teruhiko; Uezono, Yasuhito; Sasaki, Hiroki

    2015-01-01

    The dormancy of tumor cells is a major problem in chemotherapy, since it limits the therapeutic efficacy of anti-tumor drugs that only target dividing cells. One potential way to overcome chemo-resistance is to “wake up” these dormant cells. Here we show that the opioid antagonist methylnaltrexone (MNTX) enhances the effect of docetaxel (Doc) by blocking a cell growth-suppressive pathway. We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs). The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc. In comparison with the use of Doc alone, the combined use of Doc and MNTX significantly prolongs survival, alleviates abdominal pain, and diminishes Doc-resistant spheroids on the peritoneal membrane in model mice. These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs. PMID:25853862

  9. Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo.

    PubMed

    Suzuki, Masami; Chiwaki, Fumiko; Sawada, Yumi; Ashikawa, Maho; Aoyagi, Kazuhiko; Fujita, Takeshi; Yanagihara, Kazuyoshi; Komatsu, Masayuki; Narita, Minoru; Suzuki, Tsutomu; Nagase, Hiroshi; Kushima, Ryoji; Sakamoto, Hiromi; Fukagawa, Takeo; Katai, Hitoshi; Nakagama, Hitoshi; Yoshida, Teruhiko; Uezono, Yasuhito; Sasaki, Hiroki

    2015-01-01

    The dormancy of tumor cells is a major problem in chemotherapy, since it limits the therapeutic efficacy of anti-tumor drugs that only target dividing cells. One potential way to overcome chemo-resistance is to "wake up" these dormant cells. Here we show that the opioid antagonist methylnaltrexone (MNTX) enhances the effect of docetaxel (Doc) by blocking a cell growth-suppressive pathway. We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs). The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc. In comparison with the use of Doc alone, the combined use of Doc and MNTX significantly prolongs survival, alleviates abdominal pain, and diminishes Doc-resistant spheroids on the peritoneal membrane in model mice. These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs. PMID:25853862

  10. Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells

    PubMed Central

    Ding, Xiwei; Chaiteerakij, Roongruedee; Moser, Catherine D.; Shaleh, Hassan; Boakye, Jeffrey; Chen, Gang; Ndzengue, Albert; Li, Ying; Zhou, Yanling; Huang, Shengbing; Sinicrope, Frank A.; Zou, Xiaoping; Thomas, Melanie B.; Smith, Charles D.; Roberts, Lewis R.

    2016-01-01

    Sphingosine kinase 2 (Sphk2) has an oncogenic role in cancer. A recently developed first-in-class Sphk2 specific inhibitor ABC294640 displays antitumor activity in many cancer models. However, the role of Sphk2 and the antitumor activity of its inhibitor ABC294640 are not known in cholangiocarcinoma. We investigated the potential of targeting Sphk2 for the treatment of cholangiocarcinoma. We found that Sphk2 is overexpressed in five established human cholangiocarcinoma cell lines (WITT, HuCCT1, EGI-1, OZ and HuH28) and a new patient-derived cholangiocarcinoma cell line (LIV27) compared to H69 normal cholangiocytes. Inhibition of Sphk2 by ABC294640 inhibited proliferation and induced caspase-dependent apoptosis. Furthermore, we found that ABC294640 inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cholangiocarcinoma cell proliferation and survival. ABC294640 also induced autophagy. Inhibition of autophagy by bafilomycin A1 or chloroquine potentiated ABC294640-induced cytotoxicity and apoptosis. In addition, ABC294640 in combination with sorafenib synergistically inhibited cell proliferation of cholangiocarcinoma cells. Strong decreases in STAT3 phosphorylation were observed in WITT and HuCCT1 cells exposed to the ABC294640 and sorafenib combination. These findings provide novel evidence that Sphk2 may be a rational therapeutic target in cholangiocarcinoma. Combinations of ABC294640 with sorafenib and/or autophagy inhibitors may provide novel strategies for the treatment of cholangiocarcinoma. PMID:26956050

  11. Human umbilical cord mesenchymal stem cells delivering sTRAIL home to lung cancer mediated by MCP-1/CCR2 axis and exhibit antitumor effects.

    PubMed

    Yan, Cihui; Song, Xinmiao; Yu, Wenwen; Wei, Feng; Li, Hui; Lv, Mengguo; Zhang, Xinwei; Ren, Xiubao

    2016-06-01

    Mesenchymal stem cells (MSCs) are believed to be a potential vehicle delivering antitumor agents for their tumor-homing capacity, while the underlying mechanism is yet to be explored. The apoptotic ligand TNF-related apoptosis-inducing ligand (TRAIL) has been suggested as a promising candidate for cancer gene therapy owing to its advantage of selectively inducing apoptosis in cancer cells while sparing normal cells. An isoleucine zipper (ISZ) added to the N-terminal of secretable soluble TRAIL (sTRAIL) can generate the trimeric form of TRAIL (ISZ-sTRAIL) and increase its antitumor potential. However, the inefficient delivery and toxicity are still obstacles for its use. In this study, the migration of human umbilical cord mesenchymal stem cells (HUMSCs) to lung cancer was observed through transwell migration assay and animal bioluminescent imaging both in vitro and in vivo. We found that the homing ability of HUMSCs was suppressed after either knocking down the expression of monocyte chemoattractant protein-1(MCP-1) in lung cancer cells or blocking CCR2 expressed on the surface of HUMSCs, indicating the important role of MCP-1/CCR2 axis in the tropism of HUMSCs to lung cancer. Furthermore, we genetically modified HUMSCs to deliver ISZ-sTRAIL to tumor sites specifically. This targeted therapeutic system exhibited promising apoptotic induction and antitumor potential in a xenograft mouse model without obvious side effects. In conclusion, HUMSCs expressing ISZ-sTRAIL might be an efficient therapeutic approach against lung cancer and MCP-1/CCR2 axis is essential for the tumor tropism of HUMSCs. PMID:26733169

  12. In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma

    PubMed Central

    2012-01-01

    Background Metformin, which is widely used as an antidiabetic agent, has recently been reported to reduce cancer risk and improve prognosis in certain malignancies. However, the specific mechanisms underlying the effect of metformin on the development and progression of several cancers including oral squamous cell carcinoma (OSCC) remain unclear. In the present study, we investigated the effects of metformin on OSCC cells in vitro and in vivo. Methods OSCC cells treated with or without metformin were counted using a hemocytometer. The clonogenic ability of OSCC cells after metformin treatment was determined by colony formation assay. Cell cycle progression and apoptosis were assessed by flow cytometry, and the activation of related signaling pathways was examined by immunoblotting. The in vivo anti-tumor effect of metformin was examined using a xenograft mouse model. Immunohistochemistry and TUNEL staining were used to determine the expression of cyclin D1 and the presence of apoptotic cells in tumors from mice treated with or without metformin. Results Metformin inhibited proliferation in the OSCC cell lines CAL27, WSU-HN6 and SCC25 in a time- and dose-dependent manner, and significantly reduced the colony formation of OSCC cells in vitro. Metformin induced an apparent cell cycle arrest at the G0/G1 phase, which was accompanied by an obvious activation of the AMP kinase pathway and a strongly decreased activation of mammalian target of rapamycin and S6 kinase. Metformin treatment led to a remarkable decrease of cyclin D1, cyclin-dependent kinase (CDK) 4 and CDK6 protein levels and phosphorylation of retinoblastoma protein, but did not affect p21 or p27 protein expression in OSCC cells. In addition, metformin induced apoptosis in OSCC cells, significantly down-regulating the anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulating the pro-apoptotic protein Bax. Metformin also markedly reduced the expression of cyclin D1 and increased the numbers of apoptotic

  13. Effects of chemical additives on microbial enhanced oil recovery processes

    SciTech Connect

    Bryant, R.S.; Chase, K.L.; Bertus, K.M.; Stepp, A.K.

    1989-12-01

    An extensive laboratory study has been conducted to determine (1) the role of the microbial cells and products in oil displacement, (2) the relative rates of transport of microbial cells and chemical products from the metabolism of nutrient in porous media, and (3) the effects of chemical additives on the oil recovery efficiency of microbial formulations. This report describes experiments relating to the effects of additives on oil recovery efficiency of microbial formulations. The effects of additives on the oil recovery efficiency of microbial formulations were determined by conducting oil displacement experiments in 1-foot-long Berea sandstone cores. Sodium tripolyphosphate (STPP), a low-molecular-weight polyacrylamide polymer, a lignosulfonate surfactant, and sodium bicarbonate were added to a microbial formulation at a concentration of 1%. The effects of using these additives in a preflush prior to injection of the microbial formulation were also evaluated. Oil-displacement experiments with and without a sodium bicarbonate preflush were conducted in 4-foot-long Berea sandstone cores, and samples of in situ fluids were collected at various times at four intermediate points along the core. The concentrations of metabolic products and microbes in the fluid samples were determined. 9 refs., 22 figs., 8 tabs.

  14. Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic, anti-tumor effects

    PubMed Central

    Yoo, Ji Young; Hurwitz, Brian S; Bolyard, Chelsea; Yu, Jun-Ge; Zhang, Jianying; Selvendiran, Karuppaiyah; Rath, Kellie S; He, Shun; Bailey, Zachary; Eaves, David; Cripe, Timothy P; Parris, Deborah S.; Caligiuri, Michael A.; Yu, Jianhua; Old, Matthew; Kaur, Balveen

    2014-01-01

    Background Bortezomib is an FDA-approved proteasome inhibitor, and oncolytic HSV-1 (oHSV) is a promising therapeutic approach for cancer. We tested the impact of combining bortezomib with oHSV for anti-tumor efficacy. Methods The synergistic interaction between oHSV and bortezomib was calculated using Chou-Talalay analysis. Viral replication was evaluated using plaque assay and immune fluorescence. Western-blot assays were used to evaluate induction of ER stress and unfolded protein response (UPR). Inhibitors targeting Hsp90 were utilized to investigate the mechanism of cell killing. Anti-tumor efficacy in vivo was evaluated using subcutaneous and intracranial tumor xenografts of glioma and head and neck cancer. Survival was analyzed by Kaplan-Meier curves and two-sided log rank test. Results Combination treatment with bortezomib and oHSV, 34.5ENVE, displayed strong synergistic interaction in ovarian cancer, head & neck cancer, glioma, and malignant peripheral nerve sheath tumor (MPNST) cells. Bortezomib treatment induced ER stress, evident by strong induction of Grp78, CHOP, PERK and IRE1α (western blot analysis) and the UPR (induction of hsp40, 70 and 90). Bortezomib treatment of cells at both sublethal and lethal doses increased viral replication (p value <0.001), but inhibition of Hsp90 ablated this response, reducing viral replication and synergistic cell killing. The combination of bortezomib and 34.5ENVE significantly enhanced anti-tumor efficacy in multiple different tumor models in vivo. Conclusions The dramatic synergy of bortezomib and 34.5ENVE is mediated by bortezomib- induced UPR and warrants future clinical testing in patients. PMID:24815720

  15. Combined expression of miR-34a and Smac mediated by oncolytic vaccinia virus synergistically promote anti-tumor effects in Multiple Myeloma

    PubMed Central

    Lei, Wen; Wang, Shibing; Yang, Chunmei; Huang, Xianbo; Chen, Zhenzhen; He, Wei; Shen, Jianping; Liu, Xinyuan; Qian, Wenbin

    2016-01-01

    Despite great progress made in the treatment of multiple myeloma (MM), it is still incurable. Promising phase II clinical results have been reported recently for oncolytic vaccinia virus (OVV) clinic therapeutics. One reason for this has focused on the critical therapeutic importance of the immune response raised by these viruses. However, few studies have performed their applications as an optimal delivery system for therapeutic gene, especially miRNA in MM. In this study, we constructed two novel OVVs (TK deletion) that express anti-tumor genes, miR-34a and Smac, respectively, in MM cell lines and xenograft model. The results demonstrated that the novel OVV can effectively infect MM cell lines, and forcefully enhance the exogenous gene (miR-34a or Smac) expression. Furthermore, utilization of VV-miR-34a combined with VV-Smac synergistically inhibited tumor growth and induced apoptosis in vitro and in vivo. The underlying mechanism is proposed that blocking of Bcl-2 by VV-miR-34a increases the release of cytochrome c from mitochondria and then synergistically amplifies the antitumor effects of Smac-induced cell apoptosis. Our study is the first to utilize OVV as the vector for miR-34a or Smac expression to treat MM, and lays the groundwork for future clinical therapy for MM. PMID:27552933

  16. Combined expression of miR-34a and Smac mediated by oncolytic vaccinia virus synergistically promote anti-tumor effects in Multiple Myeloma.

    PubMed

    Lei, Wen; Wang, Shibing; Yang, Chunmei; Huang, Xianbo; Chen, Zhenzhen; He, Wei; Shen, Jianping; Liu, Xinyuan; Qian, Wenbin

    2016-01-01

    Despite great progress made in the treatment of multiple myeloma (MM), it is still incurable. Promising phase II clinical results have been reported recently for oncolytic vaccinia virus (OVV) clinic therapeutics. One reason for this has focused on the critical therapeutic importance of the immune response raised by these viruses. However, few studies have performed their applications as an optimal delivery system for therapeutic gene, especially miRNA in MM. In this study, we constructed two novel OVVs (TK deletion) that express anti-tumor genes, miR-34a and Smac, respectively, in MM cell lines and xenograft model. The results demonstrated that the novel OVV can effectively infect MM cell lines, and forcefully enhance the exogenous gene (miR-34a or Smac) expression. Furthermore, utilization of VV-miR-34a combined with VV-Smac synergistically inhibited tumor growth and induced apoptosis in vitro and in vivo. The underlying mechanism is proposed that blocking of Bcl-2 by VV-miR-34a increases the release of cytochrome c from mitochondria and then synergistically amplifies the antitumor effects of Smac-induced cell apoptosis. Our study is the first to utilize OVV as the vector for miR-34a or Smac expression to treat MM, and lays the groundwork for future clinical therapy for MM. PMID:27552933

  17. Fusion to an albumin-binding domain with a high affinity for albumin extends the circulatory half-life and enhances the in vivo antitumor effects of human TRAIL.

    PubMed

    Li, Rui; Yang, Hao; Jia, Dianlong; Nie, Qianxue; Cai, Huawei; Fan, Qing; Wan, Lin; Li, Lin; Lu, Xiaofeng

    2016-04-28

    Clinical applications of recombinant human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) have been limited by their poor pharmacokinetics. Using endogenous albumin as a carrier is an attractive approach for circulatory half-life extension. Here, we produced ABD-hTRAIL and hTRAIL-ABD by fusing the albumin-binding domain (ABD) from protein G to the N- or C-terminus of hTRAIL. We found that ABD-hTRAIL bound human serum albumin (HSA) with a high affinity (0.4±0.18nM) and formed nanoparticles with an average diameter (~12nm) above the threshold (~7nm) of renal filtration. ABD-hTRAIL also bound mouse serum albumin (MSA); thus, its half-life was 40-50-fold greater than that of hTRAIL (14.1±0.87h vs 0.32±0.14h). Tumor uptake of ABD-hTRAIL 8-48h post-injection was 6-16-fold that of hTRAIL. Consequently, the tumor suppression of ABD-hTRAIL in mice bearing subcutaneous xenografts was 3-4 times greater than that of hTRAIL. Additionally, the time period during which ABD-hTRAIL could kill circulating tumor cells was approximately 8 times longer than that of hTRAIL. These results demonstrate that ABD fused to the N-terminus endows hTRAIL with albumin binding ability; once it enters the vasculature, ABD mediates binding with endogenous albumin, thus prolonging the half-life and enhancing the antitumor effect of hTRAIL. However, hTRAIL-ABD did not show a high affinity for albumin and therefore did not display the prolonged circulatory half-life and enhanced antitumor effects. These results demonstrate that N-terminal, but not C-terminal, ABD-fusion is an efficient technique for enhancing the antitumor effects of hTRAIL by using endogenous albumin as a carrier. PMID:26951928

  18. Effects of additional interfering signals on adaptive array performance

    NASA Technical Reports Server (NTRS)

    Moses, Randolph L.

    1989-01-01

    The effects of additional interference signals on the performance of a fully adaptive array are considered. The case where the number of interference signals exceeds the number of array degrees of freedom is addressed. It is shown how performance is affected as a function of the number of array elements, the number of interference signals, and the directivity of the array antennas. By using directive auxiliary elements, the performance of the array can be as good as the performance when the additional interference signals are not present.

  19. Potent antitumor effect of neurotensin receptor-targeted oncolytic adenovirus co-expressing decorin and Wnt antagonist in an orthotopic pancreatic tumor model.

    PubMed

    Na, Youjin; Choi, Joung-Woo; Kasala, Dayananda; Hong, JinWoo; Oh, Eonju; Li, Yan; Jung, Soo-Jung; Kim, Sung Wan; Yun, Chae-Ok

    2015-12-28

    Pancreatic cancer is highly aggressive, malignant, and notoriously difficult to cure using conventional cancer therapies. These conventional therapies have significant limitations due to excessive extracellular matrix (ECM) of pancreatic cancer and poor cancer specificity. The excess ECM prevents infiltration of drugs into the inner layer of the solid tumor. Therefore, novel treatment modalities that can specifically target the tumor and degrade the ECM are required for effective therapy. In the present study, we used ECM-degrading and Wnt signal-disrupting oncolytic adenovirus (oAd/DCN/LRP) to achieve a desirable therapeutic outcome against pancreatic cancer. In addition, to overcome the limitations in systemic delivery of oncolytic Ad (oAd) and to specifically target pancreatic cancer, neurotensin peptide (NT)-conjugated polyethylene glycol (PEG) was chemically crosslinked to the surface of Ad, generating a systemically injectable hybrid system, oAd/DCN/LRP-PEG-NT. We tested the targeting and therapeutic efficacy of oAd/DCN/LRP-PEG-NT toward neurotensin receptor 1 (NTR)-overexpressing pancreatic cancer cells, both in vitro and in vivo. The oAd/DCN/LRP-PEG-NT elicited increased NTR-selective cancer cell killing and transduction efficiency when compared with a cognate control lacking NT (oAd/DCN/LRP-PEG). Furthermore, systemic administration of oAd/DCN/LRP-PEG-NT significantly decreased induction of innate and adaptive immune responses against Ad, and blood retention time was markedly prolonged by PEGylation. Moreover, NTR-targeting oAd elicited greater in vivo tumor growth suppression when compared with naked oAd and 9.5 × 10(6)-fold increased tumor-to-liver ratio. This significantly enhanced antitumor effect of oAd/DCN/LRP-PEG-NT was mediated by active viral replication and viral spreading, which was facilitated by ECM degradation and inhibition of Wnt signaling-related factors (Wnt, β-catenin, and/or vimentin) in the tumor tissues. Taken together, these

  20. Additive genetic effect of APOE and BDNF on hippocampus activity.

    PubMed

    Kauppi, Karolina; Nilsson, Lars-Göran; Persson, Jonas; Nyberg, Lars

    2014-04-01

    Human memory is a highly heritable polygenic trait with complex inheritance patterns. To study the genetics of memory and memory-related diseases, hippocampal functioning has served as an intermediate phenotype. The importance of investigating gene-gene effects on complex phenotypes has been emphasized, but most imaging studies still focus on single polymorphisms. APOE ε4 and BDNF Met, two of the most studied gene variants for variability in memory performance and neuropsychiatric disorders, have both separately been related to poorer episodic memory and altered hippocampal functioning. Here, we investigated the combined effect of APOE and BDNF on hippocampal activation (N=151). No non-additive interaction effects were seen. Instead, the results revealed decreased activation in bilateral hippocampus and parahippocampus as a function of the number of APOE ε4 and BDNF Met alleles present (neither, one, or both). The combined effect was stronger than either of the individual effects, and both gene variables explained significant proportions of variance in BOLD signal change. Thus, there was an additive gene-gene effect of APOE and BDNF on medial temporal lobe (MTL) activation, showing that a larger proportion of variance in brain activation attributed to genetics can be explained by considering more than one gene variant. This effect might be relevant for the understanding of normal variability in memory function as well as memory-related disorders associated with APOE and BDNF. PMID:24321557

  1. A novel curcuminoid exhibits enhanced antitumor activity in nasopharyngeal carcinoma.

    PubMed

    Pan, Yunbao; Liu, Guohong; Xiao, Jian; Su, Bojin; Zhou, Fuling; Wei, Yongchang

    2016-05-01

    Curcumin shows growth-inhibition against tumor cells through multi-target mechanisms. Nevertheless, the poor stability and pharmacokinetics considerably limit its clinical functions. Increased effort has been put into the chemical alteration of curcumin to find potential analogues with improved bioavailability and antitumor activities. In this study, the antitumor activity of a novel curcuminoid (B63) in nasopharyngeal carcinoma (NPC) was examined. The MTT and colony formation assays were used to detect NPC cell viability and proliferation. Flow cytometry was used to detect cell cycle distribution. The Annexin V/PI staining assay and cleavage PARP and cleavage caspase-3 expression were used to examine apoptosis. Western blotting was used to examine the protein expression of endoplasmic reticulum (ER) stress pathway markers, XBP-1, ATF-4 and CHOP. The suppressive effect of B63 on tumor growth was examined in vivo by subcutaneously inoculated NPC in a tumor model using nude mice. Treatment with B63 potentially caused growth inhibition and apoptosis in NPC cells in a dose- and time-responsive manner. Its antitumor effect was associated with the ER stress activation. Nevertheless, the same dose of curcumin did not activate ER stress. In addition, knockdown of Chop attenuated B63-induced cell viability inhibition, suggesting that the apoptotic pathway is ER stress-dependent. The tumor volume and weight were significantly reduced by pretreating the NPC cells with B63 before implantation in the in vivo mouse model. B63 exhibited a more potent antitumor action than curcumin in NPC. These observations on the novel compound B63 indicate a novel candidate for NPC therapy. PMID:26983360

  2. Tin nanoparticles as an effective conductive additive in silicon anodes.

    PubMed

    Zhong, L; Beaudette, C; Guo, J; Bozhilov, K; Mangolini, L

    2016-01-01

    We have found that the addition of tin nanoparticles to a silicon-based anode provides dramatic improvements in performance in terms of both charge capacity and cycling stability. Using a simple procedure and off-the-shelf additives and precursors, we developed a structure in which the tin nanoparticles are segregated at the interface between the silicon-containing active layer and the solid electrolyte interface. Even a minor addition of tin, as small as ∼2% by weight, results in a significant decrease in the anode resistance, as confirmed by electrochemical impedance spectroscopy. This leads to a decrease in charge transfer resistance, which prevents the formation of electrically inactive "dead spots" in the anode structure and enables the effective participation of silicon in the lithiation reaction. PMID:27484849

  3. Tin nanoparticles as an effective conductive additive in silicon anodes

    PubMed Central

    Zhong, L.; Beaudette, C.; Guo, J.; Bozhilov, K.; Mangolini, L.

    2016-01-01

    We have found that the addition of tin nanoparticles to a silicon-based anode provides dramatic improvements in performance in terms of both charge capacity and cycling stability. Using a simple procedure and off-the-shelf additives and precursors, we developed a structure in which the tin nanoparticles are segregated at the interface between the silicon-containing active layer and the solid electrolyte interface. Even a minor addition of tin, as small as ∼2% by weight, results in a significant decrease in the anode resistance, as confirmed by electrochemical impedance spectroscopy. This leads to a decrease in charge transfer resistance, which prevents the formation of electrically inactive “dead spots” in the anode structure and enables the effective participation of silicon in the lithiation reaction. PMID:27484849

  4. Tin nanoparticles as an effective conductive additive in silicon anodes

    NASA Astrophysics Data System (ADS)

    Zhong, L.; Beaudette, C.; Guo, J.; Bozhilov, K.; Mangolini, L.

    2016-08-01

    We have found that the addition of tin nanoparticles to a silicon-based anode provides dramatic improvements in performance in terms of both charge capacity and cycling stability. Using a simple procedure and off-the-shelf additives and precursors, we developed a structure in which the tin nanoparticles are segregated at the interface between the silicon-containing active layer and the solid electrolyte interface. Even a minor addition of tin, as small as ∼2% by weight, results in a significant decrease in the anode resistance, as confirmed by electrochemical impedance spectroscopy. This leads to a decrease in charge transfer resistance, which prevents the formation of electrically inactive “dead spots” in the anode structure and enables the effective participation of silicon in the lithiation reaction.

  5. Effectiveness of various organometallics as antiwear additives in mineral oil

    NASA Technical Reports Server (NTRS)

    Buckley, D. H.

    1977-01-01

    Sliding friction experiments were conducted with 1045 steel contacting 302 stainless steel and lubricated with various organometallics in mineral oil. Auger emission spectroscopy was used to determine the element present in the wear contact zone. The results indicate that there are organometallics which are as effective an antiwear additives as the commonly used zinc dialkyl dithiophosphate. These include dimethyl cadmium, triphenyl lead thiomethoxide, and triphenyl tin chloride. The additives were examined in concentrations to 1 weight percent. With dimethyl cadmium at concentrations of 0.5 weight percent and above, cadmium was detected in the contact zone. Coincident with the detection of cadmium, a marked decrease in the friction coefficient was observed. All additives examined reduced friction, but only the aforementioned reduced wear to a level comparable to that observed with zinc dialkyl dithiophosphate.

  6. Identification of a Novel Antibiotic from Myxobacterium Stigmatella Eracta WXNXJ-B and Evaluation of its Antitumor Effects In-vitro

    PubMed Central

    Wang, Dahong; Yuan, Jiangfeng; Tao, Wenyi

    2014-01-01

    This work was to isolate and identify the bioactive secondary metabolite which was produced by myxobacterium Stigmatella eracta WXNXJ-B, and to evaluate its antitumor and apoptosis-inducing effects. The results showed that one novel compound (molecular formula C29H25NO3) was isolated, purified by Sephadex LH-20 column chromatography and preparative RP-HPLC, and identified as 5-(6-benzyl-quinolin-3-ylmethyl)-6- phenyl-3,7-dioxa- bicycle [4.1.0] heptan-3-one (named as quinoxalone) according to its UV, IR, HRMS and NMR spectra. The compound showed strong antitumor activity on B16, HepG2, MCF-7, SGC-7901, MDA-MB231 and CT-26 six tumor cell lines in-vitro. Nevertheless, it showed less cytotoxic to the mouse normal spleen cells (IC50 was 836.27 ± 13.02 µg mL-1). The cytotoxic study on HepG2 cells in-vitro showed that quinoxalone could induce the change of cell nuclear and arrested the cell division in the S and G2/M phase. Our results suggest that quinoxalone could be a potential anti-cancer agent. PMID:24734069

  7. Synthesis and pharmacological evaluation of a novel AT1 angiotensin II receptor antagonist with anti-hypertension and anti-tumor effects.

    PubMed

    Bao, Xiaolu; Zhu, Weibo; Da, Yajing; Zhu, Linfeng; Qie, Li; Yan, Yijia; Wang, Li; Tang, Hesheng; Chen, Zhi-long

    2015-01-01

    A new compound 2-(4-((2-butyl-5-nitro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl) benzamide (1) was designed, synthesized and evaluated as a novel AT1 receptor antagonist. Compound 1 displayed high affinity to AT1 receptor with an IC50 value of 1.65 ± 0.2 nM in radio-ligand binding assays. It had an efficient and long-lasting effect in reducing blood pressure which could last for more than 12 h at the dose of 10 mg/kg in spontaneously hypertensive rats. Acute toxicity tests suggested that compound 1 was safe with the LD50 value of 2519.81 mg/kg. Besides, in vitro and in vivo tests suggested its anti-proliferative and anti-tumor activities, respectively. So compound 1 could be considered as a novel anti-hypertension, anti-tumor candidate and deserved further investigation. PMID:25919352

  8. Identification of a Novel Antibiotic from Myxobacterium Stigmatella Eracta WXNXJ-B and Evaluation of its Antitumor Effects I n - vitro.

    PubMed

    Wang, Dahong; Yuan, Jiangfeng; Tao, Wenyi

    2014-01-01

    This work was to isolate and identify the bioactive secondary metabolite which was produced by myxobacterium Stigmatella eracta WXNXJ-B, and to evaluate its antitumor and apoptosis-inducing effects. The results showed that one novel compound (molecular formula C29H25NO3) was isolated, purified by Sephadex LH-20 column chromatography and preparative RP-HPLC, and identified as 5-(6-benzyl-quinolin-3-ylmethyl)-6- phenyl-3,7-dioxa- bicycle [4.1.0] heptan-3-one (named as quinoxalone) according to its UV, IR, HRMS and NMR spectra. The compound showed strong antitumor activity on B16, HepG2, MCF-7, SGC-7901, MDA-MB231 and CT-26 six tumor cell lines in-vitro. Nevertheless, it showed less cytotoxic to the mouse normal spleen cells (IC50 was 836.27 ± 13.02 µg mL(-1)). The cytotoxic study on HepG2 cells in-vitro showed that quinoxalone could induce the change of cell nuclear and arrested the cell division in the S and G2/M phase. Our results suggest that quinoxalone could be a potential anti-cancer agent. PMID:24734069

  9. The effect of chemical additives on the synthesis of ethanol

    SciTech Connect

    Chuang, S.S.C.

    1989-02-04

    The objective of this research is to elucidate the role of various chemical additives on ethanol synthesis over Rh- and Ni-based catalysts. Chemical additives used will include S, P, Ag, Cu, Mn, and Na. The effect of additives on the surface state of the catalysts, heat of adsorption of reactant molecules, reaction intermediates, reaction pathways, reaction kinetics, and product distributions is/will be investigated by a series of studies including temperature programmed desorption, infrared study of NO adsorption, reactive probing, steady state rate measurement, and transient kinetic study. A better understanding of the role of additive may allow us to use chemical additives to manipulate the catalytic properties of Rh- and Ni-based catalysts for producing high yields of ethanol from syngas. CO insertion is known to be a key step to the formation of acetaldehyde and ethanol from CO hydrogenation over Rh catalysts. Ethylene hydroformylation has often served as a probe to determine CO insertion capabilities of Rh catalysts. The mechanism of CO insertion in ethylene hydroformylation over Rh/SiO{sub 2} was investigated.

  10. Effect of trehalose addition on volatiles responsible for strawberry aroma.

    PubMed

    Kopjar, Mirela; Hribar, Janez; Simcic, Marjan; Zlatić, Emil; Pozrl, Tomaz; Pilizota, Vlasta

    2013-12-01

    Aroma is one of the most important quality properties of food products and has a great influence on quality and acceptability of foods. Since it is very difficult to control, in this study the effect of addition of trehalose (3, 5 and 10%) to freeze-dried strawberry cream fillings was investigated as a possible means for retention of some of the aroma compounds responsible for the strawberry aroma. In samples with added trehalose, higher amounts of fruity esters were determined. Increase of trehalose content did not cause a proportional increase in the amount of fruity esters. However, results of our research showed that trehalose addition did not have the same effect on both gamma-decalactone and furaneol. PMID:24555295

  11. A phosphotyrosine switch determines the antitumor activity of ERβ

    PubMed Central

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

    2014-01-01

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

  12. Electrotransfer of Plasmid DNA Encoding an Anti-Mouse Endoglin (CD105) shRNA to B16 Melanoma Tumors with Low and High Metastatic Potential Results in Pronounced Anti-Tumor Effects

    PubMed Central

    Dolinsek, Tanja; Sersa, Gregor; Prosen, Lara; Bosnjak, Masa; Stimac, Monika; Razborsek, Urska; Cemazar, Maja

    2015-01-01

    Endoglin overexpression is associated with highly proliferative tumor endothelium and also with some tumors, including melanoma. Its targeting has anti-tumor effectiveness, which can also be obtained by RNA interference. The aim of our study was to explore the anti-tumor effectiveness of endoglin silencing by electrotransfer of plasmid DNA encoding short hairpin RNA against endoglin in two murine B16 melanoma variants with different metastatic potential on cells, spheroids and subcutaneous tumors in mice. The results demonstrate that endoglin silencing with gene electrotransfer reduces the proliferation, survival and migration of melanoma cells and also has anti-tumor effectiveness, as the therapy resulted in a high percentage of tumor cures (23% and 58% on B16F1 and B16F10 tumors, respectively). The effectiveness of the therapy correlated with endoglin expression in melanoma cells; in vitro the effects were more pronounced in B16F1 cells, which express more endoglin than B16F10. However, the opposite was observed in vivo in tumors, where there was a higher expression of endoglin and better anti-tumor effectiveness in the B16F10 tumor. In conclusion, targeting endoglin for the treatment of melanoma seems to be a concept worthy of further exploration due to the increased therapeutic effect of the therapy based on simultaneous vascular targeting and its direct effect on tumor cells. PMID:26712792

  13. Electrotransfer of Plasmid DNA Encoding an Anti-Mouse Endoglin (CD105) shRNA to B16 Melanoma Tumors with Low and High Metastatic Potential Results in Pronounced Anti-Tumor Effects.

    PubMed

    Dolinsek, Tanja; Sersa, Gregor; Prosen, Lara; Bosnjak, Masa; Stimac, Monika; Razborsek, Urska; Cemazar, Maja

    2015-01-01

    Endoglin overexpression is associated with highly proliferative tumor endothelium and also with some tumors, including melanoma. Its targeting has anti-tumor effectiveness, which can also be obtained by RNA interference. The aim of our study was to explore the anti-tumor effectiveness of endoglin silencing by electrotransfer of plasmid DNA encoding short hairpin RNA against endoglin in two murine B16 melanoma variants with different metastatic potential on cells, spheroids and subcutaneous tumors in mice. The results demonstrate that endoglin silencing with gene electrotransfer reduces the proliferation, survival and migration of melanoma cells and also has anti-tumor effectiveness, as the therapy resulted in a high percentage of tumor cures (23% and 58% on B16F1 and B16F10 tumors, respectively). The effectiveness of the therapy correlated with endoglin expression in melanoma cells; in vitro the effects were more pronounced in B16F1 cells, which express more endoglin than B16F10. However, the opposite was observed in vivo in tumors, where there was a higher expression of endoglin and better anti-tumor effectiveness in the B16F10 tumor. In conclusion, targeting endoglin for the treatment of melanoma seems to be a concept worthy of further exploration due to the increased therapeutic effect of the therapy based on simultaneous vascular targeting and its direct effect on tumor cells. PMID:26712792

  14. Antitumor effects of SEF19, a new nonsteroidal aromatase inhibitor, on 7,12-dimethylbenz[a]anthracene-induced mammary tumors in rats.

    PubMed

    Iino, Y; Karakida, T; Sugamata, N; Andoh, T; Takei, H; Takahashi, M; Yaguchi, S; Matsuno, T; Takehara, M; Sakato, M; Kawashima, S; Morishita, Y

    1998-01-01

    The antitumor and endocrine effects of a new nonsteroidal aromatase inhibitor, 2-(imidazol-1-yl)-4,6-dimorphorino-l, 3, 5-triazine (SEF19) were examined in female Sprague-Dawley rats bearing estrogen dependent 7,12-dimethylbenz[a]anthracene(DMBA)-induced mammary tumors, and the effects were compared with those of CGS20267. The rats bearing DMBA-induced mammary tumors within 6-15 weeks after the DMBA administration were divided into the treatment groups once a week every week, and they were treated with SEF19, CGS20267 and vehicle for 4 weeks. One hundred rats were sacrificed 4 hours after the last administration, and the remaining 60 rats were sacrificed after a 4-week recovery period. During the treatment and recovery period, the tumor size was generally smaller in the SEF19 and CGS20267-treated subgroups than in the control subgroup. Tumor sizes in the subgroups treated with high doses of SEF19 (25 mg/kg/day and 50 mg/kg/2 days) were reduced to the size of the CGS20267-treated subgroup. The CGS20267-treated rats showed decrease in the serum estradiol level and an increase in the serum testosterone level. Their uterine weights were reduced. SEF19 treatment failed to show any effect on the serum levels of estrone, estradiol, testosterone and androstenedione, but it suppressed uterine weight in a dose-dependent manner. After the recovery period, no effect was detected in the serum concentrations of steroid hormones and the weight of the organs. At every dose used in the present study the aromatase inhibitory activity of SEF19 was weaker than that of CGS20267, but the inhibitory effect on mammary tumor growth of SEF19 at high doses was comparable to that of CGS20267. We conclude that the antitumor effect of SEF19 is not due to aromatase inhibition but mainly to its direct cytotoxicity. PMID:9568073

  15. The Anti-Tumor Effect of A3 Adenosine Receptors Is Potentiated by Pulsed Electromagnetic Fields in Cultured Neural Cancer Cells

    PubMed Central

    Vincenzi, Fabrizio; Targa, Martina; Corciulo, Carmen; Gessi, Stefania; Merighi, Stefania; Setti, Stefania; Cadossi, Ruggero; Borea, Pier Andrea; Varani, Katia

    2012-01-01

    A3 adenosine receptors (ARs) play a pivotal role in the development of cancer and their activation is involved in the inhibition of tumor growth. The effects of pulsed electromagnetic fields (PEMFs) on cancer have been controversially discussed and the detailed mechanisms are not yet fully understood. In the past we have demonstrated that PEMFs increased A2A and A3AR density and functionality in human neutrophils, human and bovine synoviocytes, and bovine chondrocytes. In the same cells, PEMF exposure increased the anti-inflammatory effect mediated by A2A and/or A3ARs. The primary aim of the present study was to evaluate if PEMF exposure potentiated the anti-tumor effect of A3ARs in PC12 rat adrenal pheochromocytoma and U87MG human glioblastoma cell lines in comparison with rat cortical neurons. Saturation binding assays and mRNA analysis revealed that PEMF exposure up-regulated A2A and A3ARs that are well coupled to adenylate cyclase activity and cAMP production. The activation of A2A and A3ARs resulted in the decrease of nuclear factor-kappa B (NF-kB) levels in tumor cells, whilst only A3ARs are involved in the increase of p53 expression. A3AR stimulation mediated an inhibition of tumor cell proliferation evaluated by thymidine incorporation. An increase of cytotoxicity by lactate dehydrogenase (LDH) release and apoptosis by caspase-3 activation in PC12 and U87MG cells, but not in cortical neurons, was observed following A3AR activation. The effect of the A3AR agonist in tumor cells was enhanced in the presence of PEMFs and blocked by using a well-known selective antagonist. Together these results demonstrated that PEMF exposure significantly increases the anti-tumor effect modulated by A3ARs. PMID:22761760

  16. Connexin32‑mediated antitumor effects of suicide gene therapy against hepatocellular carcinoma: In vitro and in vivo anticancer activity.

    PubMed

    Wu, Lun; Zhou, Wen-Bo; Shen, Feng; Liu, Wei; Wu, Hong-Wei; Zhou, Shi-Ji; Li, Sheng-Wei

    2016-04-01

    Normal hepatocytes express connexin32 (Cx32), which forms gap junctions at cell‑cell contact areas. The aim of the present study was to investigate whether Cx32 mediates the cell death‑inducing effects of ultrasound microbubbles carrying the herpes simplex virus thymidine kinase (HSV‑TK) suicide gene against hepatocellular carcinoma cells in vitro and in vivo. HepG2 cells were exposed to different concentrations of trans‑retinoic acid (ATRA) in culture, to evaluate the intrinsic antitumor effect of ATRA. Detailed in‑vitro and in‑vivo investigations on the antitumor effects of ATRA via Cx32 mediation were performed, and the possible underlying mechanisms of action of the compound were then examined. The gene expression of HSV‑TK transfected by ultrasound wave irradiation in the HepG2 cells was quantified using reverse transcription‑quantitative polymerase chain reaction analysis. The effects on cell death were assessed using an MTT assay. The protein expression levels of Cx32 in ATRA‑untreated or ATRA‑treated tissues were quantified by immunohistochemical analysis and Western blot assays. The HSV‑TK gene was successfully transfected into the HepG2 cell using ultrasound wave irradiation, and was stably expressed. Compared with the other groups, the HSV‑TK gene group treated with ATRA exhibited an increased number of apoptotic cells (P<0.05) and improved tumor suppression (P<0.05). ATRA significantly increased the expression of Cx32 in the hepatoma tissues (P<0.01). The present study demonstrated that ATRA elevated the protein expression of Cx32 and enhanced the bystander effect of the HSV‑TK/GCV suicide gene therapy system, which may provide a potential strategy for hepatocellular carcinoma treatment. PMID:26935255

  17. Cooperative therapeutic anti-tumor effect of IL-15 agonist ALT-803 and co-targeting soluble NKG2D ligand sMIC

    PubMed Central

    Basher, Fahmin; Jeng, Emily K.; Wong, Hing; Wu, Jennifer

    2016-01-01

    Shedding of the human NKG2D ligand MIC (MHC class I-chain-related molecule) from tumor cell surfaces correlates with progression of many epithelial cancers. Shedding-derived soluble MIC (sMIC) enables tumor immune escape through multiple immune suppressive mechanisms, such as disturbing natural killer (NK) cell homeostatic maintenance, impairing NKG2D expression on NK cells and effector T cells, and facilitating the expansion of arginase I+ myeloid suppressor cells. Our recent study has demonstrated that sMIC is an effective cancer therapeutic target. Whether targeting tumor-derived sMIC would enhance current active immunotherapy is not known. Here, we determined the in vivo therapeutic effect of an antibody co-targeting sMIC with the immunostimulatory IL-15 superagonist complex, ALT-803, using genetically engineered transplantable syngeneic sMIC+ tumor models. We demonstrate that combined therapy of a nonblocking antibody neutralizing sMIC and ALT-803 improved the survival of animals bearing sMIC+ tumors in comparison to monotherapy. We further demonstrate that the enhanced therapeutic effect with combined therapy is through concurrent augmentation of NK and CD8 T cell anti-tumor responses. In particular, expression of activation-induced surface molecules and increased functional potential by cytokine secretion are improved greatly by the administration of combined therapy. Depletion of NK cells abolished the cooperative therapeutic effect. Our findings suggest that administration of the sMIC-neutralizing antibody can enhance the anti-tumor effects of ALT-803. With ALT-803 currently in clinical trials to treat progressive solid tumors, the majority of which are sMIC+, our findings provide a rationale for co-targeting sMIC to enhance the therapeutic efficacy of ALT-803 or other IL-15 agonists. PMID:26625316

  18. Gene Electrotransfer of Plasmid with Tissue Specific Promoter Encoding shRNA against Endoglin Exerts Antitumor Efficacy against Murine TS/A Tumors by Vascular Targeted Effects

    PubMed Central

    Stimac, Monika; Dolinsek, Tanja; Lampreht, Ursa; Cemazar, Maja; Sersa, Gregor

    2015-01-01

    Vascular targeted therapies, targeting specific endothelial cell markers, are promising approaches for the treatment of cancer. One of the targets is endoglin, transforming growth factor-β (TGF-β) co-receptor, which mediates proliferation, differentiation and migration of endothelial cells forming neovasculature. However, its specific, safe and long-lasting targeting remains the challenge. Therefore, in our study we evaluated the transfection efficacy, vascular targeted effects and therapeutic potential of the plasmid silencing endoglin with the tissue specific promoter, specific for endothelial cells marker endothelin-1 (ET) (TS plasmid), in comparison to the plasmid with constitutive promoter (CON plasmid), in vitro and in vivo. Tissue specificity of TS plasmid was demonstrated in vitro on several cell lines, and its antiangiogenic efficacy was demonstrated by reducing tube formation of 2H11 endothelial cells. In vivo, on a murine mammary TS/A tumor model, we demonstrated good antitumor effect of gene electrotransfer (GET) of either of both plasmids in treatment of smaller tumors still in avascular phase of growth, as well as on bigger tumors, already well vascularized. In support to the observations on predominantly vascular targeted effects of endoglin, histological analysis has demonstrated an increase in necrosis and a decrease in the number of blood vessels in therapeutic groups. A significant antitumor effect was observed in tumors in avascular and vascular phase of growth, possibly due to both, the antiangiogenic and the vascular disrupting effect. Furthermore, the study indicates on the potential use of TS plasmid in cancer gene therapy since the same efficacy as of CON plasmid was determined. PMID:25909447

  19. Effect of additives on physicochemical properties in amorphous starch matrices.

    PubMed

    Liang, Jun; Wang, Simon; Ludescher, Richard D

    2015-03-15

    The effect of the addition of non-reducing sugars or methylcellulose on the matrix physical properties and rate of non-enzymatic browning (NBR) between exogenous glucose+lysine in a starch-based glassy matrix were studied, using the methods of luminescence and FTIR. Amorphous starch-based matrices were formulated by rapidly dehydrating potato starch gel mixed with additives at weight ratios of 7:93 (additive:starch). Data on the phosphorescence emission energy and lifetime from erythrosin B dispersed in the matrices indicated that sugars decreased starch matrix mobility in a Tg-dependent manner, except for trehalose that interacted with starch in a unique mode, while methylcellulose, the additive with the highest Tg, increased the molecular mobility. Using FTIR, we found that methylcellulose decreased the strength of hydrogen bond network and sugars enhanced the hydrogen bond strength in the order: trehalose>maltitol>sucrose. Comparing those changes with the rate of NBR between exogenous glucose+lysine, we suggest that NBR rates are primarily influenced by matrix mobility, which is modulated by the hydrogen bond network, and interactions among components. PMID:25308673

  20. Effect of surfactant addition on removal of microbubbles using ultrasound.

    PubMed

    Kobayashi, Daisuke; Hayashida, Yoshiyuki; Sano, Kazuki; Terasaka, Koichi

    2014-08-01

    It is difficult to control the bubble in a liquid by the external operation, because the behavior of the bubble is controlled in buoyancy and flow of liquid. On the other hand, microbubbles, whose diameter is several decades μm, stably disperse in static liquid because of their small buoyancy and electrical repulsion. When an ultrasound, whose frequency was 2.4 MHz, was irradiated, the milky white microbubbles suspended solution became rapidly clear. In this study, the effects of surfactant addition on the removal of microbubbles from a liquid in an ultrasonic field were investigated. The efficiency of removal of microbubbles decreased with surfactant addition. Surfactant type influenced the size of agglomerated microbubbles, and the efficiency of removal of microbubbles changed. The surface of microbubble was modified by surfactant adsorption, and the steric inhibition influenced the removal of microbubbles. PMID:24745307

  1. Effects of acetylacetone additions on PZT thin film processing

    SciTech Connect

    Schwartz, R.W.; Assink, R.A.; Dimos, D.; Sinclair, M.B.; Boyle, T.J.; Buchheit, C.D.

    1995-02-01

    Sol-gel processing methods are frequently used for the fabrication of lead zirconate titanate (PZT) thin films for many electronic applications. Our standard approach for film fabrication utilizes lead acetate and acetic acid modified metal alkoxides of zirconium and titanium in the preparation of our precursor solutions. This report highlights some of our recent results on the effects of the addition of a second chelating ligand, acetylacetone, to this process. The authors discuss the changes in film drying behavior, densification and ceramic microstructure which accompany acetylacetone additions to the precursor solution and relate the observed variations in processing behavior to differences in chemical precursor structure induced by the acetylacetone ligand. Improvements in thin film microstructure, ferroelectric and optical properties are observed when acetylacetone is added to the precursor solution.

  2. 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane potentiates in vitro and in vivo antitumor effects of irinotecan on human colorectal cancer cells

    PubMed Central

    YANG, PO-SHENG; WANG, JANE-JEN; WANG, YEA-HWEY; JAN, WOAN-CHING; CHENG, SHIH-PING; HSU, YI-CHIUNG

    2016-01-01

    1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane (DPD), a diamantane derivative, was previously noted as an anticancer compound through anticancer drug screening with NCI-60 human tumor cells. Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is clinically active in the treatment of colorectal cancer, with no cross-resistance. The current study conducted a pharmacokinetic evaluation of DPD, an essential component of drug discovery. Subsequent pathway analysis of microarray gene expression data indicated that the anticancer mechanisms of DPD were associated with cell cycle progression and apoptosis. The combined effect of DPD and CPT-11 with regard to the mechanisms of apoptosis-related pathways in COLO 205 cells, and the antitumor effects in colon cancer xenograft mice, were investigated. The plasma concentration and pharmacokinetic parameters of DPD in male albino rats were analyzed following a single dose of DPD by injection. The protein expression of active caspase-3, procaspase-3 and poly ADP-ribose polymerase (PARP) in COLO 205 cells treated with DPD and CPT-11, alone or combined, was evaluated by western blotting. A trypan blue dye exclusion assay revealed that, whilst DPD alone demonstrated good antitumor effects, this effect was potentiated when combined with CPT-11. Combined treatment with DPD and CPT-11 upregulated the expression of cleaved PARP, procaspase-3, caspase-3 and active caspase-3 in COLO 205 cells. In the colon cancer xenograft model, compared with the control (vehicle-treated) mice, the sizes of the tumors were significantly lower in mice treated with DPD and CPT-11, alone or in combination. Thus, DPD may be a potential therapeutic agent for the treatment of colorectal cancer via upregulating apoptosis-related pathways. PMID:27123150

  3. Sequential use of vinorelbine followed by gefitinib enhances the antitumor effect in NSCLC cell lines poorly responsive to reversible EGFR tyrosine kinase inhibitors.

    PubMed

    Dal Bello, M G; Alama, A; Barletta, G; Coco, S; Truini, A; Vanni, I; Boccardo, S; Genova, C; Rijavec, E; Biello, F; Bottoni, G; Sambuceti, G; Grossi, F

    2015-12-15

    Preclinical studies have suggested that combining cytotoxic agents with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to treat EGFR-mutated tumors may increase their inhibitory effect depending on the order of drug administration. The antitumor efficacy of different treatment sequences using vinorelbine (VNB) and gefitinib (GEF) was investigated both in vitro and in vivo in non-small cell lung cancer (NSCLC) cell lines with the rationale of potentially translating these findings into the clinical setting. The EGFR-wild-type A549 and the EGFR-mutated (exon 21 L858R/exon 20 T790M) H1975 cell lines were treated as follows: GEF followed by VNB, VNB followed by GEF and the two drugs applied individually or concurrently. Results in vitro demonstrated that the sequence of VNB followed by GEF was significantly more active than single-agent treatments. The expression of activated EGFR and its downstream pathway genes indicated that the increased cytotoxic effect of the VNB and GEF treatment sequence was accompanied by inhibition of EGFR, AKT and ERK1/2. Moreover, the increased inhibition of tumor growth after treatment with VNB followed by GEF was also confirmed in CD1-nude mice that were xenotransplanted with H1975 cells (p < 0.0001). This effect was paralleled by a corresponding decrease in cancer glucose consumption, as assessed by micro-positron emission tomography scans (p < 0.05). These preclinical findings in NSCLC cell lines, which are poorly responsive to EGFR-TKIs, demonstrated that the sequential treatment of VNB followed by GEF induced a significant antitumor effect, which supports the translation of this treatment schedule into a clinical setting. PMID:26089022

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

    PubMed

    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. PMID:26742746

  5. Priming effects in Haplic Luvisol after different substrate additions

    NASA Astrophysics Data System (ADS)

    Bogomolova, I.; Blagodatskaya, E.; Blagodatsky, S.; Kuzyakov, Y.

    2009-04-01

    Although soils contain considerable amounts of soil organic carbon (SOC), most of it is not easily available for microorganisms. Addition of various substrates to soil (for example, plant residues, root exudates) may affect SOC mineralization. The addition of mineral nutrients, especially N, may also affect C turnover and so change the mineralization rate of SOC. Such short-term changes in mineralization of organic substance of soil were termed as "priming-effects" (Bingemann et al., 1953). Priming effect leads to additional mineralization of SOC (van Elsas and van Overbeek, 1993). It has been shown that not only plant residues induce priming effects (Sauerbeck, 1966; Stemmer et al., 1999; Bell et al., 2003), but also easily available substrates such as sugars or amino acids, which are present in soil solutions and root exudates (Vasconcellos, 1994; Shen and Bartha, 1997; Hamer and Marschner, 2002). Since easily available substrates may not only accelerate SOC mineralization, but also may retard it, Kuzyakov et al. (2000) differentiated between positive and negative priming effects. It is not clear until now, how long priming effects persists in soil after substrate addition, and if they are induced every time when a substrate becomes available in soil. So, the aim of this study was to evaluate effects of glucose and plant residues on SOM decomposition, and influence of glucose on plant residues decomposition in soil. The experimental layout was designed as two factor experiment: 1) plant residues and 2) available substrate amendment. Maize shoot residues (50 mg added to 5 g soil) were 14C labeled (9•104 DPM per 5 g soil). Soil without of any plant residues served as a control for this treatment. Two levels of D (+) glucose as easily available substrates were added after three months of pre-incubation of soil samples with maize residues: 0.009 mg glucose C g-1 soil and 0.225 mg glucose C g-1 soil. The glucose was uniformly labelled with 14C (2.37•104 DPM per 5

  6. Preparation of the core-shell structure adriamycin lipiodol microemulsions and their synergistic anti-tumor effects with diethyldithiocarbamate in vivo.

    PubMed

    Daocheng, Wu; Mingxi, Wan

    2010-11-01

    We prepared the core-shell structure adriamycin lipiodol microemulsions (ADM-CSLMs) and evaluated their in vivo antitumor effects in combination with Diethyldithiocarbamate (DDC). Two types of ADM-CSLMs, adriamycin liposome-lipiodol microemulsion(ADM-LLM) and adriamycin microsphere lipiodol microemulsion (ADM-MLM), were prepared through the emulsification method. The drug loading and encapsulation efficiency of ADM-CSLMs were measured by the high-performance liquid chromatograph (HPLC). The size and shape of the ADM-CSLMs were determined by an atom force microscopy (AFM), a transmission electron microscopy (TEM), and a particle size analyzer, respectively. The synergistic effects of DDC and ADM-CSLMs for cancer treatment of carcinoma drug-resistance cell was evaluated by the MTT method, the activation of superoxide dismutase (SOD) was detected by chemiluminescence, and the ADM accumulation in cells was measured by flow cytometry. Walker-256 carcinoma was transplanted to the livers of the male SD rats, ADM-CSLMs were administrated to the livers of the rats by intervention hepatic artery embolization through microsurgery. The tumor growth and animal survival were evaluated. The results show that the average diameter of ADM-LLM and ADM-MLM were 4.23 ± 1.2 μm and 4.67 ± 1.4 μm, respectively, and their ADM encapsulation efficiency were 83.7% and 87.2% with respect to loading efficiency of 82 μg/ml and 91 μg/ml. The tumor growth and animal survival in two of the ADM-CSLMs combined with DDC groups were significantly higher than that of ADM only treatment, ADM liposome combined with DDC (P < 0.01), as well as the ADM microsphere combined with DDC (P < 0.01). Therefore, ADM-CSLMs are useful carriers for the treatment of carcinoma and their anti-tumor effect can be enhanced by DDC in a suitable concentration. PMID:20888179

  7. PREDATOR IDENTITY AND ADDITIVE EFFECTS IN A TREEHOLE COMMUNITY

    PubMed Central

    Griswold, Marcus W.; Lounibos, L. Philip

    2007-01-01

    Multiple predator species can interact as well as strongly affect lower trophic levels, resulting in complex, nonadditive effects on prey populations and community structure. Studies of aquatic systems have shown that interactive effects of predators on prey are not necessarily predictable from the direct effects of each species alone. To test for complex interactions, the individual and combined effects of a top and intermediate predator on larvae of native and invasive mosquito prey were examined in artificial analogues of water-filled treeholes. The combined effects of the two predators were accurately predicted from single predator treatments by a multiplicative risk model, indicating additivity. Overall survivorship of both prey species decreased greatly in the presence of the top predator Toxorhynchites rutilus. By itself, the intermediate predator Corethrella appendiculata increased survivorship of the native prey species Ochlerotatus triseriatus and decreased survivorship of the invasive prey species Aedes albopictus relative to treatments without predators. Intraguild predation did not occur until alternative prey numbers had been reduced by approximately one-half. Owing to changes in size structure accompanying its growth, T. rutilus consumed more prey as time progressed, whereas C. appendiculata consumed less. The intermediate predator, C. appendiculata, changed species composition by preferentially consuming A. albopictus, while the top predator, T. rutilus, reduced prey density, regardless of species. Although species interactions were in most cases predicted from pairwise interactions, risk reduction from predator interference occurred when C. appendiculata densities were increased and when the predators were similarly sized. PMID:16676542

  8. Aliphatic acid-conjugated antimicrobial peptides--potential agents with anti-tumor, multidrug resistance-reversing activity and enhanced stability.

    PubMed

    Deng, Xin; Qiu, Qianqian; Ma, Ke; Wang, Xuekun; Huang, Wenlong; Qian, Hai

    2015-07-28

    Compared with traditional therapeutics, antimicrobial peptides as novel anti-tumor agents have prominent advantages of higher specificity and circumvention of multi-drug resistance. In a previous study, we found that B1, an antimicrobial peptide derived from Cathelicidin-BF15, presented specific anti-tumor activity against several tumor cells. Since aliphatic chain-conjugated peptides have shown ameliorative activity and stability, we conjugated aliphatic acids with different lengths to the amino terminal of B1. All the conjugated peptides exhibited improved anti-tumor activity over B1. Further investigations revealed that the peptides were capable of disrupting the cell membrane, stimulating cytochrome c release into the cytosol, which results in apoptosis. The peptides also acted against multidrug resistant cells and had multidrug resistance-reversing effects. Additionally, conjugation of aliphatic acid enhanced the peptide stability in plasma. In summary, aliphatic acid-modified peptides might be promising anti-tumor agents in the future. PMID:26083110

  9. Galfenol alloying additions and the effects on uniaxial anisotropy generation

    NASA Astrophysics Data System (ADS)

    Summers, Eric; Meloy, Rob; Restorff, J. B.

    2009-07-01

    The effects of substitutional and interstitial additions on uniaxial anisotropy (Kuni) generated via stress annealing were investigated for the galfenol (Fe-Ga) alloy system. Polycrystalline samples prepared via free stand zone melt directional solidification technique were tested under pre- and post-stress annealed conditions in order to ascertain the extent of the built-in stress (Tbuilt-in) created. Energy based modeling utilizing magnetostriction and magnetization data was used to determine Kuni and Tbuilt-in. Differential magnetomechanical properties; d33 and μr were estimated using the same model. Carbon additions from a Fe-C master alloy resulted in Kuni and Tbuilt-in values of 12.1 kJ/m3 and 55 MPa, comparable to the binary system. Low carbon steel additions resulted in a minor decrease in Kuni to 9.6 kJ/m3, but still had high Tbuilt-in values of 54 MPa. Aluminum additions exhibited the largest decreases in Kuni and Tbuilt-in. A linear decrease in both values was observed as a function of increasing aluminum content. Kuni values for Fe81.6Ga13.8Al4.6 and Fe81.6Ga9.2Al9.2 alloys were 6.7 and 4.2 kJ/m3, respectively. Tbuilt-in values for Fe81.6Ga13.8Al4.6 and Fe81.6Ga9.2Al9.2 alloys were 37 and 24 MPa, respectively. Estimated d33 and μr values ranged from 2.0 to 2.7×10-8 m/A and 120-170 for all compositions studied.

  10. Eddy damping effect of additional conductors in superconducting levitation systems

    NASA Astrophysics Data System (ADS)

    Jiang, Zhao-Fei; Gou, Xiao-Fan

    2015-12-01

    Passive superconducting levitation systems consisting of a high temperature superconductor (HTSC) and a permanent magnet (PM) have demonstrated several fascinating applications such as the maglev system, flywheel energy storage. Generally, for the HTSC-PM levitation system, the HTSC with higher critical current density Jc can obtain larger magnetic force to make the PM levitate over the HTSC (or suspended below the HTSC), however, the process of the vibration of the levitated PM, provides very limited inherent damping (essentially hysteresis). To improve the dynamic stability of the levitated PM, eddy damping of additional conductors can be considered as the most simple and effective approach. In this article, for the HTSC-PM levitation system with an additional copper damper attached to the HTSC, we numerically and comprehensively investigated the damping coefficient c, damping ratio, Joule heating of the copper damper, and the vibration frequency of the PM as well. Furthermore, we comparatively studied four different arrangements of the copper damper, on the comprehensive analyzed the damping effect, efficiency (defined by c/VCu, in which VCu is the volume of the damper) and Joule heating, and finally presented the most advisable arrangement.

  11. Effectiveness of antibacterial copper additives in silicone implants.

    PubMed

    Gosau, Martin; Bürgers, Ralf; Vollkommer, Tobias; Holzmann, Thomas; Prantl, Lukas

    2013-08-01

    Staphylococcus epidermidis plays a major role in capsular contractures of silicone breast implants. This in vitro study evaluates the antibacterial effect of copper on S. epidermidis in silicone implants. Specimens of a silicone material used for breast augmentation (Cu0) and specimens coated with different copper concentrations (Cu1, Cu2) were artificially aged. Surface roughness and surface free energy were assessed. The specimens were incubated in an S. epidermidis suspension. We assessed the quantification and the viability of adhering bacteria by live/dead cell labeling with fluorescence microscopy. Additionally, inhibition of bacterial growth was evaluated by agar diffusion, broth culture, and quantitative culture of surface bacteria. No significant differences in surface roughness and surface free energy were found between Cu0, Cu1 and Cu2. Aging did not change surface characteristics and the extent of bacterial adhesion. Fluorescence microscopy showed that the quantity of bacteria on Cu0 was significantly higher than that on Cu1 and Cu2. The ratio of dead to total adhering bacteria was significantly lower on Cu0 than on Cu1 and Cu2, and tended to be higher for Cu2 than for Cu1. Quantitative culture showed equal trends. Copper additives seem to have anti-adherence and bactericidal effects on S. epidermidis in vitro. PMID:22492200

  12. Effects of Salinity and Nutrient Addition on Mangrove Excoecaria agallocha

    PubMed Central

    Chen, Yaping; Ye, Yong

    2014-01-01

    Effects of salinity on seed germination and growth of young (1 month old) and old (2-year old) seedlings of Excoecaria agallocha were investigated. Combined effects of salinity and nutrient level were also examined on old seedlings. Seed germination was best at 0 and 5 psu salinity. 15 psu salinity significantly delayed root initiation and decreased final establishment rate. All seeds failed to establish at 25 psu salinity. Young seedlings performed best at 0 and 5 psu, but growth was stunned at 15 psu, and all seedlings died within 90 days at 25 psu. Old seedlings grew best at salinities below 5 psu and they survived the whole cultivation at 25 psu. This indicated that E. agallocha increased salt tolerance over time. Gas exchange was significantly compromised by salinities above 15 psu but evidently promoted by high nutrient. Proline accumulated considerably at high nutrient, and its contents increased from 0 to 15 psu but decreased at 25 psu salinity. Lipid peroxidation was aggravated by increasing salinity beyond 15 psu but markedly alleviated by nutrient addition. These responses indicated that E. agallocha was intolerant to high salinity but it can be greatly enhanced by nutrient addition. PMID:24691495

  13. SRJ09, a promising anticancer drug lead: Elucidation of mechanisms of antiproliferative and apoptogenic effects and assessment of in vivo antitumor efficacy.

    PubMed

    Wong, Charng Choon; Lim, Siang Hui; Sagineedu, Sreenivasa Rao; Lajis, Nordin Haji; Stanslas, Johnson

    2016-05-01

    SRJ09 (3,19-(2-bromobenzylidene)andrographolide), a semisynthetic andrographolide (AGP) derivative, was shown to induce G1 cell cycle arrest and eventually apoptosis in breast and colon cancer cell lines. The present investigation was carried out to elucidate the mechanisms cell cycle arrest and apoptosis and evaluate the in vivo antitumor activity of SRJ09. The in vitro growth inhibitory properties of compounds were assessed in colon (HCT-116) and breast (MCF-7) cancer cell lines. Immunoblotting was utilized to quantitate the protein levels in cells. The gene expressions were determined using reverse transcriptase PCR (RT-PCR). Pharmacokinetic investigation was carried out by determining SRJ09 levels in plasma of Balb/C mice using HPLC. In