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Sample records for additive antitumor effects

  1. Preexisting antitumor immunity augments the antitumor effects of chemotherapy.

    PubMed

    Zhang, Lingbing; Feng, Dongdong; Yu, Lynda X; Tsung, Kangla; Norton, Jeffrey A

    2013-06-01

    Efficacy of cancer chemotherapy is generally believed to be the result of direct drug killing of tumor cells. However, increased tumor cell killing does not always lead to improved efficacy. Herein, we demonstrate that the status of antitumor immunity at the time of chemotherapy treatment is a critical factor affecting the therapeutic outcome in that tumor-bearing mice that possess preexisting antitumor immunity respond to chemotherapy much better than those that do not. Enhancing antitumor immunity before or at the time of chemotherapy-induced antigen release increases subsequent response to chemotherapy significantly. By in vitro and in vivo measurements of antitumor immunity, we found a close correlation between the intensity of antitumor immunity activated by chemotherapy and the efficacy of treatment. Immune intervention with interleukin-12 during the early phase of chemotherapy-induced immune activation greatly amplifies the antitumor response, often resulting in complete tumor eradication not only at the chemo-treated local site, but also systemically. These findings provide additional evidence for an immune-mediated antitumor response to chemotherapy. Further, our results show that timely immune modification of chemotherapy-activated antitumor immunity can result in enhanced antitumor-immune response and complete tumor eradication.

  2. Preexisting antitumor immunity augments the antitumor effects of chemotherapy.

    PubMed

    Zhang, Lingbing; Feng, Dongdong; Yu, Lynda X; Tsung, Kangla; Norton, Jeffrey A

    2013-06-01

    Efficacy of cancer chemotherapy is generally believed to be the result of direct drug killing of tumor cells. However, increased tumor cell killing does not always lead to improved efficacy. Herein, we demonstrate that the status of antitumor immunity at the time of chemotherapy treatment is a critical factor affecting the therapeutic outcome in that tumor-bearing mice that possess preexisting antitumor immunity respond to chemotherapy much better than those that do not. Enhancing antitumor immunity before or at the time of chemotherapy-induced antigen release increases subsequent response to chemotherapy significantly. By in vitro and in vivo measurements of antitumor immunity, we found a close correlation between the intensity of antitumor immunity activated by chemotherapy and the efficacy of treatment. Immune intervention with interleukin-12 during the early phase of chemotherapy-induced immune activation greatly amplifies the antitumor response, often resulting in complete tumor eradication not only at the chemo-treated local site, but also systemically. These findings provide additional evidence for an immune-mediated antitumor response to chemotherapy. Further, our results show that timely immune modification of chemotherapy-activated antitumor immunity can result in enhanced antitumor-immune response and complete tumor eradication. PMID:23595208

  3. 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

  4. 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

  5. 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

  6. Involvement of nitric oxide in anti-tumor effects of OK-432, a streptococcal anti-tumor immunotherapeutic agent.

    PubMed

    Oshikawa, Tetsuya; Okamoto, Masato; Tano, Tomoyuki; Uddin Ahmed, Sharif; Sasai, Akiko; Kan, Shin; Moriya, Yoichiro; Ryoma, Yoshiki; Saito, Motoo; Sato, Mitsunobu

    2006-05-01

    We examined the role of nitric oxide (NO) induced by OK-432, a streptococcal immunotherapeutic agent, in anti-tumor effects of the OK-432 by in vitro and in vivo experiments using an NO synthase inhibitor, N-monomethyl-l-arginine acetate (NMA). The in vitro treatment of mouse splenocytes with OK-432 increased the expression of inducible NO synthase (iNOS) gene and NO production in a dose-dependent manner. Although it is well known that OK-432 induces cytokines such as interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, both of which are known to be potent NO inducers, we observed only a partial reduction of OK-432-induced NO production with the addition of anti-IFN-gamma and/or anti-TNF-alpha neutralizing antibodies. The cytotoxicity of the splenocytes increased by in vitro OK-432 stimulation was almost completely inhibited by the treatment with NMA. OK-432 administration resulted in a marked prolongation of survival and a significant inhibition of tumor growth in syngeneic tumor-bearing mice, whereas NMA significantly inhibited the anti-tumor effects of OK-432. Although the increased cytotoxicity of adherent splenocytes derived from OK-432-treated tumor-bearing mice was almost completely inhibited by NMA, only partial inhibition by NMA was observed in the cytotoxicity of the nonadherent splenocytes. These findings strongly suggest that the iNOS/NO induced by OK-432 is intimately involved in the anti-tumor effects of OK-432.

  7. Intratumoral immunocytokine treatment results in enhanced antitumor effects.

    PubMed

    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

    2008-12-01

    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 (111)In-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.

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Antitumor effects of the combination of cholesterol reducing drugs.

    PubMed

    Issat, Tadeusz; Nowis, Dominika; Bil, Jacek; Winiarska, Magdalena; Jakobisiak, Marek; Golab, Jakub

    2011-07-01

    There are a number of potential mechanisms linking cholesterol homeostasis to processes that are tightly linked with carcinogenesis. Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR), the rate-limiting enzyme in the mevalonic acid synthesis pathway, exert cytostatic and cytotoxic effects towards tumor cells. It seems that the cytostatic and cytotoxic effects of statins result from blocking protein prenylation, leading to inhibition of isoprenoid compound synthesis. Another compound which affects cholesterol metabolism is the plant alkaloid berberine. The aim of this study was to investigate potential antitumor effects of lovastatin combined with berberine. Combined with berberine, lovastatin appeared to exert potentiated cytostatic and/or cytotoxic effects against human MDA-MB231 breast cancer and murine Panc 02 pancreatic cancer cells. The obtained results indicated that the effect of berberine is not dependent on blocking protein prenylation in cells, and the toxic effect of lovastatin combined with berberine is reversed by addition of the substrates of this pathway to the level brought out by lovastatin alone. Lovastatin-berberine combination caused cell cycle inhibition in G1 phase after 48 h of incubation with drugs. In a Panc 02 pancreatic cancer model in mice, lovastatin-berberine combination slightly, but significantly, slowed down tumor growth. Taking into account the number of patients treated with the investigated drugs one may suppose that the described interactions may be of clinical value.

  14. 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.

  15. Antioxidant, antimutagenic, and antitumor effects of pine needles (Pinus densiflora).

    PubMed

    Kwak, Chung Shil; Moon, Sung Chae; Lee, Mee Sook

    2006-01-01

    Pine needles (Pinus densiflora Siebold et Zuccarini) have long been used as a traditional health-promoting medicinal food in Korea. To investigate their potential anticancer effects, antioxidant, antimutagenic, and antitumor activities were assessed in vitro and/or in vivo. Pine needle ethanol extract (PNE) significantly inhibited Fe(2+)-induced lipid peroxidation and scavenged 1,1-diphenyl- 2-picrylhydrazyl radical in vitro. PNE markedly inhibited mutagenicity of 2-anthramine, 2-nitrofluorene, or sodium azide in Salmonella typhimurium TA98 or TA100 in Ames tests. PNE exposure effectively inhibited the growth of cancer cells (MCF-7, SNU-638, and HL-60) compared with normal cell (HDF) in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In in vivo antitumor studies, freeze-dried pine needle powder supplemented (5%, wt/wt) diet was fed to mice inoculated with Sarcoma-180 cells or rats treated with mammary carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA, 50 mg/kg body weight). Tumorigenesis was suppressed by pine needle supplementation in the two model systems. Moreover, blood urea nitrogen and aspartate aminotransferase levels were significantly lower in pine needle-supplemented rats in the DMBA-induced mammary tumor model. These results demonstrate that pine needles exhibit strong antioxidant, antimutagenic, and antiproliferative effects on cancer cells and also antitumor effects in vivo and point to their potential usefulness in cancer prevention. PMID:17474862

  16. Curcuma increasing antitumor effect of Rhizoma paridis saponins through absorptive enhancement of paridis saponins.

    PubMed

    Man, Shuli; Li, Yuanyuan; Fan, Wei; Gao, Wenyuan; Liu, Zhen; Li, Nan; Zhang, Yao; Liu, Changxiao

    2013-09-15

    Rhizoma paridis saponins (RPS) played a good antitumor role in many clinical applications. However, low oral bioavailability limited its application. In this research, water extract of Curcuma (CW) significantly increased antitumor effect of Rhizoma paridis saponins (RPS). GC-MS was used to identify its polar composition. HPLC was applied for determination of the content of curcuminoids in CW. As a result, 47 analytes with 0.65% of curcuminoids were identified in CW. According to the in vivo anti-tumor data, the best proportion of curcuminoids in CW with RPS was 16:500 (w/w). Using this ratio, curcuminoids significantly increased absorption of RPS in the everted rat duodenum sac system. In addition, curcuminoids decreased the promotion of RPS on rhodamine 123 efflux. The effect of curcuminoids was similar to that of the P-gp inhibitor, cyclosporin A in combination with RPS. In conclusion, drug combination of water extract of Curcuma with RPS was a good method to increase the antitumor effect of RPS. This combination would be a potent anticancer agent used in the prospective application.

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. The research progress of antitumorous effectiveness of Stichopus japonicus acid mucopolysaccharide in north of China.

    PubMed

    Lu, Yun; Wang, Bao-Lei

    2009-03-01

    The sea cucumbers growing in the estuary of the Pohai of northern China are called Stichopus japonicus and are the orthodox holothurians in traditional Chinese medicine. There are multiple biological active ingredients in S. japonicus, and S. japonicus acid mucopolysaccharide (SJAMP) is one of the important ingredients. SJAMP has multiple pharmacologic actions, such as antitumor, immunologic regulation, anticoagulated blood, and antivirus. The research on antitumor has been carried out by way of animal experiments aiming at studying internal tumor-inhibiting effect of SJAMP, and the route of administration is usually peritoneal or intragastric. Additionally, sea cucumbers have been widely recognized and applied as medicated food or therapeutic prescriptions during and after the treatment of some tumors.

  8. 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.

  9. 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

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

    PubMed

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

    2016-01-12

    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.

  11. Antitumor effects of saffron-derived carotenoids in prostate cancer cell models.

    PubMed

    Festuccia, Claudio; Mancini, Andrea; Gravina, Giovanni Luca; Scarsella, Luca; Llorens, Silvia; Alonso, Gonzalo L; Tatone, Carla; Di Cesare, Ernesto; Jannini, Emmanuele A; Lenzi, Andrea; D'Alessandro, Anna M; Carmona, Manuel

    2014-01-01

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

  12. Antitumor effects of saffron-derived carotenoids in prostate cancer cell models.

    PubMed

    Festuccia, Claudio; Mancini, Andrea; Gravina, Giovanni Luca; Scarsella, Luca; Llorens, Silvia; Alonso, Gonzalo L; Tatone, Carla; Di Cesare, Ernesto; Jannini, Emmanuele A; Lenzi, Andrea; D'Alessandro, Anna M; Carmona, Manuel

    2014-01-01

    Crocus sativus L. extracts (saffron) are rich in carotenoids. Preclinical studies have shown that dietary intake of carotenoids has antitumor effects suggesting their potential preventive and/or therapeutic roles. We have recently reported that saffron (SE) and crocin (CR) exhibit anticancer activity by promoting cell cycle arrest in prostate cancer (PCa) cells. It has also been demonstrated that crocetin esters are produced after SE gastrointestinal digestion by CR hydrolysis. The aim of the present report was to investigate if SE, crocetin (CCT), and CR affected in vivo tumor growth of two aggressive PCa cell lines (PC3 and 22rv1) which were xenografted in male nude mice treated by oral gavage with SE, CR, and CCT. We demonstrated that the antitumor effects of CCT were higher when compared to CR and SE and treatments reverted the epithelial-mesenchymal transdifferentiation (EMT) as attested by the significant reduction of N-cadherin and beta-catenin expression and the increased expression of E-cadherin. Additionally, SE, CR, and CCT inhibited PCa cell invasion and migration through the downmodulation of metalloproteinase and urokinase expression/activity suggesting that these agents may affect metastatic processes. Our findings suggest that CR and CCT may be dietary phytochemicals with potential antitumor effects in biologically aggressive PCa cells. PMID:24900952

  13. Proteomic Study to Survey the CIGB-552 Antitumor Effect

    PubMed Central

    Rodríguez-Ulloa, Arielis; Gil, Jeovanis; Ramos, Yassel; Hernández-Álvarez, Lilian; Flores, Lisandra; Oliva, Brizaida; García, Dayana; Sánchez-Puente, Aniel; Musacchio-Lasa, Alexis; Fernández-de-Cossio, Jorge; Padrón, Gabriel; González López, Luis J.; Besada, Vladimir; Guerra-Vallespí, Maribel

    2015-01-01

    CIGB-552 is a cell-penetrating peptide that exerts in vitro and in vivo antitumor effect on cancer cells. In the present work, the mechanism involved in such anticancer activity was studied using chemical proteomics and expression-based proteomics in culture cancer cell lines. CIGB-552 interacts with at least 55 proteins, as determined by chemical proteomics. A temporal differential proteomics based on iTRAQ quantification method was performed to identify CIGB-552 modulated proteins. The proteomic profile includes 72 differentially expressed proteins in response to CIGB-552 treatment. Proteins related to cell proliferation and apoptosis were identified by both approaches. In line with previous findings, proteomic data revealed that CIGB-552 triggers the inhibition of NF-κB signaling pathway. Furthermore, proteins related to cell invasion were differentially modulated by CIGB-552 treatment suggesting new potentialities of CIGB-552 as anticancer agent. Overall, the current study contributes to a better understanding of the antitumor action mechanism of CIGB-552. PMID:26576414

  14. In vivo CD40 ligation can induce T-cell-independent antitumor effects that involve macrophages.

    PubMed

    Lum, Hillary D; Buhtoiarov, Ilia N; Schmidt, Brian E; Berke, Gideon; Paulnock, Donna M; Sondel, Paul M; Rakhmilevich, Alexander L

    2006-06-01

    We have previously demonstrated T cell-independent antitumor and antimetastatic effects of CD40 ligation that involved natural killer (NK) cells. As CD40 molecules are expressed on the surface of macrophages (Mphi), we hypothesized that Mphi may also serve as antitumor effector cells when activated by CD40 ligation. Progression of subcutaneous NXS2 murine neuroblastomas was delayed significantly by agonistic CD40 monoclonal antibody (anti-CD40 mAb) therapy in immunocompetent A/J mice, as well as in T and B cell-deficient severe combined immunodeficiency (SCID) mice. Although NK cells can be activated by anti-CD40 mAb, anti-CD40 mAb treatment also induced a significant antitumor effect in SCID/beige mice in the absence of T and NK effector cells, even when noncytolytic NK cells and polymorphonuclear cells (PMN) were depleted. Furthermore, in vivo treatment with anti-CD40 mAb resulted in enhanced expression of cytokines and cell surface activation markers, as well as Mphi-mediated tumor inhibition in A/J mice, C57BL/6 mice, and SCID/beige mice, as measured in vitro. A role for Mphi was shown by reduction in the antitumor effect of anti-CD40 mAb when Mphi functions were inhibited in vivo by silica. In addition, activation of peritoneal Mphi by anti-CD40 mAb resulted in survival benefits in mice bearing intraperitoneal tumors. Taken together, our results show that anti-CD40 mAb immunotherapy of mice can inhibit tumor growth in the absence of T cells, NK cells, and PMN through the involvement of activated Mphi.

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

    PubMed

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

    2016-10-01

    The effects of culture medium composition (i.e., carbon and nitrogen sources) on the growth of mycelia, molecular weight distribution and antitumor activity of intracellular polysaccharides (IPS) from Cordyceps gunnii were investigated. Sucrose and peptone were proved to be the best carbon and nitrogen sources for mycelia growth and remarkably improved IPS production. When the sucrose concentration was 2.0%, the mycelium yield reached up to 15.94±1.26 g/L, but with lower IPS yield; whereas the sucrose concentration was 4.5%, IPS yield reached to a maximum of 138.78±3.89 mg/100 mL. The effects of different carbon/nitrogen (C/N) ratios with equal amounts of carbon source matter on the mycelia and IPS formation were optimized. It found that the yield of mycelia and IPS were both reached to the highest at a C/N ratio of 10:3. In addition, the IPS had the highest macro molecular polysaccharide content and antitumor activity when sucrose concentration was 3.5% and the C/N ratio was 10:1.5. Thus, there was a positive correlation between molecular weight distribution and antitumor activity of IPS by C. gunnii. PMID:27074949

  16. 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.

  17. Addition of an induction regimen of antiangiogenesis and antitumor immunity to standard chemotherapy improves survival in advanced malignancies.

    PubMed

    Lasalvia-Prisco, Eduardo; Goldschmidt, Pablo; Galmarini, Felipe; Cucchi, Silvia; Vázquez, Jesús; Aghazarian, Martha; Lasalvia-Galante, Eduardo; Golomar, Wilson; Gordon, William

    2012-12-01

    Studies have shown that cancer requires two conditions for tumor progression: cancer cell proliferation and an environment permissive to and conditioned by malignancy. Chemotherapy aims to control the number and proliferation of cancer cells, but it does not effectively control the two best-known conditions of the tumor-permissive environment: neoangiogenesis and tolerogenic immunity. Many malignant diseases exhibit poor outcomes after treatment with chemotherapy. Therefore, we investigated the potential benefits of adding an induction regimen of antiangiogenesis and antitumor immunity to chemotherapy in poor outcome disease. In a prospective, randomized trial, we included patients with advanced, unresectable pancreatic adenocarcinomas, non-small cell lung cancer, or prostate cancer. Two groups of each primary condition were compared: group 1 (G1), n = 30, was treated with the standard chemotherapy and used as a control, and group 2 (G2), n = 30, was treated with chemotherapy plus an induction regimen of antiangiogenesis and antitumor immunity. This induction regimen included a low dose of metronomic cyclophosphamide, a high dose of Cox-2 inhibitor, granulocyte colony-stimulating factor, a sulfhydryl (SH) donor, and a hemoderivative that contained autologous tumor antigens released from patient tumors into the blood. After treatment, the G2 group demonstrated significantly longer survival, lower blood level of neoangiogenesis and immune-tolerance mediators, and higher blood levels of antiangiogenesis and antitumor immunity mediators compared with the G1 group. Toxicity and quality of life were not significantly different between the groups. In conclusion, in several advanced malignancies of different primary localizations, an increase in survival was observed by adding an induction regimen of antiangiogenesis and antitumor immunity to standard chemotherapy.

  18. Antitumor effect of novel gallium compounds and efficacy of nanoparticle-mediated gallium delivery in lung cancer.

    PubMed

    Wehrung, Daniel; Oyewumi, Moses O

    2012-02-01

    The widespread application of gallium (Ga) in cancer therapy has been greatly hampered by lack of specificity resulting in poor tumor accumulation and retention. To address the challenge, two lipophilic gallium (III) compounds (gallium hexanedione; GaH and gallium acetylacetonate; GaAcAc) were synthesized and antitumor studies were conducted in human lung adenocarcinoma (A549) cells. Nanoparticles (NPs) containing various concentrations of the Ga compounds were prepared using a binary mixture of Gelucire 44/14 and cetyl alcohol as matrix materials. NPs were characterized based on size, morphology, stability and biocompatibility. Antitumor effects of free or NP-loaded Ga compounds were investigated based on cell viability, production of reactive oxygen species and reduction of mitochondrial potential. Compared to free Ga compounds, cytotoxicity of NP-loaded Ga (5-150 microg/ml) was less dependent on concentration and incubation time (exposure) with A549 cells. NP-mediated delivery (5-150 microg Ga/ml) enhanced antitumor effects of Ga compounds and the effect was pronounced at: (i) shorter incubation times; and (ii) at low concentrations of gallium (approximately 50 microg/ml) (p < 0.0006). Additional studies showed that NP-mediated Ga delivery was not dependent on transferrin receptor uptake mechanism (p > 0.13) suggesting the potential in overcoming gallium resistance in some tumors. In general, preparation of stable and biocompatible NPs that facilitated Ga tumor uptake and antitumor effects could be effective in gallium-based cancer therapy.

  19. 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

  20. Antitumor effect of Deoxypodophyllotoxin on human breast cancer xenograft transplanted in BALB/c nude mice model.

    PubMed

    Khaled, Meyada; Belaaloui, Ghania; Jiang, Zhen-Zhou; Zhu, Xiong; Zhang, Lu-Yong

    2016-10-01

    Recently, biologically active compounds isolated from plants used in herbal medicine have been the center of interest. Deoxypodophyllotoxin (DPT), structurally closely related to the lignan podophyllotoxin, was found to be a potent antitumor and antiproliferative agent, in several tumor cells, in vitro. However, DPT has not been used clinically yet because of the lack of in vivo studies. This study is the first report demonstrating the antitumor effect of DPT on MDA-MB-231 human breast cancer xenografts in nude mice. DPT, significantly, inhibited the growth of MDA-MB-231 xenograft in BALB/c nude mice. The T/C value (the value of the relative tumor volume of treatment group compared to the control group) of groups treated with 5, 10, and 20 mg/kg of intravenous DPT-HP-β-CD was 42.87%, 34.04% and 9.63%, respectively, suggesting the positive antitumor activity of DPT. In addition, the antitumor effect of DPT-HP-β-CD (20 mg/kg) in human breast cancer MDA-MB-231 xenograft was more effective than etoposide (VP-16) (20 mg/kg) and docetaxel (20 mg/kg). These findings suggest that this drug is a promising chemotherapy candidate against human breast carcinoma. PMID:27578026

  1. Effect of diabetes on biodistribution, nephrotoxicity and antitumor activity of cisplatin in mice.

    PubMed

    da Silva Faria, Marcia C; Santos, Neife A G Dos; Carvalho Rodrigues, Maria A; Rodrigues, Jairo Lisboa; Barbosa Junior, Fernando; Santos, Antonio Cardozo Dos

    2015-03-01

    Both types of diabetes are associated with higher incidence of some types of cancer. Treating cancer in diabetic patients without aggravating diabetes-related complications is a challenge for clinicians. Additionally, little is known about how diabetes affects the treatment of cancer. One of the most effective chemotherapeutic drugs is cisplatin, which is nephrotoxic. Studies suggest that diabetes acts as a protective factor against the nephrotoxicity of cisplatin, but the mechanisms involved have not been elucidated yet. This renal protection has been attributed to decreased accumulation of cisplatin in the kidneys, which could be associated with deficient active transport of proximal tubular cells or to pharmacokinetic alterations caused by diabetes. However, it is uncertain if diabetes also compromises the antitumor activity of cisplatin. To address this issue, we developed a mouse model bearing cisplatin-induced nephrotoxicity, Sarcoma 180 and streptozotocin-induced diabetes. Four groups of treatment were defined: (i) control, (ii) diabetic, (iii) cisplatin and (iv) diabetic treated with cisplatin. The following parameters were evaluated: renal function, oxidative stress, apoptosis, renal histopathology, tumor remission, survival rate, genotoxicity and platinum concentration in tumor and several organs. Results indicate that diabetes protects against the renal damage induced by cisplatin, while also compromises its antitumor effectiveness. This is the first study to demonstrate this effect. PMID:25665769

  2. Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model.

    PubMed

    Serrano, Oscar K; Parrow, Nermi L; Violet, Pierre-Christian; Yang, Jacqueline; Zornjak, Jennifer; Basseville, Agnes; Levine, Mark

    2015-10-01

    Because 5-year survival rates for patients with metastatic melanoma remain below 25%, there is continued need for new therapeutic approaches. For some tumors, pharmacologic ascorbate treatment may have a beneficial antitumor effect and may work synergistically with standard chemotherapeutics. To investigate this possibility in melanoma, we examined the effect of pharmacologic ascorbate on B16-F10 cells. Murine models were employed to compare tumor size following treatment with ascorbate, and the chemotherapeutic agents dacarbazine or valproic acid, alone or in combination with ascorbate. Results indicated that nearly all melanoma cell lines were susceptible to ascorbate-mediated cytotoxicity. Compared to saline controls, pharmacologic ascorbate decreased tumor size in both C57BL/6 (P < 0.0001) and NOD-scid tumor bearing mice (P < 0.0001). Pharmacologic ascorbate was superior or equivalent to dacarbazine as an antitumor agent. Synergy was not apparent when ascorbate was combined with either dacarbazine or valproic acid; the latter combination may have additional toxicities. Pharmacologic ascorbate induced DNA damage in melanoma cells, as evidenced by increased phosphorylation of the histone variant, H2A.X. Differences were not evident in tumor samples from C57BL/6 mice treated with pharmacologic ascorbate compared to tumors from saline-treated controls. Together, these results suggest that pharmacologic ascorbate has a cytotoxic effect against melanoma that is largely independent of lymphocytic immune functions and that continued investigation of pharmacologic ascorbate in cancer treatment is warranted. PMID:26119785

  3. 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

  4. The anti-tumor effect and increased tregs infiltration mediated by rAAV-SLC vector.

    PubMed

    Li, Rilun; Hu, Heng; Ma, Huiying; Chen, Long; Zhou, Binbin; Liu, Yinkun; Liang, Chunmin

    2013-10-01

    To explore the anti-tumor effect and immune mechanism mediated by a new recombinant adeno-associated virus (rAAV) encoding secondary lymphoid tissue chemokine (SLC) mature peptide gene. AAV Helper-Free system was used for rAAV-SLC package. The anti-tumor effect of SLC was detected by bearing tumor established from Hepal-6 cells both in C57BL/6J and nude mice. Flow cytometry analysis and IHC for Tumor-infiltrating T cells and CD11c+DCs were also investigated to explore the immunological mechanism. rAAV-SLC was successfully packaged in AAV293 cells and transfected Hepal-6 tumor cells at high efficiency. The anti-tumor effect was demonstrated by less tumor weight and longer survival outcome. Coincident with the anti-tumor response, local elaboration of SLC within the tumor bed elicited a heavy infiltration of CD4+, CD8+T cells and CD11c+ dendritic cells into the tumor sites. More importantly, there was higher infiltration of Foxp3+ regulatory T cells (Tregs). Local elaboration of SLC mediated by rAAV-SLC has strong T cell mediated anti-tumor effect. The study also suggested that Tregs in the tumor microenvironment tampered the anti-tumor effect.

  5. 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

  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. 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.

  8. Antitumor effect of boron nitride nanotubes in combination with thermal neutron irradiation on BNCT.

    PubMed

    Nakamura, Hiroyuki; Koganei, Hayato; Miyoshi, Tatsuro; Sakurai, Yoshinori; Ono, Koji; Suzuki, Minoru

    2015-01-15

    The first BNCT antitumor effects of BNNTs toward B16 melanoma cells were demonstrated. The use of DSPE-PEG2000 was effective for preparation of the BNNT-suspended aqueous solution. BNNT-DSPE-PEG2000 accumulated in B16 melanoma cells approximately three times higher than BSH and the higher BNCT antitumor effect was observed in the cells treated with BNNT-DSPE-PEG2000 compared to those treated with BSH, indicating that BNNT-DSPE-PEG2000 would be a possible candidate as a boron delivery vehicle for BNCT.

  9. 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

  10. Antitumoral effects of vasoactive intestinal peptide in human renal cell carcinoma xenografts in athymic nude mice.

    PubMed

    Vacas, Eva; Arenas, M Isabel; Muñoz-Moreno, Laura; Bajo, Ana M; Sánchez-Chapado, Manuel; Prieto, Juan C; Carmena, María J

    2013-08-01

    We studied antitumor effect of VIP in human renal cell carcinoma (RCC) (A498 cells xenografted in immunosuppressed mice). VIP-treated cells gave resulted in p53 upregulation and decreased nuclear β-catenin translocation and NFκB expression, MMP-2 and MMP-9 activities, VEGF levels and CD-34 expression. VIP led to a more differentiated tubular organization in tumours and less metastatic areas. Thus, VIP inhibits growth of A498-cell tumours acting on the major issues involved in RCC progression such as cell proliferation, microenvironment remodelling, tumour invasion, angiogenesis and metastatic ability. These antitumoral effects of VIP offer new therapeutical possibilities in RCC treatment.

  11. Antitumor effect of humus extract on murine transplantable L1210 leukemia.

    PubMed

    Kodama, Hiroshi

    2007-10-01

    Humic substances are formed during the decomposition of organic matter in humus that found in many natural environments in which organic materials and microorganisms have been present. In the present study, humus extract exhibited antitumor effect on L1210 tumor development in isogeneic DBA/2 mice with the delay of tumor formation and a significant smaller tumor mass that infer a significant increase of life span of mice. The antitumor effect was not due to direct killing of L1210 or induction of apoptosis in tumor cells by humus extract.

  12. 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.

  13. 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

  14. 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

  15. 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

  16. 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.

  17. Nilotinib combined with interleukin-2 mediates antitumor and immunological effects in a B16 melanoma model.

    PubMed

    Geisler, K; Reischer, A; Kroeger, I; Jacobs, B; Meinhardt, K; Bauer, R; Ryffel, B; Mackensen, A; Ullrich, E

    2014-05-01

    The immune system contributes to tumor cell killing which can be enhanced by cancer chemotherapeutics and immune modulatory pharmaceuticals such as tyrosine kinase inhibitors (TKIs). Recently, the beneficial effect of natural killer (NK) cells was demonstrated when combining interleukin-2 (IL-2) with the TKI imatinib. The aim of the present study was to address the antitumor and immunological effects of recently approved TKIs. Therefore, we focused on the comparison of the efficacy between imatinib and nilotinib in combination with IL-2 in a murine B16F10 melanoma model. Both TKIs possessed antitumor activity in vivo. However, the combination of nilotinib and IL-2 showed a superior outcome. Importantly, both the use of immunodeficient Rag2γc-/- mice, which lack T-lymphocytes, B-lymphocytes and NK cells, as well as NK cell-depletion in C57Bl/6 mice reduced the therapeutic effect of nilotinib. Flow cytometry revealed a significant increase in the IFN-γ-producing CD27+ NK cell subpopulation following treatment with nilotinib and IL-2. Furthermore, the therapeutic antitumor effect of nilotinib/IL-2 was completely lost in IFN-γ-/- mice. In summary, we suggest that nilotinib combined with IL-2 confers high antitumor activity involving the subset of IFN-γ-producing CD27+ NK cells. These new insights are of high importance for the understanding and development of immunotherapeutic protocols using TKIs.

  18. 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

  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. 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.

  1. 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

  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.

  3. Clinical effects of sulphite additives.

    PubMed

    Vally, H; Misso, N L A; Madan, V

    2009-11-01

    Sulphites are widely used as preservative and antioxidant additives in the food and pharmaceutical industries. Topical, oral or parenteral exposure to sulphites has been reported to induce a range of adverse clinical effects in sensitive individuals, ranging from dermatitis, urticaria, flushing, hypotension, abdominal pain and diarrhoea to life-threatening anaphylactic and asthmatic reactions. Exposure to the sulphites arises mainly from the consumption of foods and drinks that contain these additives; however, exposure may also occur through the use of pharmaceutical products, as well as in occupational settings. While contact sensitivity to sulphite additives in topical medications is increasingly being recognized, skin reactions also occur after ingestion of or parenteral exposure to sulphites. Most studies report a 3-10% prevalence of sulphite sensitivity among asthmatic subjects following ingestion of these additives. However, the severity of these reactions varies, and steroid-dependent asthmatics, those with marked airway hyperresponsiveness, and children with chronic asthma, appear to be at greater risk. In addition to episodic and acute symptoms, sulphites may also contribute to chronic skin and respiratory symptoms. To date, the mechanisms underlying sulphite sensitivity remain unclear, although a number of potential mechanisms have been proposed. Physicians should be aware of the range of clinical manifestations of sulphite sensitivity, as well as the potential sources of exposure. Minor modifications to diet or behaviour lead to excellent clinical outcomes for sulphite-sensitive individuals.

  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. PKC/MEK inhibitors suppress oxaliplatin-induced neuropathy and potentiate the antitumor effects.

    PubMed

    Tsubaki, Masanobu; Takeda, Tomoya; Tani, Tadahumi; Shimaoka, Hirotaka; Suzuyama, Naohiro; Sakamoto, Kotaro; Fujita, Arisa; Ogawa, Naoki; Itoh, Tatsuki; Imano, Motohiro; Funakami, Yoshinori; Ichida, Seiji; Satou, Takao; Nishida, Shozo

    2015-07-01

    Oxaliplatin is a key drug commonly used in colorectal cancer treatment. Despite high clinical efficacy, its therapeutic application is limited by common, dose-limiting occurrence of neuropathy. As usual symptomatic neuropathy treatments fail to improve the patients' condition, there is an urgent need to advance our understanding of the pathogenesis of neuropathy to propose effective therapy and ensure adequate pain management. Oxaliplatin-induced neuropathy was recently reported to be associated with protein kinase C (PKC) activation. It is unclear, however, whether PKC inhibition can prevent neuropathy. In our current studies, we found that a PKC inhibitor, tamoxifen, inhibited oxaliplatin-induced neuropathy via the PKC/extracellular signal-regulated kinase (ERK)/c-Fos pathway in lumbar spinal cords (lumbar segments 4-6). Additionally, tamoxifen was shown to act in synergy with oxaliplatin to inhibit growth in tumor cells-implanted mice. Moreover, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, PD0325901, suppressed oxaliplatin-induced neuropathy and enhanced oxaliplatin efficacy. Our results indicate that oxaliplatin-induced neuropathy is associated with PKC/ERK/c-Fos pathway in lumbar spinal cord. Additionally, we demonstrate that disruption of this pathway by PKC and MEK inhibitors suppresses oxaliplatin-induced neuropathy, thereby suggesting that PKC and MEK inhibitors may be therapeutically useful in preventing oxaliplatin-induced neuropathy and could aid in combination antitumor pharmacotherapy.

  6. 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

  7. 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

  8. The Mozart Effect: Additional Data.

    PubMed

    Hughes, John R.

    2002-04-01

    After the review of the Mozart effect was published in this journal (Hughes JR. Epilepsy Behav 2001;2:369-417), additional data from the music of Haydn and Liszt have been analyzed that may account for the decrease in seizure activity originally reported during Mozart music. Even with these added data Mozart music continued to score significantly higher than the selections from the other six composers in one of the important characteristics of this music, namely, the repetition of the melody. However Haydn's values were second highest among Mozart, J. S. Bach, Wagner, Beethoven, Chopin, and Liszt.

  9. 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

  10. Linalool exhibits cytotoxic effects by activating antitumor immunity.

    PubMed

    Chang, Mei-Yin; Shen, Yi-Ling

    2014-01-01

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

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

    PubMed

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

    2016-02-01

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

  12. Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation.

    PubMed

    Ciceri, Fabio; Bonini, Chiara; Marktel, Sarah; Zappone, Elisabetta; Servida, Paolo; Bernardi, Massimo; Pescarollo, Alessandra; Bondanza, Attilio; Peccatori, Jacopo; Rossini, Silvano; Magnani, Zulma; Salomoni, Monica; Benati, Claudia; Ponzoni, Maurilio; Callegaro, Luciano; Corradini, Paolo; Bregni, Marco; Traversari, Catia; Bordignon, Claudio

    2007-06-01

    The extensive exploitation of the antitumor effect of donor lymphocytes infused after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is limited by the risk of graft-versus-host disease (GvHD). To overcome this limitation, we investigated the therapeutic potential of donor lymphocytes engineered with the suicide gene thymidine kinase of herpes simplex virus (TK) in 23 patients experiencing recurrence of hematologic malignancies after allo-HSCT. Long-term follow-up of infused patients included analysis of engraftment of genetically engineered lymphocytes, in vivo assessment of antitumor effect, and control of GvHD by ganciclovir. All 17 patients evaluable for engraftment and graft-versus-leukemia (GvL) had circulating TK(+) cells detectable beginning at a median time of 18 days. Eleven patients (65%) experienced a substantial clinical benefit resulting in 6 (35%) complete remissions and 5 (29%) partial responses. The antitumor effect tightly correlated with the in vivo expansion of TK(+) cells. Seven patients received ganciclovir, resulting in elimination of TK(+) cells and effective and selective treatment of GvHD. Immunization against HSV-TK was observed in 7 patients but did not preclude an effective GvL. These data validate the feasibility, safety, and efficacy of TK(+) cells in the context of allografting and represent the basis for a broader application of this technology. PMID:17327416

  13. 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

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

    PubMed

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

    2015-05-01

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

  15. 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

  16. 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

  17. 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

  18. 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.

  19. p53-independent anti-tumor effects of the nitrogen-containing bisphosphonate zoledronic acid.

    PubMed

    Kuroda, Junya; Kimura, Shinya; Segawa, Hidekazu; Sato, Kiyoshi; Matsumoto, Seiji; Nogawa, Masaki; Yuasa, Takeshi; Kobayashi, Yutaka; Yoshikawa, Toshikazu; Ottmann, Oliver G; Maekawa, Taira

    2004-02-01

    Zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, exerts anti-tumor effects by inhibiting the prenylation of small GTPases. We have also reported that ZOL shows an anti-leukemic effect by inducing apoptosis throughout the S phase to the G(2) / M boundary. Here, we studied the effects of ZOL on various cell cycle regulators, including p53, cyclin-dependent kinases (CDKs), CDK inhibitors and cyclins, using BV173 leukemia and HCT116 colorectal carcinoma cell lines, harboring wild-type (wt-) p53. ZOL induced the accumulation of neither p53 nor p21(WAF1/CIP1) during the execution of apoptosis in BV173 cells. Therefore, we investigated the dependence of ZOL-induced apoptosis on intact p53 by using wt-p53 HCT116 and a p53-degraded HCT116 subline, and observed no significant difference. p57(KIP2) was upregulated by ZOL in BV173 cells, but not in HCT116 cells. Flow cytometric analyses showed that ZOL also impaired the cell cycle-dependent expression patterns of cyclins A, B and D3 in BV173. In conclusion, the p53-independent anti-tumor activities of ZOL suggest that it may be an attractive agent for treating cancers, including those with chemoresistance resulting from the loss of p53 function. ZOL also affected the coordinate expression patterns of several cell cycle regulators during the execution of anti-tumor activity.

  20. 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.

  1. Downregulation of amplified in breast cancer 1 contributes to the anti-tumor effects of sorafenib on human hepatocellular carcinoma

    PubMed Central

    Dan, Yuzhen; Tong, Zhangwei; Chen, Wenbo; Qin, Liping; Liu, Kun; Li, Wengang; Mo, Pingli; Yu, Chundong

    2016-01-01

    Multi-kinase inhibitor sorafenib represents a major breakthrough in the therapy of advanced hepatocellular carcinoma (HCC). Amplified in breast cancer 1 (AIB1) is frequently overexpressed in human HCC tissues and promotes HCC progression. In this study, we investigated the effects of sorafenib on AIB1 expression and the role of AIB1 in anti-tumor effects of sorafenib. We found that sorafenib downregulated AIB1 protein expression by inhibiting AIB1 mRNA translation through simultaneously blocking eIF4E and mTOR/p70S6K/RP-S6 signaling. Knockdown of AIB1 significantly promoted sorafenib-induced cell death, whereas overexpression of AIB1 substantially diminished sorafenib-induced cell death. Downregulation of AIB1 contributed to sorafenib-induced cell death at least in part through upregulating the levels of reactive oxygen species in HCC cells. In addition, resistance to sorafenib-induced downregulation of AIB1 protein contributes to the acquired resistance of HCC cells to sorafenib-induced cell death. Collectively, our study implicates that AIB1 is a molecular target of sorafenib and downregulation of AIB1 contributes to the anti-tumor effects of sorafenib. PMID:27105488

  2. 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.

  3. 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

  4. 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.

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

    PubMed Central

    Bergadà, Laura; Yeramian, Andree; Sorolla, Annabel

    2014-01-01

    We have recently demonstrated that histone deacetylase inhibitor, Vorinostat, applied as a single therapy or in combination with caspase-8 downregulation exhibits high anti-tumoral activity on endometrial carcinoma cell lines. In the present study, we have assessed the signalling processes underlying anti-tumoral effects of Vorinostat. Increasing evidence suggests that reactive oxygen species are responsible for histone deacetylase inhibitor-induced cell killing. We have found that Vorinostat induces formation of reactive oxygen species and DNA damage. To investigate the role of oxidative stress as anti-neoplastic mechanism, we have evaluated the effects of different antioxidants (Bha, Nac and Tiron) on endometrial carcinoma cell line Ishikawa treated with Vorinostat. We show that Bha, Nac and Tiron markedly inhibited the cytotoxic effects of Vorinostat, increasing cell viability in vitro. We found that all three antioxidants did not inhibited accumulation of acetyl Histone H4, so that antioxidants did not inhibit Vorinostat activity. Finally, we have evaluated the effects of antioxidants on anti-tumoral activity of Vorinostat as monotherapy or in combination with caspase-8 downregulation in vivo. Interestingly, antioxidants blocked the reduction of tumour growth caused by Vorinostat, but they were unable to inhibit anti-tumoral activity of Vorinostat plus caspase-8 inhibition. PMID:24651472

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. Enhanced antitumor effect of novel dual-targeted paclitaxel liposomes

    NASA Astrophysics Data System (ADS)

    Meng, Shuyan; Su, Bo; Li, Wei; Ding, Yongmei; Tang, Liang; Zhou, Wei; Song, Yin; Li, Heyan; Zhou, Caicun

    2010-10-01

    A novel dual-targeted peptide containing an alpha V integrins specific ligand and a neuropilin-1 specific motif was developed which showed an increased specific targeting affinity to tumors. Active dual-targeted liposomes were then produced with this peptide and exhibited greater binding activity than single-targeted liposomes in vitro. Paclitaxel entrapped in this formulation greatly increased the uptake of paclitaxel in the targeting cells and significantly suppressed the growth of HUVEC and A549 cells compared with general paclitaxel injections (Taxol) and single-targeted paclitaxel liposomes. The treatment of tumor xenograft models with dual-targeted paclitaxel liposomes also resulted in better tumor growth inhibition than any other treatment groups. Therefore, the dual-targeted paclitaxel liposomes prepared in the present study might be a more promising drug for cancer treatment. Furthermore, the dual-targeting approach may produce synergistic effects that can be applied in the development of new targeted drug delivery systems.

  12. 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

  13. 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

  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.

  15. Effects of pirarubicin, an antitumor antibiotic, on the cardiovascular system.

    PubMed

    Hirano, S; Agata, N; Hara, Y; Iguchi, H; Shirai, M; Tone, H; Urakawa, N

    1991-01-01

    In the present study we examined the effects of pirarubicin [(2"R)-4'-O-tetrahydropyranyladriamycin, THP] on a cardiovascular system. An injection of THP (0.39-3.13 mg/kg, i.v.) reduced the mean blood pressure and caused an increase in the respiratory air rate in anesthetized rats. At 1.5 x 10(-6)-1.5 x 10(-5) M, THP markedly relaxed a contraction induced by 10(-7) M norepinephrine in rat aorta with endothelium but not in that without endothelium. At a dose of 0.02-0.5 mg, THP produced an increase in the contractile force and the perfusion flow of isolated perfused guinea pig hearts. At a higher concentration (4.5 x 10(-5)-1.5 x 10(-4) M), it produced a slight increase in the contractile force of the left atria in guinea pigs. This positive inotropic action of THP was inhibited by diphenhydramine (10(-6)-5 x 10(-5) M), chlorpheniramine (3 x 10(-7)-3 x 10(-5) M), and tripelennamine (3 x 10(-7)-3 x 10(-5) M) but not by propranolol (10(-6) M), cimetidine (10(-5) M), diltiazem (10(-6) M), or ryanodine (10(-8) M). THP given i.v. at 2.5 mg/kg elevated the plasma histamine level in anesthetized dogs. From these data, we conclude that THP mainly relaxed the rat aorta in the presence of endothelium and that at higher concentrations, it increased the contractile force in the cardiac muscle, probably mediated through the release of histamine.

  16. 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

  17. 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

  18. 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

  19. 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

  20. Evaluation of the anti-tumor effects of lactate dehydrogenase inhibitor galloflavin in endometrial cancer cells.

    PubMed

    Han, Xiaoyun; Sheng, Xiugui; Jones, Hannah M; Jackson, Amanda L; Kilgore, Joshua; Stine, Jessica E; Schointuch, Monica N; Zhou, Chunxiao; Bae-Jump, Victoria L

    2015-01-29

    High rates of aerobic glycolysis represent a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. The present study was aimed at evaluating the potential of a novel lactate dehydrogenase (LDH) inhibitor, Galloflavin, as a therapeutic agent for endometrial cancer. Our results revealed that Galloflavin effectively inhibited cell growth in endometrial cancer cell lines and primary cultures of human endometrial cancer through its involvement in multiple signaling pathways that regulate metabolism, cell cycle, apoptosis, cell stress and metastasis.

  1. Targeting antitumor effect of rhTNF-α fusion protein mediated by matrix metalloproteinase-2.

    PubMed

    Shao, Xin; Ren, Hui; Wang, Yue-Li; Wang, Fa; Hou, Gan; Huang, Di-Nan

    2015-02-01

    The aim of this study was to examine the tumor therapy, targeting effects and side effects of tumor-targeting rhTNF-α fusion protein mediated by matrix metalloproteinase-2 in an animal model in order to provide experimental data for future development of drugs. The median lethal dose (LD50) was obtained from acute toxicity experiments. The A549 lung cancer xenograft model was established, and then randomly divided into the saline, standard substance, and low-, middle- and high-dose fusion protein experiment groups. Each group was administered drugs for 18 days. The length and width of the xenografts were measured every three days, after which the xenograft growth curve was drawn. The mice were sacrificed in each group following treatment and the tumor volume and weight were measured. The targeting, effectiveness and toxicity of the transformed fusion protein, and pathological changes of tumor and organ tissues were examined by hematoxylin and eosin (H&E) staining. Additionally, biochemical markers were used to detect damage of various organs after protein processing. Cell apoptosis and angiogenesis were determined using terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling (TUNEL) testing and immunohistochemistry, respectively, in different dose groups. Tumor growth was markedly retarded in the high-dose experimental and standard hTNF-α groups with antitumor rates of 85.91 and 72.25%, respectively, as compared with the control group. Furthermore, the tumor tissue showed obvious apoptosis (the apoptotic index was 78.78 and 66.65%, respectively) and pathological changes in the high-dose experimental and standard hTNF-α groups. Tumor angiogenesis in each fusion protein group was inhibited (P<0.01) and the biochemical markers of various organs were greatly reduced in the high-dose experimental group (P<0.05). This finding indicated that slight toxic effects of fusion proteins were evident for the heart, liver and kidney. The reforming fusion protein

  2. Macrophage PPARγ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone

    PubMed Central

    Cheng, Wing Yin; Huynh, HoangDinh; Chen, Peiwen; Peña-Llopis, Samuel; Wan, Yihong

    2016-01-01

    Tumor-associated macrophage (TAM) significantly contributes to cancer progression. Human cancer is enhanced by PPARγ loss-of-function mutations, but inhibited by PPARγ agonists such as TZD diabetes drugs including rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPARγ tumor-suppressive functions. Here we report that macrophage PPARγ deletion in mice not only exacerbates mammary tumor development but also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPARγ target in macrophage whose expression is enhanced by PPARγ loss but repressed by PPARγ activation. Functionally, macrophage Gpr132 is pro-inflammatory and pro-tumor. Genetic Gpr132 deletion not only retards inflammation and cancer growth but also abrogates the anti-tumor effects of PPARγ and rosiglitazone. Pharmacological Gpr132 inhibition significantly impedes mammary tumor malignancy. These findings uncover macrophage PPARγ and Gpr132 as critical TAM modulators, new cancer therapeutic targets, and essential mediators of TZD anti-cancer effects. DOI: http://dx.doi.org/10.7554/eLife.18501.001 PMID:27692066

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

    PubMed

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

    2014-01-01

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

  4. 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

  5. [Study of anti-tumor effects of hyperthermia combined with hydralazine on experimental tumor].

    PubMed

    Aoki, Y; Akagi, K; Kitada, N; Tanaka, Y; Fritz-Zieroth, B

    1995-11-01

    We analyzed tumor growth delay in experimental tumors after hyperthermia alone, hydralazine (HDZ) injection alone and the combination of these modalities. We also analyzed the energy parameter (ATP/Pi ratio) obtained by 31P-MRS (magnetic resonance spectroscopy). The purpose of this study was to evaluate the usefulness of 31P-MRS as an index of anti-tumor effect. FM3A tumor cells were transplanted subcutaneously in the hind legs of C3H/He mice. We dipped the tumors into a heated circulating water bath. 31P-MRS was performed with a CSI spectrometer. The anti-tumor effect obtained with HDZ alone was insignificant, but combined treatment with hyperthermia and HDZ had a significant synergistic effect. The ATP/Pi ratios for all groups treated separately with HDZ or hyperthermia were not different from the control, but the ATP/Pi ratio decreased after combined use of these agents. There was a significant correlation between the decrease in ATP/Pi ratio and tumor growth delay. We observed a direct relation between the delay in tumor growth and the decline in ATP/Pi ratio after combined treatment with HDZ and hyperthermia. The ATP/Pi ratio 24 hr after treatment may be useful in predicting the efficacy of the combined use of HDZ and hyperthermia.

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

    PubMed

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

    2014-01-01

    Saffron, a spice derived from the flower of Crocus sativus, is rich in carotenoids. Two main natural carotenoids of saffron, crocin and crocetin, are responsible for its color. Preclinical studies have shown that dietary intake of some carotenoids have potent anti-tumor effects both in vitro and in vivo, suggesting their potential preventive and/or therapeutic roles in several tissues. The reports represent that the use of carotenoids without the potential for conversion to vitamin A may provide further protection and avoid toxicity. The mechanisms underlying cancer chemo-preventive activities of carotenoids include modulation of carcinogen metabolism, regulation of cell growth and cell cycle progression, inhibition of cell proliferation, anti-oxidant activity, immune modulation, enhancement of cell differentiation, stimulation of cell-to-cell gap junction communication, apoptosis and retinoid-dependent signaling. Taken together, different hypotheses for the antitumor actions of saffron and its components have been proposed such as a) the inhibitory effect on cellular DNA and RNA synthesis, but not on protein synthesis; b) the inhibitory effect on free radical chain reactions; c) the metabolic conversion of naturally occurring carotenoids to retinoids; d) the interaction of carotenoids with topoisomerase II, an enzyme involved in cellular DNA-protein interaction. Furthermore, the immunomodulatory activity of saffron was studied on driving toward Th1 and Th2 limbs of the immune system. In this mini-review, we briefly describe biochemical and immunological activities and chemo-preventive properties of saffron and natural carotenoids as an anticancer drug. PMID:24269582

  7. 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.

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

    PubMed

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

    2013-04-01

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

  9. Fusion Protein of Mutant B7-DC and Fc Enhances the Antitumor Immune Effect of GM-CSF-secreting Whole-cell Vaccine

    PubMed Central

    Kojima, Masatsugu; Murata, Satoshi; Mekata, Eiji; Takebayashi, Katsushi; Jaffee, Elizabeth M.; Tani, Tohru

    2015-01-01

    Summary B7-DC [also known as programmed death ligand 2 (PD-L2)] is a costimulatory molecule expressed predominantly on dendritic cells (DCs) and macrophages. In addition to its coinhibitory receptor, programmed death receptor 1 (PD-1), evidence suggests that B7-DC interacts with an unidentified costimulatory receptor on T cells. B7-DC mutants with selective binding capacity for the costimulatory receptor may be effective in stimulating antitumor immune responses, while avoiding the inhibitory effects of PD-1. In this study, we concomitantly administered a GM-CSF-secreting whole cell vaccine together with a fusion protein of mutant B7-DC and Fc portion (mB7-DC-Fc), which binds selectively to the costimulatory receptor. This lead to an increased number of tumor antigen-specific cytotoxic T lymphocytes both in the spleen and at the tumor site and complete elimination of established tumors in vivo. In addition, mB7-DC-Fc increased IFN-γ and IL-2 production and decreased IL-4 and IL-10 production in vitro, indicating that mB7-DC-Fc tips the Th1/Th2 balance toward Th1 dominance, which is more favorable for antitumor immunity. Furthermore, mB7-DC-Fc decreased the PD-1 + proportion of CD8 + T cells in vitro and tumor-infiltrating CD8 + T cells in vivo, suggesting that mB7-DC-Fc may maintain tumor-infiltrating CD8 + T cells in a nonexhausted state. In conclusion, mB7-DC-Fc administration during the T-cell priming phase enhances antitumor effects of vaccine by generating more tumor antigen-specific cytotoxic T lymphocytes and leading to their accumulation at the tumor site. We suggest that this combination approach may be a promising strategy for antitumor immunotherapy. PMID:24598447

  10. Role of natural killer cells in the mechanism of the antitumor effect of interferon on Moloney sarcoma virus-transformed cells.

    PubMed

    Fresa, K L; Murasko, D M

    1986-01-01

    The growth of tumors induced by inoculation of cells transformed by Moloney sarcoma virus can be inhibited by in situ administration of interferon (IFN) beginning one day after tumor challenge and continuing for 2 or 3 additional days. Inhibition of tumor growth by IFN was associated with a marked augmentation of natural killer (NK) cell activity, both in the spleen and at the site of tumor challenge, by day 5 after tumor challenge. However, using optimal conditions for IFN treatment, depletion of NK cells by in vivo treatment with anti-asialo GM1 prior to tumor challenge had no significant effect on inhibition of tumor growth by IFN. When the tumor load was greater or when IFN treatment was shorter, treatment with anti-asialo-GM1 partially abrogated the inhibition of tumor growth by IFN. In vitro assays gave no evidence of IFN enhancement of specific T-cell or activated macrophage antitumor effect. These results suggest that under optimal treatment conditions, the mechanism of the antitumor effect of IFN was independent of augmentation of NK activity, but under suboptimal conditions NK cells play a role in the mechanism of the antitumor effect of IFN. PMID:3940213

  11. [Antitumor effect of low-intensity extremely high-frequency electromagnetic radiation on a model of solid Ehrlich carcinoma].

    PubMed

    Gapeev, A B; Shved, D M; Mikhaĭlik, E N; Korystov, Iu N; Levitman, M Kh; Shaposhnikova, V V; Sadovnikov, V B; Alekhin, A I; Goncharov, N G; Chemeris, N K

    2009-01-01

    The influence of different exposure regimes of low-intensity extremely high-frequency electromagnetic radiation on the growth rate of solid Ehrlich carcinoma in mice has been studied. It was shown that, at an optimum repetition factor of exposure (20 min daily for five consecutive days after the tumor inoculation), there is a clearly pronounced frequency dependence of the antitumor effect. The analysis of experimental data indicates that the mechanisms of antitumor effects of the radiation may be related to the modification of the immune status of the organism. The results obtained show that extremely high-frequency electromagnetic radiation at a proper selection of exposure regimes can result in distinct and stable antitumor effects.

  12. 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

  13. Glucose conjugated platinum(II) complex: antitumor superiority to oxaliplatin, combination effect and mechanism of action.

    PubMed

    Li, Hong; Gao, Xiangqian; Liu, Ran; Wang, Yu; Zhang, Menghua; Fu, Zheng; Mi, Yi; Wang, Yiqiang; Yao, Zhi; Gao, Qingzhi

    2015-08-28

    A glucose-conjugate of (trans-R,R-cyclohexane-1,2-diamine)-2-fluoromalonato-platinum(II) complex (Glu-Pt) is designed to target tumor-specific active glucose transporters (GLUTs). Despite of very high water solubility, Glu-Pt exhibits improved cytotoxicity as compared to oxaliplatin. In this study, we investigated the in vivo toxicity profiles with the maximum tolerated dose (MTD) evaluation followed by antitumor efficacy study in leukemia-bearing DBA/2 mice. Glu-Pt showed 6-fold increase in the MTD and was more efficacious against mouse L1210 ascetic leukemia than oxaliplatin at equitoxic doses. To explore the combination effect of Glu-Pt and compare with oxaliplatin-based FOLFOX chemotherapy, we investigated the two-component synergistic antitumor activity of Glu-Pt with folinic acid (FA) and 5-fluorouracil (5-FU) respectively in five human cancer cell lines followed by a comparison study with oxaliplatin in a fixed three-component in vitro FOFLOX combination. As the result, Glu-Pt exhibited superior synergistic cytotoxicity compared to oxaliplatin. Flow cytometry-based cell cycle and apoptosis study demonstrated that Glu-Pt follows the same mechanistic principles as of oxaliplatin. Glu-Pt monotherapy and its combination with FA and 5-FU may result in improved efficacy over oxaliplatin and FOLFOX regimen. The study provides fundamental data supporting the potential of Glu-Pt as a drug candidate for further (pre)clinical development.

  14. Dll4 Blockade in Stromal Cells Mediates Antitumor Effects in Preclinical Models of Ovarian Cancer.

    PubMed

    Kuhnert, Frank; Chen, Guoying; Coetzee, Sandra; Thambi, Nithya; Hickey, Carlos; Shan, Jing; Kovalenko, Pavel; Noguera-Troise, Irene; Smith, Eric; Fairhurst, Jeanette; Andreev, Julian; Kirshner, Jessica R; Papadopoulos, Nicholas; Thurston, Gavin

    2015-10-01

    The Notch ligand delta-like 4 (Dll4) has been identified as a promising target in tumor angiogenesis in preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. In this study, we report the development of REGN421 (enoticumab), a fully human IgG1 monoclonal antibody that binds human Dll4 with sub-nanomolar affinity and inhibits Notch signaling. Administering REGN421 to immunodeficient mice engineered to express human Dll4 inhibited the growth of several human tumor xenografts in association with the formation of nonfunctional tumor blood vessels. In ovarian tumor xenograft models, Dll4 was expressed specifically by the tumor endothelium, and Dll4 blockade by human-specific or mouse-specific Dll4 antibodies exerted potent antitumor activity, which relied entirely on targeting Dll4 expressed by tumor stromal cells but not by the tumor cells themselves. However, Dll4 blockade reduced Notch signaling in both blood vessels and tumor cells surrounding the blood vessels, suggesting that endothelial-expressed Dll4 might induce Notch signaling in adjacent ovarian tumor cells. The antitumor effects of targeting Dll4 were augmented significantly by simultaneous inhibition of VEGF signaling, whereas this combined blockade reversed normal organ vascular changes induced by Dll4 blockade alone. Overall, our findings deepen the rationale for antibody-based strategies to target Dll4 in ovarian cancers, especially in combination with VEGF blockade.

  15. 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

  16. 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

  17. Dosing of zoledronic acid with its anti-tumor effects in breast cancer

    PubMed Central

    Zhao, Xinmin; Hu, Xichun

    2015-01-01

    Bisphosphonates have played an important role in the treatment of breast cancer, mainly in patients with bone metastasis, by reducing the risk of fracture, spinal cord compression, and hypercalcemia. Zoledronic acid, the most frequently used intravenous agent, has been traditionally administered on a monthly dosing schedule. Preclinical studies have demonstrated that zoledronic acid can inhibit angiogenesis, invasion, and adhesion of tumor cells. Several clinical studies of different timings and schedules of zoledronic acid therapy have demonstrated its anti-tumor effects, as well as its protective effect on bone health, in postmenopausal women during adjuvant breast cancer therapy. In general, early initiation of zoledronic acid, concomitantly with adjuvant therapy, has been found to be most beneficial. However, questions remain over the most effective schedule of treatment and relative potency of zoledronic acid. Therefore, we review the existing clinical studies to examine the influence of dosing of zoledronic acid therapy on clinical outcomes in patients with breast cancer. PMID:26587376

  18. 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.

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

    PubMed Central

    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

  20. 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

  1. Identification and characterization of thiosemicarbazones with antifungal and antitumor effects: cellular iron chelation mediating cytotoxic activity.

    PubMed

    Opletalová, Veronika; Kalinowski, Danuta S; Vejsová, Marcela; Kunes, Jirí; Pour, Milan; Jampílek, Josef; Buchta, Vladimír; Richardson, Des R

    2008-09-01

    Thiosemicarbazones derived from acetylpyrazines were prepared by condensing an acetylpyrazine or a ring-substituted acetylpyrazine with thiosemicarbazide. Using the same procedure, N, N-dimethylthiosemicarbazones were synthesized from acetylpyrazines and N, N-dimethylthiosemicarbazide. A total of 20 compounds (16 novel) were chemically characterized and then tested for antifungal effects on eight strains of fungi and also for antitumor activity against SK-N-MC neuroepithelioma cells. The most effective compound identified in terms of both antifungal and antitumor activity was N, N-dimethyl-2-(1-pyrazin-2-ylethylidene)hydrazinecarbothioamide (5a). The mechanism of action of this and its related thiosemicarbazones was due, at least in part, to its ability to act as a tridentate ligand that binds metal ions. This was deduced from preparation of the related thiosemicarbazones [acetophenone thiosemicarbazone (6) and acetophenone N, N-dimethylthiosemicarbazone (7)] that do not possess a coordinating ring-N, which plays a vital role in metal ion chelation. Furthermore, 5a and several other thiosemicarbazones that showed high antiproliferative activity were demonstrated to have marked iron (Fe) chelation efficacy. In fact, these agents were highly effective at mobilizing (59)Fe from prelabeled SK-N-MC cells and preventing (59)Fe uptake from the serum Fe transport protein, transferrin. In contrast, compounds 6 and 7 that do not possess a tridentate metal-binding site showed little activity. Further studies examining ascorbate oxidation demonstrated that the Fe complexes of the most effective compounds were redox-inactive. Thus, in contrast to other thiosemicarbazones with potent antiproliferative activity, Fe chelation and mobilization rather than free radical generation played a significant role in the cytotoxic effects of the current ligands. PMID:18698850

  2. 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

  3. 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

  4. 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

  5. Snake venom L-amino acid oxidases: an overview on their antitumor effects

    PubMed Central

    2014-01-01

    The L-amino acid oxidases (LAAOs) constitute a major component of snake venoms and have been widely studied due to their widespread presence and various effects, such as apoptosis induction, cytotoxicity, induction and/or inhibition of platelet aggregation, hemorrhage, hemolysis, edema, as well as antimicrobial, antiparasitic and anti-HIV activities. The isolated and characterized snake venom LAAOs have become important research targets due to their potential biotechnological applications in pursuit for new drugs of interest in the scientific and medical fields. The current study discusses the antitumor effects of snake venom LAAOs described in the literature to date, highlighting the mechanisms of apoptosis induction proposed for this class of proteins. PMID:24940304

  6. Antitumor effect of antitissue factor antibody‐MMAE conjugate in human pancreatic tumor xenografts

    PubMed Central

    Koga, Yoshikatsu; Manabe, Shino; Aihara, Yoshiyuki; Sato, Ryuta; Tsumura, Ryo; Iwafuji, Hikaru; Furuya, Fumiaki; Fuchigami, Hirobumi; Fujiwara, Yuki; Hisada, Yohei; Yamamoto, Yoshiyuki; Yasunaga, Masahiro

    2015-01-01

    Tissue factor (TF) triggers the extrinsic blood coagulation cascade and is highly expressed in various types of cancer. In this study, we investigated the antitumor effect of an antibody–drug conjugate (ADC) consisting of an anti‐TF monoclonal antibody and monomethyl auristatin E (MMAE). MMAE was conjugated to an anti‐human TF or anti‐mouse TF antibody using a valine‐citrulline linker that could be potentially hydrolyzed by cathepsin B in the acidic environment of the lysosome. The cytotoxic and antitumor effects of the ADCs against four pancreatic cancer cell lines were analyzed. Both the ADC with the anti‐human TF antibody and that with the anti‐mouse TF antibody were stable under physiological conditions. The anti‐human ADC was internalized in TF‐expressing human tumor cell lines, followed by effective MMAE release. The half maximal inhibitory concentration (IC50) of MMAE was approximately 1 nM for all of the cell lines used. Meanwhile, the IC50 of anti‐human ADC was 1.15 nM in the cell lines showing high TF expression, while exceeding 100 nM in the cells showing low TF expression levels. Anti‐human ADC with passive and active targeting ability exerted significant suppression of tumor growth as compared to that observed in the saline group (p < 0.01). Also significant tumor growth suppressions were seen at the anti‐mouse ADC and control ADC groups compared to the saline group (p < 0.01) due to EPR effect. Because various clinical human cancers express highly amount of TF, this new anti‐TF ADC may deserve a clinical evaluation. PMID:25704403

  7. 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

  8. Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer

    PubMed Central

    Paik, Woo Hyun; Ryu, Ji Kon; Jeong, Kyoung-Sin; Park, Jin Myung; Song, Byeong Jun; Lee, Sang Hyub; Kim, Yong-Tae; Yoon, Yong Bum

    2014-01-01

    AIM: To evaluate the anti-tumor effect of clobenpropit, which is a specific H3 antagonist and H4 agonist, in combination with gemcitabine in a pancreatic cancer cell line. METHODS: Three kinds of human pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and AsPC-1) were used in this study. Expression of H3 and H4 receptors in pancreatic cancer cells was identified with Western blotting. Effects of clobenpropit on cell proliferation, migration and apoptosis were evaluated. Alteration of epithelial and mesenchymal markers after administration of clobenpropit was analyzed. An in vivo study with a Panc-1 xenograft mouse model was also performed. RESULTS: H4 receptors were present as 2 subunits in human pancreatic cancer cells, while there was no expression of H3 receptor. Clobenpropit inhibited cell migration and increased apoptosis of pancreatic cancer cells in combination with gemcitabine. Clobenpropit up-regulated E-cadherin, but down-regulated vimentin and matrix metalloproteinase 9 in real-time polymerase chain reaction. Also, clobenpropit inhibited tumor growth (gemcitabine 294 ± 46 mg vs combination 154 ± 54 mg, P = 0.02) and enhanced apoptosis in combination with gemcitabine (control 2.5%, gemcitabine 25.8%, clobenpropit 9.7% and combination 40.9%, P = 0.001) by up-regulation of E-cadherin and down-regulation of Zeb1 in Panc-1 xenograft mouse. CONCLUSION: Clobenpropit enhanced the anti-tumor effect of gemcitabine in pancreatic cancer cells through inhibition of the epithelial-mesenchymal transition process. PMID:25024609

  9. Anti-tumor effects of AMT in the renal cell carcinoma model.

    PubMed

    Caballero, Marcello; Scheele, Jürgen; Zirrgiebel, Ute; Esser, Norbert; Schächtele, Christoph; Soltau, Jens; Rentschler, Jochen; Diergarten, Klaus; Drevs, Joachim

    2010-01-01

    Auron-Misheil-Therapy (AMT) is a defined but unique combination of approved pharmaceuticals. It consists of insulin, chlorpheniramine and an aqueous camomile extract, and it has been successfully applied clinically in late-stage cancer patients. The purpose of this study was to elucidate the anti-tumor efficacy of AMT in a validated murine renal cell carcinoma animal model (RENCA). There were two independent studies; each animal group consisted of 16 mice. During a 6-week pretreatment period, vehicle (group A) and AMT (1.6 mg/kg/d) (group B) were administered once daily in a 5 days/week schedule either intramuscularly or subcutaneously. Tumor challenge at day 0 was followed by a 3-week treatment period (either vehicle or AMT once daily intramuscularly for 21 days consecutively). In study 2 the AMT dosage was increased up to 4-fold by doubling individual doses and switching to a twice daily schedule. The injections were all intramuscular. With the exception of group D, a six-week pretreatment period preceded the tumor challenge at day 0. Tumor challenge was followed by a 3-week treatment period (vehicle, AMT at either 3.2 mg/kg/d) (group A) or 6.4 mg/kg/d (group B), or AMT0, an AMT preparation which does not stimulate IL-6 secretion (6.4 mg/kg/d, group C) continuously for 21 days. AMT administration for group D (6.4 mg/kg/d) was limited to the treatment period from day 1 to 21. All mice were sacrificed 21 days after tumour transplantation. AMT administration was safe and well tolerated, and significantly reduced primary tumor volume in pretreated animals. The effective route of application was intramuscular, with dose escalation resulting in an improved anti-tumor effect. This is the first demonstration of a significant anti-tumorigenic effect of AMT in a validated tumor model.

  10. 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

  11. Gold nanoparticles enhance anti-tumor effect of radiotherapy to hypoxic tumor

    PubMed Central

    Kim, Mi Sun; Lee, Eun-Jung; Kim, Jae-Won; Chung, Ui Seok; Koh, Won-Gun; Keum, Ki Chang; Koom, Woong Sub

    2016-01-01

    Purpose Hypoxia can impair the therapeutic efficacy of radiotherapy (RT). Therefore, a new strategy is necessary for enhancing the response to RT. In this study, we investigated whether the combination of nanoparticles and RT is effective in eliminating the radioresistance of hypoxic tumors. Materials and Methods Gold nanoparticles (GNPs) consisting of a silica core with a gold shell were used. CT26 colon cancer mouse model was developed to study whether the combination of RT and GNPs reduced hypoxia-induced radioresistance. Hypoxia inducible factor-1α (HIF-1α) was used as a hypoxia marker. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were conducted to evaluate cell death. Results Hypoxic tumor cells had an impaired response to RT. GNPs combined with RT enhanced anti-tumor effect in hypoxic tumor compared with RT alone. The combination of GNPs and RT decreased tumor cell viability compare to RT alone in vitro. Under hypoxia, tumors treated with GNPs + RT showed a higher response than that shown by tumors treated with RT alone. When a reactive oxygen species (ROS) scavenger was added, the enhanced antitumor effect of GNPs + RT was diminished. Conclusion In the present study, hypoxic tumors treated with GNPs + RT showed favorable responses, which might be attributable to the ROS production induced by GNPs + RT. Taken together, GNPs combined with RT seems to be potential modality for enhancing the response to RT in hypoxic tumors. PMID:27730800

  12. Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy

    PubMed Central

    Mangala, Lingegowda S.; Wang, Hongyu; Jiang, Dahai; Wu, Sherry Y.; Somasunderam, Anoma; Volk, David E.; Lokesh, Ganesh L. R.; Li, Xin; Pradeep, Sunila; Yang, Xianbin; Haemmerle, Monika; Nagaraja, Archana S; Bayraktar, Emine; Bayraktar, Recep; Li, Li; Tanaka, Takemi; Hu, Wei; Gharpure, Kshipra M; McGuire, Michael H.; Thiviyanathan, Varatharasa; Zhang, Xinna; Maiti, Sourindra N.; Bulayeva, Nataliya; Dorniak, Piotr L.; Cooper, Laurence J.N.; Rosenblatt, Kevin P.; Lopez-Berestein, Gabriel; Gorenstein, David G.; Sood, Anil K.

    2016-01-01

    Current antiangiogenesis therapy relies on inhibiting newly developed immature tumor blood vessels and starving tumor cells. This strategy has shown transient and modest efficacy. Here, we report a better approach to target cancer-associated endothelial cells (ECs), reverse permeability and leakiness of tumor blood vessels, and improve delivery of chemotherapeutic agents to the tumor. First, we identified deregulated microRNAs (miRs) from patient-derived cancer-associated ECs. Silencing these miRs led to decreased vascular permeability and increased maturation of blood vessels. Next, we screened a thioaptamer (TA) library to identify TAs selective for tumor-associated ECs. An annexin A2–targeted TA was identified and used for delivery of miR106b-5p and miR30c-5p inhibitors, resulting in vascular maturation and antitumor effects without inducing hypoxia. These findings could have implications for improving vascular-targeted therapy. PMID:27777972

  13. [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

  14. 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.

  15. 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.

  16. Antitumor effect of TRAIL on oral squamous cell carcinoma using magnetic nanoparticle-mediated gene expression.

    PubMed

    Miao, Leiying; Liu, Chao; Ge, Jiuyu; Yang, Weidong; Liu, Jinzhong; Sun, Weibin; Yang, Bai; Zheng, Changyu; Sun, Hongchen; Hu, Qingang

    2014-07-01

    We developed a new magnetic nanovector to improve the efficiency and targeting of transgene therapy for oral squamous cell carcinoma (OSCC). Positively charged polymer PEI-modified Fe(3)O(4) magnetic nanoparticles were tested as gene transfer vectors in the presence of a magnetic field. The Fe(3)O(4) nanoparticles were prepared by a co-precipitation method and had good dispersibility in water. These nanoparticles modified by PEI were combined with negatively charged pACTERT-EGFP via electrostatic interaction. The transfection efficiency of the magnetic nano-gene vector with the magnetic field was determined by a fluorescence-inverted microscope and flow cytometry. The results showed significant improvement compared with the control group (p < 0.05). The magnetic complexes also exhibited up to 6-times higher transfection efficiency compared with commonly used PEI or lipofectin. On the basis of these results, the antitumor effect with suicide gene therapy using pACTERT-TRAIL in vitro and vivo was evaluated. In vitro apoptosis was determined with the Annexin V-FITC Apoptosis Detection Kit. The results suggested that PEI-modified Fe(3)O(4) nanoparticles could mediate the killing of Tca83 cells. Furthermore, treatment with pACTERT-TRAIL delivered by magnetic nanoparticles showed a significant cytostatic effect through the induction of apoptosis in a xenograft model. This indicates that magnetic nano-gene vectors could improve the transgene efficiency for Tca83 cells and could exhibit antitumor functions with the plasmid pACTERT-TRAIL. This may be a new way to treat OSCC.

  17. 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

  18. Do Helper T Cell Subtypes in Lymphocytic Thyroiditis Play a Role in the Antitumor Effect?

    PubMed Central

    Yang, Seok Woo; Kang, Seong-Ho; Kim, Kyung Rae; Choi, In Hong; Chang, Hang Seok; Oh, Young Lyun; Hong, Soon Won

    2016-01-01

    Background Papillary thyroid carcinoma (PTC) is frequently accompanied by lymphocytic thyroiditis (LT). Some reports claim that Hashimoto’s thyroiditis (the clinical form of LT) enhances the likelihood of PTC; however, others suggest that LT has antitumor activity. This study was aimed to find out the relationship between the patterns of helper T cell (Th) cytokines in thyroid tissue of PTC with or without LT and the clinicopathological manifestation of PTC. Methods Fresh surgical samples of PTC with (13 cases) or without (10 cases) LT were used. The prognostic parameters (tumor size, extra-thyroidal extension of PTC, and lymph node metastasis) were analyzed. The mRNA levels of two subtypes of Th cytokines, Th1 (tumor necrosis factor α [TNF-α], interferon γ [IFN-γ ], and interleukin [IL] 2) and Th2 (IL-4 and IL-10), were analyzed. Because most PTC cases were microcarcinomas and recent cases without clinical follow-up, negative or faint p27 immunoreactivity was used as a surrogate marker for lymph node metastasis. Results PTC with LT cases showed significantly higher expression of TNF-α (p = .043), IFN-γ (p < .010), IL-4 (p = .015) than those without LT cases. Although the data were not statistically significant, all analyzed cytokines (except for IL-4) were highly expressed in the cases with higher expression of p27 surrogate marker. Conclusions These results indicate that mixed Th1 (TNF-α, IFN-γ , and IL-2) and Th2 (IL-10) immunity might play a role in the antitumor effect in terms of lymph node metastasis. PMID:27681413

  19. 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

  20. Rebamipide does not interfere with the antitumor effect of radiotherapy or chemotherapy in human oral tumor-bearing nude mice.

    PubMed

    Shibamori, Masafumi; Sato, Masayuki; Uematsu, Naoya; Nakashima, Takako; Sato, Asuka; Yamamura, Yoshiya; Sasabe, Hiroyuki; Umehara, Ken; Sakurai, Kazushi

    2015-09-01

    Recent studies have shown that rebamipide, which suppresses reactive oxygen species, prevents chemoradiotherapy-induced oral mucositis in patients with head and neck cancers. However, anticancer action of radiotherapy and chemotherapy is believed to be partially associated with generation of reactive oxygen species. The aim of this study was to determine whether rebamipide interferes with the antitumor action of radiotherapy and chemotherapy. The effect of rebamipide on tumor cell growth was investigated using a human oral squamous carcinoma cell line, HSC-2, in vitro and in vivo. Rebamipide showed no significant effect on cell or tumor growth in HSC-2 tumor-bearing nude mice. Influences of rebamipide on the antitumor action of radiotherapy and of chemotherapy with cisplatin or docetaxel were investigated using the same animal model. In radiotherapy, the tumor was treated with 2.5 Gy of X-rays for 5 days, and rebamipide (300 mg/kg p.o.) was administered during irradiation periods. In chemotherapy, tumor-bearing mice were treated once with cisplatin (8 mg/kg, i.v.) or docetaxel (15 mg/kg i.v.) and rebamipide (300 mg/kg p.o.) was administered for 5 days following the antitumor drug treatment. Rebamipide did not interfere with the antitumor action of radiotherapy and chemotherapy.

  1. 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

  2. Antitumor Effects of OSU-2S, a Non-immunosuppressive Analogue of FTY720, in Hepatocellular Carcinoma

    PubMed Central

    Omar, Hany A.; Chou, Chih-Chien; Berman-Booty, Lisa D.; Ma, Yihui; Hung, Jui-Hsiang; Wang, Dasheng; Kogure, Takayuki; Patel, Tushar; Terracciano, Luigi; Muthusamy, Natarajan; Byrd, John C.; Kulp, Samuel K.; Chen, Ching-Shih

    2011-01-01

    Accumulating evidence suggests the therapeutic potential of the immunosuppressive agent FTY720 (fingolimod) in hepatocellular carcinoma (HCC). Based on our previous finding that FTY720 mediates apoptosis in HCC cells by activating reactive oxygen species (ROS)-protein kinase (PK)Cδ signaling independent of effects on sphingosine-1-phosphate (S1P) receptors, we embarked on the pharmacological exploitation of FTY720 to develop a non-immunosuppressive analogue with antitumor activity. This effort led to the development of OSU-2S, which exhibits higher potency than FTY720 in suppressing HCC cell growth through PKCδ activation. In contrast to FTY720, OSU-2S was not phosphorylated by sphingosine kinase (SphK)2 in vitro, and did not cause S1P1 receptor internalization in HCC cells or T lymphocyte homing in immunocompetent mice. Though devoid of S1P1 receptor activity, OSU-2S exhibited higher in vitro antiproliferative efficacy relative to FTY720 against HCC cells without cytotoxicity in normal hepatocytes. Several lines of pharmacological and molecular genetic evidence indicate that ROS-PKCδ-caspase-3 signaling underlies OSU-2S-mediated antitumor effects, and that differences in the antitumor activity between FTY720 and OSU-2S were attributable to SphK2-mediated phosphorylation of FTY720, which represents a metabolic inactivation of its antitumor activity. Finally, OSU-2S exhibited high in vivo potency in suppressing xenograft tumor growth in both ectopic and orthotopic models without overt toxicity. Conclusion: Using the molecular platform of FTY720, we developed OSU-2S, a novel PKCδ-targeted antitumor agent, which is devoid of S1P1 receptor activity and is highly effective in suppressing HCC tumor growth in vivo. These findings suggest that OSU-2S has clinical value in therapeutic strategies for HCC and warrants continued investigation in this regard. PMID:21391227

  3. Antitumor and immunoregulatory effects of astragalus on nasopharyngeal carcinoma in vivo and in vitro.

    PubMed

    Song, Yan; Yang, Jing; Bai, Wei-liang; Ji, Wen-yue

    2011-06-01

    This study was carried out to evaluate the effects of Astragalus on human nasopharyngeal carcinoma (NPC) viability and apoptosis and to investigate the mechanism of Astragalus in a NPC cell line (CNE2). Cell viability was measured using the MTT assay. CNE2 cells treated with Astragalus were stained with acridine orange/ethidium bromide and subjected to fluorescence microscopy. Bcl-2, Bax, caspase-3 and -8 were measured by western blotting. Rat NPC cells were used to establish a NPC model. Tumor weight, immune organ index and T lymphocyte subsets were employed to detect the immunoregulatory and antitumor effects of Astragalus after administration. Astragalus was effective in inducing apoptosis in CNE2 cells. Morphological changes associated with cell injury were found. Western analysis showed caspase-3, -8, and Bax protein levels were increased after Astragalus treatment, while the bcl-2 protein level was decreased. Astragalus increased the percentage of CD3(+) , CD4(+) T-lymphocytes, and the ratio of CD4(+) /CD8(+) . Astragalus also restored the immunological effects of DDP-induced immunosuppression. These findings suggest that the immunomodulatory and anticancer effects of DDP + Astragalus were better than those of DDP alone, and Astragalus could inhibit immunosuppression induced by DDP. The combination of CDDP + Astragalus could be developed as an effective chemotherapeutic regimen in the treatment of nasopharyngeal carcinoma.

  4. Anti-inflammatory and antitumor-promoting effects of the triterpene acids from the leaves of Eriobotrya japonica.

    PubMed

    Banno, Norihiro; Akihisa, Toshihiro; Tokuda, Harukuni; Yasukawa, Ken; Taguchi, Yosuke; Akazawa, Hiroyuki; Ukiya, Motohiko; Kimura, Yumiko; Suzuki, Takashi; Nishino, Hoyoku

    2005-10-01

    Sixteen triterpene acids, viz., five of the oleanane-type (1-5), nine of the ursane-type (6-14), and two of the lupane-type (15, 16), were isolated and identified from the ethyl acetate-soluble fraction of the methanol extract of the leaves of loquat, Eriobotrya japonica LINDL. (Rosaceae). Twelve of these compounds, 1-4, 6, 8-13, and 15, were evaluated for their inhibitory effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice. All the compounds tested showed a marked anti-inflammatory effect, with a 50% inhibitory dose (ID50) of 0.03-0.43 mg per ear. In addition, an evaluation against the Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA for all of the compounds, 12 and 13 showed potent inhibitory effects on EBV-EA induction. Furthermore, euscaphic acid (12) exhibited marked antitumor-promoting activity in an in vivo two-stage carcinogenesis test of mouse tumor by using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter.

  5. 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

  6. 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.

  7. 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

  8. Type I Interferons Exert Anti-tumor Effect via Reversing Immunosuppression Mediated by Mesenchymal Stromal Cells

    PubMed Central

    Shou, Peishun; Chen, Qing; Jiang, Jingting; Xu, Chunliang; Zhang, Jimin; Zheng, Chunxing; Jiang, Menghui; Velletri, Tania; Cao, Wei; Huang, Yin; Yang, Qian; Han, Xiaoyan; Zhang, Liying; Wei, Lixin; Rabson, Arnold B.; Chin, Y. Eugene; Wang, Ying; Shi, Yufang

    2016-01-01

    Mesenchymal stromal cells (MSCs) are strongly immunosuppressive via producing nitric oxide (NO) and known to migrate into tumor sites to promote tumor growth, but the underlying mechanisms remain largely elusive. Here, we found that IFNα-secreting MSCs showed more dramatic inhibition effect on tumor progression than that of IFNα alone. Interestingly, IFNα-primed MSCs could also effectively suppress tumor growth. Mechanistically, we demonstrated that both IFNα and IFNβ (type I IFNs) reversed the immunosuppressive effect of MSCs on splenocyte proliferation. This effect of type I IFNs was exerted through inhibiting iNOS (inducible nitric oxide synthase) expression in IFNγ and TNFα-stimulated MSCs. Notably, only NO production was inhibited by IFNα; production of other cytokines or chemokines tested was not suppressed. Furthermore, IFNα promoted the switch from Stat1 homodimers to Stat1-Stat2 heterodimers. Studies using the luciferase reporter system and chromatin immunoprecipitation assay revealed that IFNα suppressed iNOS transcription through inhibiting the binding of Stat1 to iNOS promoter. Therefore, the synergistic anti-tumor effects of type I IFNs and MSCs were achieved by inhibiting NO production. This study provides essential information for understanding the mechanisms of MSC-mediated immunosuppression and for the development of better clinical strategies using IFNs and MSCs for cancer immunotherapy. PMID:27109100

  9. In vitro and in vivo antitumor effect of trachylobane-360, a diterpene from Xylopia langsdorffiana.

    PubMed

    Pita, João Carlos Lima Rodrigues; Xavier, Aline Lira; de Sousa, Tatyanna Kelvia Gomes; Mangueira, Vivianne Mendes; Tavares, Josean Fechine; de Oliveira Júnior, Robson José; Veras, Robson Cavalcante; Pessoa, Hilzeth de Luna Freire; da Silva, Marcelo Sobral; Morelli, Sandra; Ávila, Veridiana de Melo Rodrigues; da Silva, Teresinha Gonçalves; Diniz, Margareth de Fátima Formiga Melo; Castello-Branco, Marianna Vieira Sobral

    2012-01-01

    Trachylobane-360 (ent-7α-acetoxytrachyloban-18-oic acid) was isolated from Xylopia langsdorffiana. Studies have shown that it has weak cytotoxic activity against tumor and non-tumor cells. This study investigated the in vitro and in vivo antitumor effects of trachylobane-360, as well as its cytotoxicity in mouse erythrocytes. In order to evaluate the in vivo toxicological aspects related to trachylobane-360 administration, hematological, biochemical and histopathological analyses of the treated animals were performed. The compound exhibited a concentration-dependent effect in inducing hemolysis with HC₅₀ of 273.6 µM, and a moderate in vitro concentration-dependent inhibitory effect on the proliferation of sarcoma 180 cells with IC₅₀ values of 150.8 µM and 150.4 µM, evaluated by the trypan blue exclusion test and MTT reduction assay, respectively. The in vivo inhibition rates of sarcoma 180 tumor development were 45.60, 71.99 and 80.06% at doses of 12.5 and 25 mg/kg of trachylobane-360 and 25 mg/kg of 5-FU, respectively. Biochemical parameters were not altered. Leukopenia was observed after 5-FU treatment, but this effect was not seen with trachylobane-360 treatment. The histopathological analysis of liver and kidney showed that both organs were mildly affected by trachylobane-360 treatment. Trachylobane-360 showed no immunosuppressive effect. In conclusion, these data reinforce the anticancer potential of this natural diterpene.

  10. IFN-γ Mediates the Antitumor Effects of Radiation Therapy in a Murine Colon Tumor

    PubMed Central

    Gerber, Scott A.; Sedlacek, Abigail L.; Cron, Kyle R.; Murphy, Shawn P.; Frelinger, John G.; Lord, Edith M.

    2014-01-01

    Cancer treatments using ionizing radiation (IR) therapy are thought to act primarily through the induction of tumor cell damage at a molecular level. However, a new concept has recently emerged, suggesting that the immune system is required for effective IR therapy. Our work here has identified interferon gamma (IFN-γ) as an essential cytokine for the efficacy of IR therapy. Local IR (15 Gy) to mice bearing Colon38, a colon adenocarcinoma, decreases tumor burden in wild-type animals. Interestingly, IR therapy had no effect on tumor burden in IFNγKO mice. We further determined that intratumoral levels of IFN-γ increased 2 days following IR, which directly correlated with a decrease in tumor burden that was not a result of direct cytotoxic effects of IFN-γ on tumor cells. T cells from IR-treated tumors exhibited a far greater capacity to lyse tumor cells in a 51Cr release assay, a process that was dependent on IFN-γ. CD8+ T cells were the predominant producers of IFN-γ, as demonstrated by IFN-γ intracellular staining and studies in IFN-γ reporter mice. Elimination of CD8+ T cells by antibody treatment reduced the intratumoral levels of IFN-γ by over 90%. More importantly, elimination of CD8+ T cells completely abrogated the effects of radiation therapy. Our data suggest that IFN-γ plays a pivotal role in mediating the antitumor effects of IR therapy. PMID:23583648

  11. 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.

  12. 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

  13. 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

  14. 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.

  15. Magnolol and honokiol exert a synergistic anti-tumor effect through autophagy and apoptosis in human glioblastomas

    PubMed Central

    Cheng, Yu-Chen; Hueng, Dueng-Yuan; Huang, Hua-Yin; Chen, Jang-Yi; Chen, Ying

    2016-01-01

    Glioblastoma (GBM) is a malignant brain tumor associated with a high mortality rate. The aim of this study is to investigate the synergistic effects of honokiol (Hono) and magnolol (Mag), extracted from Magnolia officinalis, on cytotoxicity and inhibition of human GBM tumor progression in cellular and animal models. In comparison with Hono or Mag alone, co-treatment with Hono and Mag (Hono-Mag) decreased cyclin A, D1 and cyclin-dependent kinase 2, 4, 6 significantly, leading to cell cycle arrest in U87MG and LN229 human glioma cells. In addition, phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, and Ki67 were decreased after Hono-Mag treatment, showing proliferation inhibition. Hono-Mag treatment also reduced p-p38 and p-JNK but elevated p-ERK expression. Besides, Hono-Mag treatment induced autophagy and intrinsic and extrinsic apoptosis. Both ERK and autophagy inhibitors enhanced Hono-Mag-induced apoptosis in LN229 cells, indicating a rescuer role of ERK. In human GBM orthotopic xenograft model, the Hono-Mag treatment inhibited the tumor progression and induced apoptosis more efficiently than Temozolomide, Hono, or Mag group. In conclusion, the Hono-Mag exerts a synergistic anti-tumor effect by inhibiting cell proliferation and inducing autophagy and apoptosis in human GBM cells. The Hono-Mag may be applied as an adjuvant therapy to improve the therapeutic efficacy of GBM treatment. PMID:27074557

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

    PubMed Central

    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

    2015-01-01

    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

  17. 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

  18. 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

  19. Metformin displays in vitro and in vivo antitumor effect against osteosarcoma

    PubMed Central

    Ko, Yunmi; Choi, Aery; Lee, Minyoung

    2016-01-01

    Purpose Patients with unresectable, relapsed, or refractory osteosarcoma need a novel therapeutic agent. Metformin is a biguanide derivative used in the treatment of type II diabetes, and is recently gaining attention in cancer research. Methods We evaluated the effect of metformin against human osteosarcoma. Four osteosarcoma cell lines (KHOS/NP, HOS, MG-63, U-2 OS) were treated with metformin and cell proliferation was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle progression and apoptosis were evaluated using flow cytometric analysis, and migration and wound healing assay were performed. Fourteen female Balb/c-nude mice received KHOS/NP cell grafts in their thigh, and were allowed access to metformin containing water (2 mg/mL) ad libitum. Tumor volume was measured every 3–4 days for a period of 4 weeks. Results Metformin had a significant antiproliferative effect on human osteosarcoma cells. In particular, metformin inhibited the proliferation and migration of KHOS/NP cells by activation of AMP-activated protein kinase and consequent inhibition of the mammalian target of rapamycin pathway. It also inhibited the proliferation of cisplatin-resistant KHOS/NP clone cells. Analysis of KHOS/NP xenograft Balb/c-nude models indicated that metformin displayed potent in vivo antitumor effects. Conclusion Further studies are necessary to explore metformin's therapeutic potential and the possibilities for its use as an adjuvant agent for osteosarcoma. PMID:27721842

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

    PubMed Central

    Wang, Zhi-Yong; Zhang, Jun-Ai; Wu, Xian-Jin; Liang, Yan-Fang; Lu, Yuan-Bin; Gao, Yu-Chi; Dai, You-Chao; Yu, Shi-Yan; Jia, Yan; Fu, Xiao-Xia; Rao, Xiaoquan; Xu, Jun-Fa

    2016-01-01

    Recent studies suggest that tumor-associated macrophage-produced IL-6 is an important mediator within the tumor microenvironment that promotes tumor growth. The activation of IL-6/STAT3 axis has been associated with chemoresistance and poor prognosis of a variety of cancers including colorectal carcinoma and thus serves as a potential immunotherapeutic target for cancer treatment. However, it is not fully understood whether anticytokine therapy could reverse chemosensitivity and enhance the suppressive effect of chemotherapy on tumor growth. In this study, we aimed to investigate the effect of IL-6 inhibition therapy on the antitumor effect of carboplatin. Enhanced expression of IL-6 and activation of STAT3 were observed in human colorectal carcinoma samples compared to normal colorectal tissue, with higher levels of IL-6/STAT3 in low grade carcinomas. Treatment of carboplatin (CBP) dose-dependently increased IL-6 production and STAT3 activation in human colorectal LoVo cells. Blockade of IL-6 with neutralizing antibody enhanced chemosensitivity of LoVo cells to carboplatin as evidenced by increased cell apoptosis. IL-6 blockade abolished carboplatin-induced STAT3 activation. IL-6 blockade and carboplatin synergistically reduced cyclin D1 expression and enhanced caspase-3 activity in LoVo cells. Our results suggest that inhibition of IL-6 may enhance chemosensitivity of colon cancers with overactive STAT3 to platinum agents. PMID:27006530

  1. 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

  2. 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

  3. Antitumor Effect of Periplocin in TRAIL-Resistant Human Hepatocellular Carcinoma Cells through Downregulation of IAPs.

    PubMed

    Cheng, Chieh-Fang; Lu, I-Huang; Tseng, Hsiang-Wen; Sun, Chung-Yuan; Lin, Li-Tsen; Kuo, Zong-Keng; Pan, I-Horng; Ko, Ching-Huai

    2013-01-01

    Cortex periplocae is the dried root bark of Periploca sepium Bge., a traditional Chinese herb medicine. It contains high amounts of cardiac glycosides. Several cardiac glycosides have been reported to inhibit tumor growth or induce tumor cell apoptosis. We extracted and purified cortex periplocae and identified periplocin as the active ingredient that inhibited the growth of TNF-related apoptosis-inducing ligand-(TRAIL-) resistant hepatocellular carcinoma cells. The antitumor activity of periplocin was further increased by TRAIL cotreatment. Periplocin sensitized TRAIL-resistant HCC through the following two mechanisms. First, periplocin induced the expression of DR4 and FADD. Second, the cotreatment of TRAIL and periplocin suppressed several inhibitors of apoptosis (IAPs). Both mechanisms resulted in the activation of caspase 3, 8, and 9 and led to cell apoptosis. In addition, intraperitoneal injection (IP) of periplocin repressed the growth of hepatocellular carcinoma (HCC) in xenograft tumor model in mice. In summary, periplocin sensitized TRAIL-resistant HCC cells to TRAIL treatment and resulted in tumor cell apoptosis and the repression of tumor growth in vivo.

  4. 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.

  5. 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

  6. Effective antitumor therapy based on a novel antibody-drug conjugate targeting the Tn carbohydrate antigen.

    PubMed

    Sedlik, Christine; Heitzmann, Adèle; Viel, Sophie; Ait Sarkouh, Rafik; Batisse, Cornélie; Schmidt, Frédéric; De La Rochere, Philippe; Amzallag, Nathalie; Osinaga, Eduardo; Oppezzo, Pablo; Pritsch, Otto; Sastre-Garau, Xavier; Hubert, Pascale; Amigorena, Sebastian; Piaggio, Eliane

    2016-07-01

    Antibody-drug conjugates (ADC), combining the specificity of tumor recognition by monoclonal antibodies (mAb) and the powerful cytotoxicity of anticancer drugs, are currently under growing interest and development. Here, we studied the potential of Chi-Tn, a mAb directed to a glyco-peptidic tumor-associated antigen, to be used as an ADC for cancer treatment. First, we demonstrated that Chi-Tn specifically targeted tumor cells in vivo. Also, using flow cytometry and deconvolution microscopy, we showed that the Chi-Tn mAb is rapidly internalized - condition necessary to ensure the delivery of conjugated cytotoxic drugs in an active form, and targeted to early and recycling endosomes. When conjugated to saporin (SAP) or to auristatin F, the Chi-Tn ADC exhibited effective cytotoxicity to Tn-positive tumor cells in vitro, which correlated with the level of tumoral Tn expression. Furthermore, the Chi-Tn mAb conjugated to auristatin F also exhibited efficient antitumor activity in vivo, validating for the first time the use of an anti-Tn antibody as an effective ADC. PMID:27622021

  7. High cytokine production and effective antitumor activity of a recombinant vaccinia virus encoding murine interleukin 12.

    PubMed

    Meko, J B; Yim, J H; Tsung, K; Norton, J A

    1995-11-01

    We have constructed a recombinant vaccinia virus (recVV), vKT0334 mIL-12, containing the genes encoding the p35 and p40 subunits of murine interleukin-12 (mIL-12). In vitro experiments demonstrated that vKT0334 mIL-12 efficiently infected a variety of murine and human tumor cell lines and produced very high amounts (1.5 micrograms/10(6) cells/24 h) of biologically active mIL-12. Mice injected s.c. with 10(6) MCA 105 sarcoma cells, followed by injection at the same site with saline or a control recVV, vKT033, containing no mIL-12 genes, all developed progressively growing tumor, whereas 60% of animals injected with vKT0334 mIL-12 remained tumor free (P < 0.0005). Furthermore, tumor growth was significantly reduced in the remaining mice treated with vKT0334 mIL-12 that did develop tumor compared with mice treated with vKT033 (P < 0.03) or saline (P < 0.0001). We conclude that recVV expressing high levels of mIL-12 offers an effective in vivo method of cytokine gene delivery and expression in tumors with subsequent antitumor effect.

  8. Antitumor and antimetastasis effects of macerating solutions from an injectable chitosan-based hydrogel on hepatocarcinoma.

    PubMed

    Wang, Hui; Song, Fulai; Chen, Quan; Hu, Rui; Jiang, Zhiwen; Yang, Yan; Han, Baoqin

    2015-12-01

    In our previous studies, injectable chitosan-based hydrogel (CH) was prepared and its application in surgery removal of tumor was studied. In this study, the antitumor and antimetastasis effects of the macerating solutions from CH were investigated. Our in vitro results showed that macerating solutions from CH significantly increased the proliferation of human normal liver L02 cells. In contrast, macerating solutions from CH showed significant inhibitory effects on the growth of human hepatoma Bel-7402 cells. In a mouse H22 tumor model, intraperitoneal injection of macerating solutions from CH decreased tumor growth and prevented tumor diffusion. Tumor weight was decreased dramatically in mice treated with macerating solutions from CH. The thymus index and spleen index were significantly increased by treatment with macerating solutions from CH. Administration of macerating solutions from CH also remarkably increased serum levels of TNF-α, IL-2, IFN-γ, and decreased serum VEGF content as compared with the control group treated with saline. The antimetastasis studies showed that the number of pulmonary nodules, pulmonary metastases index, and lymph nodes index were significantly decreased in experimental groups treated with macerating solutions from CH. This study provided more supporting data for the potential clinical application of CH after surgical removal of tumor.

  9. Determinants for in vivo antitumor effect of angiogenesis inhibitor SU5416 formulated in PEGylated emulsion.

    PubMed

    Ogawara, Ken-Ichi; Abe, Shigeki; Un, Keita; Yoshizawa, Yuta; Kimura, Toshikiro; Higaki, Kazutaka

    2014-08-01

    Angiogenesis, the sprouting of capillaries from preexisting ones, is essential for the sustained growth of solid tumors. In this study, we used SU5416, a hydrophobic molecule with potent tyrosine kinase inhibitor of type 2 receptor for vascular endothelial growth factor (VEGF), as PEGylated emulsion (SU5416-PE), and evaluated the antitumor potency of this formulation in Lewis lung cancer (LLC), Colon-26 (C26), and B16BL6 melanoma (B16) tumor-bearing mice. Intravenous injection of SU5416-PE into tumor-bearing mice significantly suppressed the growth of C26 and B16 tumors, but had no effect on the growth of LLC tumors. MTT assay revealed that SU5416 inhibited the proliferation of human umbilical vein endothelial cells in a concentration-dependent manner but did not show such an inhibitory effect on all types of tumor cells examined, demonstrating the specificity of SU5416 for endothelial cells. Considering that VEGF levels within C26 and B16 tumors were found to be about 10-fold and 20-fold higher than that in LLC tumors, respectively, it was suggested that SU5416-PE would inhibit angiogenesis in certain types of tumor tissue such as C26 and B16 where VEGF plays a major role for promoting angiogenesis, leading to the suppression of in vivo tumor growth.

  10. 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

  11. Development of high boron content liposomes and their promising antitumor effect for neutron capture therapy of cancers.

    PubMed

    Koganei, Hayato; Ueno, Manabu; Tachikawa, Shoji; Tasaki, Lisa; Ban, Hyun Seung; Suzuki, Minoru; Shiraishi, Kouichi; Kawano, Kumi; Yokoyama, Masayuki; Maitani, Yoshie; Ono, Koji; Nakamura, Hiroyuki

    2013-01-16

    Mercaptoundecahydrododecaborate (BSH)-encapsulating 10% distearoyl boron lipid (DSBL) liposomes were developed as a boron delivery vehicle for neutron capture therapy. The current approach is unique because the liposome shell itself possesses cytocidal potential in addition to its encapsulated agents. BSH-encapsulating 10% DSBL liposomes have high boron content (B/P ratio: 2.6) that enables us to prepare liposome solution with 5000 ppm boron concentration. BSH-encapsulating 10% DSBL liposomes displayed excellent boron delivery efficacy to tumor: boron concentrations reached 174, 93, and 32 ppm at doses of 50, 30, and 15 mg B/kg, respectively. Magnescope was also encapsulated in the 10% DSBL liposomes and the real-time biodistribution of the Magnescope-encapsulating DSBL liposomes was measured in a living body using MRI. Significant antitumor effect was observed in mice injected with BSH-encapsulating 10% DSBL liposomes even at the dose of 15 mg B/kg; the tumor completely disappeared three weeks after thermal neutron irradiation ((1.5-1.8) × 10(12) neutrons/cm(2)). The current results enabled us to reduce the total dose of liposomes to less than one-fifth compared with that of the BSH-encapsulating liposomes without reducing the efficacy of boron neutron capture therapy (BNCT).

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

    PubMed Central

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

    2013-01-01

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

  13. 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

  14. 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.

  15. Immunomodulatory and anti-tumor effects of Nigella glandulifera freyn and sint seeds on ehrlich ascites carcinoma in mouse model

    PubMed Central

    Aikemu, Ainiwaer; Xiaerfuding, Xiadiya; Shiwenhui, Chengyufeng; Abudureyimu, Meiliwan; Maimaitiyiming, Dilinuer

    2013-01-01

    Aim: This study investigated the immunomodulatory and anti-tumor effects of Nigella glandulifera Freyn and Sint seeds (NGS) on Ehrlich ascites carcinoma in a mouse model. Materials and Methods: Kunming mice with transplanted Ehrlich ascites tumor cells (EAC) were treated with NGS by oral administration. On the 11th day after the EAC implant, mouse thymus, liver, spleen and kidney tumors were removed for histopathological analysis. Blood samples were taken for hematological and biochemical analyses. Results: The results indicate that NGS treatment leads to an increase in TNF-α, IL-1β, and IL-2 blood serum levels. Absence of viable EAC and presence of necrotic cells were observed in the tumor tissue of the NGS-treated animals. Conclusions: The study results indicated that a water extract of NGS had the highest anti-tumor effect. Moreover, NGS treatment also showed an increase in the immune system activity. PMID:23929999

  16. The antitumor effects of methyl-β-cyclodextrin against primary effusion lymphoma via the depletion of cholesterol from lipid rafts.

    PubMed

    Gotoh, Kumiko; Kariya, Ryusho; Alam, Md Masud; Matsuda, Kouki; Hattori, Shinichiro; Maeda, Yuki; Motoyama, Keiichi; Kojima, Akihiro; Arima, Hidetoshi; Okada, Seiji

    2014-12-12

    Primary effusion lymphoma (PEL) is a subtype of aggressive and chemotherapy-resistant non-Hodgkin lymphoma that occurs predominantly in patients with advanced AIDS. In this study, we examined the antitumor activity of methyl-β-cyclodextrin (M-β-CyD) in vitro and in vivo. M-β-CyD quickly induced caspase-dependent apoptosis in PEL cells via cholesterol depletion from the plasma membrane. In a PEL xenograft mouse model, M-β-CyD significantly inhibited the growth and invasion of PEL cells without apparent adverse effects. These results strongly suggest that M-β-CyD has the potential to be an effective antitumor agent against PEL.

  17. The antitumor effects of tetrodotoxin and/or doxorubicin on Ehrlich ascites carcinoma-bearing female mice.

    PubMed

    El-Dayem, Samiha M Abd; Fouda, Fatma M; Ali, Elham H A; Motelp, Bosy A Abd El

    2013-06-01

    The study aimed to investigate the antitumor effect of tetrodotoxin (TTX) and/or doxorubicin (DOX) on Ehrlich ascites carcinoma (EAC)-bearing mice through the investigated biochemical parameters. TTX and/or DOX with or without N-acetylcystiene were administrated after 10 days into EAC-female mice for a period of 2 weeks in six equal doses. Treatment with TTX or DOX caused a significant decrease in the mean tumor weight and an increase in the cumulative mean survival time when compared with EAC group. All the treatments reduced the elevated liver tumor markers and increased liver antioxidant enzymes under investigation in comparison with EAC. Hepatic cells, suffered severely from degeneration and karriolysis in EAC group, revealed some improvement as appearance of healthy hepatocytes by TTX treatment. The present results suggested that TTX had a more powerful inhibitor effect on EAC growth than DOX and TTX plus DOX treatments reflected by antitumor biochemical and histological studies.

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects

    PubMed Central

    Kujawski, Maciej; Zhang, Chunyan; Herrmann, Andreas; Reckamp, Karen; Scuto, Anna; Jensen, Michael; Deng, Jiehui; Forman, Stephen; Figlin, Robert; Yu, Hua

    2010-01-01

    Adoptive cell therapy with engineered T cells to improve natural immune response and antitumor functions has shown promise for treating cancer. However, the requirement for extensive ex vivo manipulation of T cells and the immunosuppressive effects of the tumor microenvironment limit this therapeutic modality. In the present study, we investigated the possibility to circumvent these limitations by engineering Stat3-deficient CD8+ T cells or by targeting Stat3 in the tumor microenvironment. We show that ablating Stat3 in CD8+ T cells prior to their transfer allows their efficient tumor infiltration and robust proliferation, resulting in increased tumor antigen-specific T cell activity and tumor growth inhibition. For potential clinical translation, we combined adoptive T cell therapy with an FDA-approved tyrosine kinase inhibitor, sunitinib, in renal cell carcinoma and melanoma tumor models. Sunitinib inhibited Stat3 in dendritic cells and T cells, reduced conversion of transferred Foxp3− T cells to tumor-associated T regulatory cells while increasing transferred CD8+ T cell infiltration and activation at the tumor site, leading to inhibition of primary tumor growth. These data demonstrate that adoptively transferred T cells can be expanded and activated in vivo either by engineering Stat3 silenced T cells or by targeting Stat3 systemically with small-molecule inhibitors. PMID:21118964

  3. Effective antitumor gene therapy delivered by polyethylenimine-conjugated stearic acid-g-chitosan oligosaccharide micelles.

    PubMed

    Hu, F-Q; Chen, W-W; Zhao, M-D; Yuan, H; Du, Y-Z

    2013-06-01

    Non-viral vesicle composing of low-molecular weight polyethylenimine-conjugated stearic acid-g-chitosan oligosaccharide (CSOSA-g-PEI) was synthesized for gene delivery and therapy. The synthesized CSOSA-g-PEI had good ion-buffer capabilities and DNA-binding capacity, which could form positively charged nano-sized particles (100-150 nm) with plasmid DNA; in vitro gene transfection tests demonstrated that CSOSA-g-PEI presented much lower cytotoxicity and corresponding transfection efficiency in comparison with Lipofectamine 2000 in both human cancer cells (Hela and MCF-7). The gene transfection of CSOSA-g-PEI/pDNA could be further enhanced in the presence of serum or by adding arginine during incubation of CSOSA-g-PEI micelles with plasmid DNA. The biodistribution experiments demonstrated CSOSA-g-PEI conjugate highly localized in the tumor tissue and indicated a persistently increased accumulation. In vivo antitumor activity results showed that CSOSA-g-PEI/plasmid pigment epithelium-derived factor formulation could effectively suppress the tumor growth (above 60% tumor inhibition) without systematic toxicity against animal body after intravenous injection.

  4. 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

  5. The effect of stealth liposomes on pharmacokinetics, tissue distribution and anti-tumor activity of oridonin.

    PubMed

    Wang, Chuanjin; Wei, Yunyang; Yu, Li; Zhang, Liang

    2009-01-01

    High-purity oridonin was isolated and identified from Rabdosia rubescens hemsl by preparative high-performance liquid chromatography (HPLC). Stealth liposomes of oridonin were prepared by thin-film ultrasonic dispersion using polyethylene glycol-distearoylphosphatidyleth-anolamine(PEG2000-DSPE) as the surface-coating material. A reversed-phase HPLC method was developed and validated to determine the concentrations of oridonin in the serum and tissues of mice. The tissue distribution and pharmacokinetics of oridonin stealth liposomes and oridonin solution in mice were investigated. The results showed that the distribution and pharmacokinetics of oridonin stealth liposomes in mice were changed as compared to the distribution and pharmacokinetics of oridonin solution. The levels of stealth liposomal oridonin in the heart tissues were reduced, while the levels of stealth liposomal oridonin in the blood were increased. The stealth liposomes were very effective at inhibiting the rate of solid tumor growth. The PEG2000-DSPE of liposomes prolonged the circulation time of oridonin in mouse blood, reduced accumulation in the reticuloendothelial system and increased the anti-tumor activity of oridonin.

  6. 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.

  7. Improving aqueous solubility and antitumor effects by nanosized gambogic acid-mPEG2000 micelles

    PubMed Central

    Cai, Lulu; Qiu, Neng; Xiang, Mingli; Tong, Rongsheng; Yan, Junfeng; He, Lin; Shi, Jianyou; Chen, Tao; Wen, Jiaolin; Wang, Wenwen; Chen, Lijuan

    2014-01-01

    The clinical application of gambogic acid, a natural component with promising antitumor activity, is limited due to its extremely poor aqueous solubility, short half-life in blood, and severe systemic toxicity. To solve these problems, an amphiphilic polymer-drug conjugate was prepared by attachment of low molecular weight (ie, 2 kDa) methoxy poly(ethylene glycol) methyl ether (mPEG) to gambogic acid (GA-mPEG2000) through an ester linkage and characterized by 1H nuclear magnetic resonance. The GA-mPEG2000 conjugates self-assembled to form nanosized micelles, with mean diameters of less than 50 nm, and a very narrow particle size distribution. The properties of the GA-mPEG2000 micelles, including morphology, stability, molecular modeling, and drug release profile, were evaluated. MTT (3-(4,5-dimethylthiazo l-2-yl)-2,5 diphenyl tetrazolium bromide) tests demonstrated that the GA-mPEG2000 micelle formulation had obvious cytotoxicity to tumor cells and human umbilical vein endothelial cells. Further, GA-mPEG2000 micelles were effective in inhibiting tumor growth and prolonged survival in subcutaneous B16-F10 and C26 tumor models. Our findings suggest that GA-mPEG2000 micelles may have promising applications in tumor therapy. PMID:24403830

  8. 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

  9. Additive effects on lubricant fuel economy

    SciTech Connect

    Kennedy, S.; Moore, L.D.

    1987-01-01

    Bench and engine tests were used to determine the effects of typical lubricating oil components on the fuel economy performance of energy conserving oils. The bench studies identified negative fuel economy effects of zinc dialkyldithiophosphates and positive effects of overbased sulfonates. The Sequence VI dynamometer test quantified viscometric influences on fuel economy; results indicated that SAE 5W-30 oils are not always more fuel efficient than 10W-30 analogs, and that viscosity index improver type has a large impact on fuel economy. These effects were integrated with additive effects on other formulation criteria to design an overall system.

  10. 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

  11. 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.

  12. Combination of bubble liposomes and high-intensity focused ultrasound (HIFU) enhanced antitumor effect by tumor ablation.

    PubMed

    Hamano, Nobuhito; Negishi, Yoichi; Takatori, Kyohei; Endo-Takahashi, Yoko; Suzuki, Ryo; Maruyama, Kazuo; Niidome, Takuro; Aramaki, Yukihiko

    2014-01-01

    Ultrasound (US) is used in the clinical setting not only for diagnosis but also for therapy. As a therapeutic US technique, high-intensity focused ultrasound (HIFU) can be applied to treat cancer in a clinical setting. Microbubbles increased temperature and improved the low therapeutic efficiency under HIFU; however, microbubbles have room for improvement in size, stability, and targeting ability. To solve these issues, we reported that "Bubble liposomes" (BLs) containing the US imaging gas (perfluoropropane gas) liposomes were suitable for ultrasound imaging and gene delivery. In this study, we examined whether BLs and HIFU could enhance the ablation area of the tumor and the antitumor effect. First, we histologically analyzed the tumor after BLs and HIFU. The ablation area of the treatment of BLs and HIFU was broader than that of HIFU alone. Next, we monitored the temperature of the tumor, and examined the antitumor effect. The temperature increase with BLs and HIFU treatment was faster and higher than that with HIFU alone. Moreover, treatment with BLs and HIFU enhanced the antitumor effect, which was better than with HIFU alone. Thus, the combination of BLs and HIFU could be efficacious for cancer therapy.

  13. Transient Low Doses of DNA Demethylating Agents Exert Durable Anti-tumor Effects on Hematological and Epithelial Tumor Cells

    PubMed Central

    Tsai, Hsing-Chen; Li, Huili; Van Neste, Leander; Cai, Yi; Robert, Carine; Rassool, Feyruz V.; Shin, James J.; Harbom, Kirsten M.; Beaty, Robert; Pappou, Emmanouil; Harris, James; Yen, Ray-Whay Chiu; Ahuja, Nita; Brock, Malcolm V.; Stearns, Vered; Feller-Kopman, David; Yarmus, Lonny B.; Lin, Yi-Chun; Welm, Alana L.; Issa, Jean-Pierre; Minn, Il; Matsui, William; Jang, Yoon-Young; Sharkis, Saul J.; Baylin, Stephen B.; Zahnow, Cynthia A.

    2012-01-01

    SUMMARY Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically-relevant nanomolar doses, without causing immediate cytotoxicity, produce an anti-tumor “memory” response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genome-wide promoter DNA methylation, gene re-expression, and anti-tumor changes in key cellular regulatory pathways. Low dose decitabine and azacitidine may have broad applicability for cancer management. PMID:22439938

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

    PubMed

    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.

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

    PubMed

    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.

  16. Effect of additives on protein aggregation.

    PubMed

    Hamada, Hiroyuki; Arakawa, Tsutomu; Shiraki, Kentaro

    2009-06-01

    This paper overviews solution additives that affect protein stability and aggregation during refolding, heating, and freezing processes. Solution additives are mainly grouped into two classes, i.e., protein denaturants and stabilizers. The former includes guanidine, urea, strong ionic detergents, and certain chaotropic salts; the latter includes certain amino acids, sugars, polyhydric alcohols, osmolytes, and kosmotropic salts. However, there are solution additives that are not unambiguously placed into these two classes, including arginine, certain divalent cation salts (e.g., MgCl(2)) and certain polyhydric alcohols (e.g., ethylene glycol). Certain non-ionic or non-detergent surfactants, ionic liquids, amino acid derivatives, polyamines, and certain amphiphilic polymers may belong to this class. They have marginal effects on protein structure and stability, but are able to disrupt protein interactions. Information on additives that do not catalyze chemical reactions nor affect protein functions helps us to design protein solutions for increased stability or reduced aggregation. PMID:19519415

  17. Antitumor Effects of a Sirtuin Inhibitor, Tenovin-6, against Gastric Cancer Cells via Death Receptor 5 Up-Regulation

    PubMed Central

    Hirai, Sachiko; Endo, Shinji; Saito, Rie; Hirose, Mitsuaki; Ueno, Takunori; Suzuki, Hideo; Yamato, Kenji; Abei, Masato; Hyodo, Ichinosuke

    2014-01-01

    Up-regulated sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53). Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5). In the KatoIII cell line (TP53-null), DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors. PMID:25033286

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

    PubMed

    Hirai, Sachiko; Endo, Shinji; Saito, Rie; Hirose, Mitsuaki; Ueno, Takunori; Suzuki, Hideo; Yamato, Kenji; Abei, Masato; Hyodo, Ichinosuke

    2014-01-01

    Up-regulated sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53). Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5). In the KatoIII cell line (TP53-null), DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors. PMID:25033286

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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

  6. Antiangiogenic activity and direct antitumor effect from a sulfated polysaccharide isolated from seaweed.

    PubMed

    Guerra Dore, Celina Maria P; Faustino Alves, Monique Gabriela C; Santos, Nednaldo D; Cruz, Ana Katarina M; Câmara, Rafael Barros G; Castro, Allisson Jonathan G; Guimarães Alves, Luciana; Nader, Helena B; Leite, Edda Lisboa

    2013-07-01

    Angiogenesis is a dynamic proliferation and differentiation process. It requires endothelial proliferation, migration and tube formation. In this context, endothelial cells are a preferred target for several studies and therapies. Anionic polysaccharides (SV1 and PSV1) from brown seaweed Sargassum vulgare were fractionated (SV1), purified (PSV1) and displayed with high total sugars, sulfate content and very low level of protein. The antiangiogenic efficacy of polysaccharides was examined in vivo in the chick chorioallantoic membrane (CAM) model by using fertilized eggs. Decreases in the density of the capillaries were assessed and scored. The results showed that SV1 and PSV1 have an inhibitory effect on angiogenesis. These results were also confirmed by the inhibition of tubulogenesis in rabbit aorta endothelial cell (RAEC) in matrigel. These compounds were assessed in an apoptosis assay (Annexin V-FITC/PI) and cell viability by MTT assay of RAEC. These polysaccharides did not affect the viability and did not have apoptotic or necrotic action. RAEC cell when incubated with SV1and PSV1 showed inhibition of VEGF secretion, observed when compounds were incubated at 25, 50 and 100 μg/μL. The VEGF secretion with the RAEC cell line for 24 h was more effective for PSV1 at 50 μg/μL (71.4%) than for SV1 at 100 μg/μL (75.9%). SV1 and PSV1 had an antiproliferative action (47%) against tumor cell line HeLa. Our results indicate that these sulfated polysaccharides have antiangiogenic and antitumor actions. PMID:23507505

  7. 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.

  8. Multilineage hematopoietic recovery with concomitant antitumor effects using low dose Interleukin-12 in myelosuppressed tumor-bearing mice

    PubMed Central

    Basile, Lena A; Gallaher, Timothy K; Shibata, Darryl; Miller, Joseph D; Douer, Dan

    2008-01-01

    Background Interleukin-12 (IL-12) is a cytokine well known for its role in immunity. A lesser known function of IL-12 is its role in hematopoiesis. The promising data obtained in the preclinical models of antitumor immunotherapy raised hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity, largely due to repeat dose regimens, and modest clinical response observed in the clinical trials have pointed to the necessity to design protocols that minimize toxicity without affecting the anti-tumor effect of IL-12. We have focused on the lesser known role of IL-12 in hematopoiesis and hypothesized that an important clinical role for IL-12 in cancer may be as an adjuvant hematological cancer therapy. In this putative clinical function, IL-12 is utilized for the prevention of cancer therapy-related cytopenias, while providing concomitant anti-tumor responses over and above responses observed with the primary therapy alone. This putative clinical function of IL-12 focuses on the dual role of IL-12 in hematopoiesis and immunity. Methods We assessed the ability of IL-12 to facilitate hematopoietic recovery from radiation (625 rad) and chemotherapy (cyclophosphamide) in two tumor-bearing murine models, namely the EL4 lymphoma and the Lewis lung cancer models. Antitumor effects and changes in bone marrow cellularity were also assessed. Results We show herein that carefully designed protocols, in mice, utilizing IL-12 as an adjuvant to radiation or chemotherapy yield facile and consistent, multilineage hematopoietic recovery from cancer therapy-induced cytopenias, as compared to vehicle and the clinically-utilized cytokine granulocyte colony-stimulating factor (G-CSF) (positive control), while still providing concomitant antitumor responses over and above the effects of the primary therapy alone. Moreover, our protocol design utilizes single, low doses of IL-12 that did not yield any apparent toxicity. Conclusion Our results

  9. Antitumor and immunomodulatory effects of weikangfu granule compound in tumor-bearing mice

    PubMed Central

    Nie, Xiaohua; Shi, Baojun; Ding, Yuting; Tao, Wenyi

    2006-01-01

    Background: Weikangfu granule compound (WKC) is a drug preparation based on a clinical prescription drug, Weikangfu-tang, which has been found to have therapeutic effects on gastric cancer. WKC comprises 7 components, including polysaccharides, saponin, flavonoids, and essential oil. Objective: The purpose of this study was to assess the antitumor and immunomodulatory effects of WKC in a tumor-bearing rodent model. Methods: Male and female Kuming mice weighing ∼20 g were subcutaneously implanted with sarcoma 180 (S180) tumor cells and randomly assigned to 1 of 5 treatment groups: oral WKC 175, 350, or 525 mg/kg·d, isotonic saline (negative control), or intraperitoneal cyclophosphamide 25 mg/kg·d (positive control). All treatments were administered daily for 10 days. After euthanization on day 11, the mice, tumors, and spleens were weighed. Lymphocyte proliferation and cytotoxic T lymphocyte (CTL) activity were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cellular viability assay method. Macrophage phagocytosis was identified using a yeast test. Results: Fifty mice were included in the study (10 mice were assigned to each group). The tumors of the mice administered WKC 175, 350, and 525 mg/kg·d were significantly regressed, as determined using MICs, compared with those in the negative-control group (P<0.05, P<0.01, and P<0.01, respectively), and the inhibitory rates were 30.43%, 46.72%, and 54.35%, respectively. Compared with those in the negative-control group, CTL activities and lymphocyte proliferations in the presence of concanavalin A were significantly greater in the WKC-treated groups at all doses (CTL activities: P<0.05, P<0.01, and P<0.01, respectively; lymphocyte proliferations: P<0.05, P<0.01, and P<0.01, respectively). In the groups receiving WKC 175, 350, and 525 mg/kg·d, the phagocytic rates were 1.5- to 2.0-fold those in the negative-control group (P<0.05, P<0.01, and P<0.01, respectively). In the groups

  10. Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma.

    PubMed

    Di Marzo, Domenico; Forte, Iris Maria; Indovina, Paola; Di Gennaro, Elena; Rizzo, Valeria; Giorgi, Francesca; Mattioli, Eliseo; Iannuzzi, Carmelina Antonella; Budillon, Alfredo; Giordano, Antonio; Pentimalli, Francesca

    2014-01-01

    Malignant mesothelioma, a very aggressive tumor associated to asbestos exposure, is expected to increase in incidence, and unfortunately, no curative modality exists. Reactivation of p53 is a new attractive antitumoral strategy. p53 is rarely mutated in mesothelioma, but it is inactivated in most tumors by the lack of p14(ARF). Here, we evaluated the feasibility of this approach in pleural mesothelioma by testing RITA and nutlin-3, two molecules able to restore p53 function through a different mechanism, on a panel of mesothelioma cell lines representing the epithelioid (NCI-H28, NCI-H2452, IST-MES 2), biphasic (MSTO-211H), and sarcomatoid (NCI-H2052) histotypes compared with the normal mesothelial HMC-hTERT. RITA triggered robust caspase-dependent apoptosis specifically in epithelioid and biphasic mesothelioma cell lines, both through wild-type and mutant p53, concomitant to p21 downregulation. Conversely, nutlin-3 induced a p21-dependent growth arrest, rather than apoptosis, and was slightly toxic on HMC-hTERT.   Interestingly, we identified a previously undetected point mutation of p53 (p.Arg249Ser) in IST-MES 2, and showed that RITA is also able to reactivate this p53 mutant protein and its apoptotic function. RITA reduced tumor growth in a MSTO-211H-derived xenograft model of mesothelioma and synergized with cisplatin, which is the mainstay of treatment for this tumor. Our data indicate that reactivation of p53 and concomitant p21 downregulation effectively induce cell death in mesothelioma, a tumor characterized by a high intrinsic resistance to apoptosis. Altogether, our findings provide the preclinical framework supporting the use of p53-reactivating agents alone, or in combination regimens, to improve the outcome of patients with mesothelioma.

  11. Effect of anti-tumor necrosis factor alpha antibodies on histopathology of primary Salmonella infections.

    PubMed

    Mastroeni, P; Skepper, J N; Hormaeche, C E

    1995-09-01

    We reported that administration of anti-tumor necrosis factor alpha (anti-TNF-alpha) antibodies exacerbates the course of a Salmonella infection in both susceptible and resistant mice by preventing the suppression of bacterial growth in the reticuloendothelial system. In the present study, we evaluated the effect of in vivo neutralization of TNF-alpha on the histopathology of primary Salmonella infections. We show that in primary infections, the suppression of bacterial growth in the reticuloendothelial system coincides with granuloma formation in the spleen and liver. Administration of anti-TNF-alpha globulins on day -1 of salmonellosis affected neither the histological picture nor the course of the infection in the early stages of the disease (days 1 to 3), with splenic and hepatic lesions consisting mainly of polymorphonuclear leukocytes (PMNs); conversely, later in infection (days 3 to 7), the treatment inhibited the formation of granulomas. When the anti-TNF-alpha treatment was started well after the suppression of bacterial growth in the reticuloendothelial system and the formation of granulomatous lesions in the spleen and liver, a prompt relapse of the infection and regression of already established granulomas were seen. In anti-TNF-alpha-treated mice, salmonellae were found inside macrophages and PMNs and extracellularly in the necrotic tissue of the spleen, while in the liver the organisms were seen mainly in inflammatory mononuclear cells, resident Kupffer cells, and hepatocytes and occasionally in the extracellular compartment within necrotic lesions. The bacteria appeared most often in clusters, being morphologically intact when in the extracellular space or within hepatocytes, while undergoing various degrees of degeneration when inside phagocytes. The results suggest that TNF-alpha is required for granuloma formation in salmonellosis and that its neutralization does not completely abrogate the bactericidal activity of macrophages and PMNs

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. Abscopal antitumor immune effects of magnet-mediated hyperthermia at a high therapeutic temperature on Walker-256 carcinosarcomas in rats

    PubMed Central

    WANG, HUI; ZHANG, LI; SHI, YINGRUI; JAVIDIPARSIJANI, SARA; WANG, GUIRONG; LI, XIAO; OUYANG, WEIWEI; ZHOU, JUMEI; ZHAO, LINGYUN; WANG, XIAOWEN; ZHANG, XIAODONG; GAO, FUPING; LIU, JINGSHI; LUO, JUNMING; TANG, JINTIAN

    2014-01-01

    The abscopal effect has previously been described in various tumors and is associated with radiation therapy and hyperthermia, with possible underlying mechanisms explaining each observed case. In the present study, we aimed to investigate the antitumor effects of magnet-mediated hyperthermia on Walker-256 carcinosarcomas in rats at two different temperature ranges (42–46°C and 50–55°C). We also aimed to identify whether a higher therapeutic temperature of magnetic-mediated hyperthermia improves the abscopal antitumor effects, where localised irradiation of the tumor causes not only the irradiated tumor to shrink, but also tumors located far from the area of irradiation. Following induction of carcinosarcoma in both sides of the body, magnet-mediated hyperthermia was applied to one side only, leaving the other side as a control. The changes in tumor growth were observed. Our results demonstrated that magnet-mediated hyperthermia at a higher temperature inhibited the growth of carcinosarcoma at the site of treatment. Furthermore, the growth of the carcinosarcoma on the untreated side was also inhibited. The expression levels of proliferating cell nuclear antigen were decreased in the hyperthermia group, which was more significant in the higher temperature test group. Flow cytometric analysis showed an increased number of CD4- and CD8-positive T cells, and enzyme-linked immunosorbent assay showed increased levels of interferon-γ and interleukin-2 in the higher temperature group. These results suggested that magnet-mediated hyperthermia at a higher temperature (50–55°C) can improve the abscopal antitumor effects and stimulate a greater endogenous immune response in carcinosarcoma-bearing rats. PMID:24527084

  17. 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

  18. Abscopal antitumor immune effects of magnet-mediated hyperthermia at a high therapeutic temperature on Walker-256 carcinosarcomas in rats.

    PubMed

    Wang, Hui; Zhang, Li; Shi, Yingrui; Javidiparsijani, Sara; Wang, Guirong; Li, Xiao; Ouyang, Weiwei; Zhou, Jumei; Zhao, Lingyun; Wang, Xiaowen; Zhang, Xiaodong; Gao, Fuping; Liu, Jingshi; Luo, Junming; Tang, Jintian

    2014-03-01

    The abscopal effect has previously been described in various tumors and is associated with radiation therapy and hyperthermia, with possible underlying mechanisms explaining each observed case. In the present study, we aimed to investigate the antitumor effects of magnet-mediated hyperthermia on Walker-256 carcinosarcomas in rats at two different temperature ranges (42-46°C and 50-55°C). We also aimed to identify whether a higher therapeutic temperature of magnetic-mediated hyperthermia improves the abscopal antitumor effects, where localised irradiation of the tumor causes not only the irradiated tumor to shrink, but also tumors located far from the area of irradiation. Following induction of carcinosarcoma in both sides of the body, magnet-mediated hyperthermia was applied to one side only, leaving the other side as a control. The changes in tumor growth were observed. Our results demonstrated that magnet-mediated hyperthermia at a higher temperature inhibited the growth of carcinosarcoma at the site of treatment. Furthermore, the growth of the carcinosarcoma on the untreated side was also inhibited. The expression levels of proliferating cell nuclear antigen were decreased in the hyperthermia group, which was more significant in the higher temperature test group. Flow cytometric analysis showed an increased number of CD4- and CD8-positive T cells, and enzyme-linked immunosorbent assay showed increased levels of interferon-γ and interleukin-2 in the higher temperature group. These results suggested that magnet-mediated hyperthermia at a higher temperature (50-55°C) can improve the abscopal antitumor effects and stimulate a greater endogenous immune response in carcinosarcoma-bearing rats.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. Mechanism responsible for the antitumor effect of BCG-CWS using the LEEL method in a mouse bladder cancer model.

    PubMed

    Nakamura, Takashi; Fukiage, Masafumi; Suzuki, Yoshiteru; Yano, Ikuya; Miyazaki, Jun; Nishiyama, Hiroyuki; Akaza, Hideyuki; Harashima, Hideyoshi

    2014-12-28

    We previously reported on the development of a water soluble formulation of the cell wall skeleton of BCG (BCG-CWS), a major immune active center of BCG, by encapsulating it into a nanoparticle (CWS-NP). The CWS-NP allowed us to clarify the machinery associated with the BCG mediated anti-bladder tumor effect, especially the roles of bladder cancer cells and dendritic cells (DCs) in the initial step, which remains poorly understood. We show herein that the internalization of BCG-CWS by bladder cancer cells, but not DCs, is indispensable for the induction of an antitumor effect against bladder cancer. Tumor growth was significantly inhibited in mice that had been inoculated with mouse bladder cancer (MBT-2) cells containing internalized BCG-CWS. On the other hand, the internalization of BCG-CWS by DCs had only a minor effect on inducing an antitumor effect against MBT-2 tumors. This was clarified for the first time by using the CWS-NP. This finding provides insights into our understanding of the role of bladder cancer cells and DCs in BCG therapy against bladder cancer.

  4. In vitro Anti-Tumor Effects of Statins on Head and Neck Squamous Cell Carcinoma: A Systematic Review

    PubMed Central

    Pavan, Ludmila Madeira Cardoso; Rêgo, Daniela Fortunato; Elias, Silvia Taveira; De Luca Canto, Graziela; Guerra, Eliete Neves Silva

    2015-01-01

    Background Statins are commonly used against arteriosclerotic disease, but recent retrospective analyses have suggested that statins also prevent cancer. The aim of this systematic review is to verify the vitro anti-tumor effects of statins on head and neck squamous cell carcinoma. Methods Studies were gathered by searching Cochrane, MEDLINE, EMBASE, LILACS, and PubMed, up until May 9, 2015, with no time or language restrictions. Only in vitro studies that discuss the effect of statins on head and neck carcinoma were selected. Results Of 153 identified papers, 14 studies met the inclusion criteria. These studies demonstrated that statins had a significant effect on head and neck squamous cell carcinoma cell lines and influenced cell viability, cell cycle, cell death, and protein expression levels involved in pathways of carcinogenesis, which corroborates with the potential in vitro anti-tumor effects. It provides highlights about the biological mechanisms of statins used alone or associated with traditional therapy for cancer. Conclusions Though there are few studies on the topic, currently available evidence suggests that statins shows that preclinical experiments supports the potentiality of statin as an adjuvant agent in chemotherapy and/or radiotherapy approaches routinely used in the management of HNSCC and should undergo further clinical assessment. PMID:26098683

  5. 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

  6. 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.

  7. 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.

  8. The Fruit Hull of Gleditsia sinensis Enhances the Anti-Tumor Effect of cis-Diammine Dichloridoplatinum II (Cisplatin)

    PubMed Central

    Han, Chang-Woo; Yoon, Seong Hoon; Kim, Yun Seong; Kim, Jong-In

    2016-01-01

    Lung cancer has substantial mortality worldwide, and chemotherapy is a routine regimen for the treatment of patients with lung cancer, despite undesirable effects such as drug resistance and chemotoxicity. Here, given a possible antitumor effect of the fruit hull of Gleditsia sinensis (FGS), we tested whether FGS enhances the effectiveness of cis-diammine dichloridoplatinum (II) (CDDP), a chemotherapeutic drug. We found that CDDP, when administered with FGS, significantly decreased the viability and increased the apoptosis and cell cycle arrest of Lewis lung carcinoma (LLC) cells, which were associated with the increase of p21 and decreases of cyclin D1 and CDK4. Concordantly, when combined with FGS, CDDP significantly reduced the volume and weight of tumors derived from LLC subcutaneously injected into C57BL/6 mice, with concomitant increases of phosphor-p53 and p21 in tumor tissue. Together, these results show that FGS could enhance the antitumor activity of CDDP, suggesting that FGS can be used as a complementary measure to enhance the efficacy of a chemotherapeutic agent such as CDDP. PMID:27721894

  9. Synergistic antitumor effects of 131I-LC-1 IgM and IL-12 vaccine on Lewis lung carcinoma.

    PubMed

    Yin, Xiao Ling; Yan, Xuexian; Wen, Ming; Peng, Zhi Ping; Li, Shao Lin

    2010-03-01

    This study was designed to determine the antitumor effects of iodine-131 labeled monoclonal antibody LC-1 ((131)I-LC-1), interleukin-12 (IL-12) vaccine, or the combination of both on C57BL/6 mice bearing Lewis lung carcinoma (LLC) tumors. Tumor-bearing mice models were randomly divided into 4 groups that were respectively injected intratumorally with phosphate buffered solution (PBS), IL-12 vaccine gene therapy (GT), (131)I-LC-1 radioimmuno-therapy (RIT), or GT+RIT. Tumor volumes were measured before and after treatment. ELISA and RT-PCR determined the expression of IL-l2. LC-1 monoclonal antibody (Mab) was labeled with Na(131)I. Cytolytic T lymphocyte (CTL) activity assay, Natural Killer cell (NK) activity assay and apoptosis analysis were performed. Intratumoral (131)I-LC-1 injection leads to higher delivery of the antibody to the tumor. Tumor apoptosis occurred in the GT, RIT and GT+RIT groups. Tumor growth was inhibited in the GT, RIT and GT+RIT groups. Compared with other groups, the combination of GT+RIT up-regulated the expression of IL-l2 gene and inhibited the tumor growth more effectively than either GT or RIT alone (p<0.05). These results suggest that GT+RIT have the synergistic antitumor effects on tumor-bearing mice.

  10. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice.

    PubMed

    Wang, Zili; Celis, Esteban

    2015-08-01

    Therapeutic vaccines to induce anti-tumor CD8 T cells have been used in clinical trials for advanced melanoma patients, but the clinical response rate and overall survival time have not improved much. We believe that these dismal outcomes are caused by inadequate number of antigen-specific CD8 T cells generated by most vaccines. In contrast, huge CD8 T cell responses readily occur during acute viral infections. High levels of type-I interferon (IFN-I) are produced during these infections, and this cytokine not only exhibits anti-viral activity but also promotes CD8 T cell responses. The studies described here were performed to determine whether promoting the production of IFN-I could enhance the potency of a peptide vaccine. We report that cyclic diguanylate monophosphate (c-di-GMP), which activates the stimulator of interferon genes, potentiated the immunogenicity and anti-tumor effects of a peptide vaccine against mouse B16 melanoma. The synergistic effects of c-di-GMP required co-administration of costimulatory anti-CD40 antibody, the adjuvant poly-IC, and were mediated in part by IFN-I. These findings demonstrate that peptides representing CD8 T cell epitopes can be effective inducers of large CD8 T cell responses in vaccination strategies that mimic acute viral infections.

  11. The anti-tumor effect of resveratrol alone or in combination with immunotherapy in a neuroblastoma model.

    PubMed

    Soto, Brenda L; Hank, Jacquelyn A; Van De Voort, Tyler J; Subramanian, Lalita; Polans, Arthur S; Rakhmilevich, Alexander L; Yang, Richard K; Seo, Songwong; Kim, KyungMann; Reisfeld, Ralph A; Gillies, Stephen D; Sondel, Paul M

    2011-05-01

    We investigated the anti-tumor effect of peritumoral resveratrol in combination with immunotherapy in vivo in neuroblastoma-bearing mice. Subcutaneous NXS2 tumors were induced in A/J mice. On day 10, some mice received 15 mcg of intravenous immunocytokine for 5 days, mice received 20 mg of peritumoral resveratrol twice a week (starting on day 12) for a total of 5 injections, and a separate group received a combination of both regimens. Tumor progression and survival were assessed every 3-4 days. Blood and primary tumor tissue samples were collected on day 20 for Complete Blood Count and CD45 immunohistochemistry and histology, respectively. The primary tumor regressed in all mice receiving peritumoral resveratrol. Most of these mice receiving peritumoral resveratrol alone developed metastatic tumors and recurrence of the primary tumor after cessation of therapy. When resveratrol and immunocytokine regimens were combined, 61% of the mice receiving this combination therapy resolved their primary tumors and survived without developing metastatic tumors, compared to 15 and 13% receiving resveratrol or immunocytokine alone, respectively. None of the therapeutic regimes prevented lymphocyte infiltration or affected the complete blood count. Greater necrosis was observed microscopically in tumors from mice receiving the combination therapy. These results demonstrate that the combination therapy of peritumoral resveratrol plus intravenous immunocytokine provides better anti-tumor effects in this model than either therapy alone.

  12. 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

  13. 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

  14. 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.

  15. Enhanced anti-tumor effect of a gene gun-delivered DNA vaccine encoding the human papillomavirus type 16 oncoproteins genetically fused to the herpes simplex virus glycoprotein D.

    PubMed

    Diniz, M O; Ferreira, L C S

    2011-05-01

    Anti-cancer DNA vaccines have attracted growing interest as a simple and non-invasive method for both the treatment and prevention of tumors induced by human papillomaviruses. Nonetheless, the low immunogenicity of parenterally administered vaccines, particularly regarding the activation of cytotoxic CD8+ T cell responses, suggests that further improvements in both vaccine composition and administration routes are still required. In the present study, we report the immune responses and anti-tumor effects of a DNA vaccine (pgD-E7E6E5) expressing three proteins (E7, E6, and E5) of the human papillomavirus type 16 genetically fused to the glycoprotein D of the human herpes simplex virus type 1, which was administered to mice by the intradermal (id) route using a gene gun. A single id dose of pgD-E7E6E5 (2 µg/dose) induced a strong activation of E7-specific interferon-γ (INF-γ)-producing CD8+ T cells and full prophylactic anti-tumor effects in the vaccinated mice. Three vaccine doses inhibited tumor growth in 70% of the mice with established tumors. In addition, a single vaccine dose consisting of the co-administration of pgD-E7E6E5 and the vector encoding interleukin-12 or granulocyte-macrophage colony-stimulating factor further enhanced the therapeutic anti-tumor effects and conferred protection to 60 and 50% of the vaccinated mice, respectively. In conclusion, id administration of pgD-E7E6E5 significantly enhanced the immunogenicity and anti-tumor effects of the DNA vaccine, representing a promising administration route for future clinical trials.

  16. 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

  17. 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

  18. Efficient presentation of naturally processed HLA class I peptides by artificial antigen-presenting cells for the generation of effective antitumor responses.

    PubMed

    Hirano, Naoto; Butler, Marcus O; Xia, Zhinan; Berezovskaya, Alla; Murray, Andrew P; Ansén, Sascha; Nadler, Lee M

    2006-05-15

    Appropriate presentation of tumor-associated antigens (TAA) by antigen-presenting cells (APC) is required for the development of clinically relevant antitumor T-cell responses. One common approach, which uses APC pulsed with synthetic peptides, can sometimes generate ineffective immune responses. This failure may, in part, be attributed to the formation of HLA/synthetic pulsed peptide complexes that possess different conformations compared with those of endogenously presented peptides. In addition, endogenous peptides may undergo post-translational modifications, which do not occur with synthetic peptides. Because our goal is to induce immunity that can recognize TAA that are endogenously presented by tumors, we designed an APC that would not only express the required immunoaccessory molecules but also naturally process and present target antigenic peptides. In this study, we generated an artificial APC (aAPC) that can endogenously present any chosen HLA-A*0201 (A2)-restricted peptide by processing a fusion protein that contains a unique "LTK" sequence linked to the antigenic peptide. Proteasome-dependent processing is so effective that the presented peptide can be directly eluted from the cell surface and identified by biochemical methods. Furthermore, we found that aAPC, engineered to endogenously present peptide derived from the melanoma antigen MART1, can be used to prime and expand antitumor CTL that target MART1-expressing tumor cells in a HLA-A2-restricted manner. Our engineered aAPC could serve as an "off-the-shelf" APC designed to constitutively express class I-restricted TAA peptides and could be used to generate effective T-cell responses to treat human disease. PMID:16707591

  19. Honokiol exhibits enhanced antitumor effects with chloroquine by inducing cell death and inhibiting autophagy in human non-small cell lung cancer cells.

    PubMed

    Lv, Xiaoqin; Liu, Fang; Shang, Yue; Chen, Shu-Zhen

    2015-09-01

    Honokiol (HNK), a potential antitumor compound, has been widely studied in recent years. It induces apoptosis and affects autophagy in cancer cells, yet the mechanism of its antitumor efficacy remains obscure. Chloroquine (CQ), an autophagy inhibitor, is often applied to sensitize antitumor drugs in clinical trials. Here, we investigated the antitumor effect of HNK or CQ alone or in combination in non-small cell lung cancer (NSCLC) cells. Using an experimental approach, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) or sulforhodamine B (SRB) was used to determine the cytotoxicity of the agents. The expression levels of proteins were detected by western blotting. Apoptosis was examined via Annexin V-FITC and PI staining. H460 cell xenografts in nude mice were used to study the effects of HNK and/or CQ in vivo. Transfection with siRNA was applied to knock down cathepsin D. The results demonstrated the enhanced effects of HNK combined with CQ on the inhibition of proliferation, induction of apoptosis in vitro and the reduction in growth in vivo. It was confirmed that HNK and/or CQ triggered apoptosis via a caspase-dependent manner. Furthermore, HNK significantly increased the expression of p62 and LC3-Ⅱ in the A549 and H460 cells and inhibited autophagy and induced apoptosis in a cathepsin D-involved manner. In conclusion, an enhanced antitumor effect was demonstrated following treatment with HNK combined with CQ by inhibiting autophagy and inducing apoptosis via a caspase-dependent and cathepsin D-involved manner. This combination may be a novel and useful antitumor approach for chemotherapy in NSCLC. PMID:26136140

  20. A tumor lysate is an effective vaccine antigen for the stimulation of CD4+ T-cell function and subsequent induction of antitumor immunity mediated by CD8+ T cells

    PubMed Central

    Kawahara, Mamoru; Takaku, Hiroshi

    2015-01-01

    To develop a potent cancer vaccine, it is important to study how to prepare highly immunogenic antigens and to identify the most appropriate adjuvants for the antigens. Here we show that a tumor lysate works as an effective antigen to prime CD4+ T-cell help when baculovirus is employed as an adjuvant. When immunized intradermally with the combination (BLP) of baculovirus, a CT26 tumor lysate, and a cytotoxic T-cell epitope peptide before a tumor challenge, 60% of mice rejected tumors. In contrast, all mice vaccinated with baculovirus plus a tumor lysate (BL) developed tumors. In addition, flow cytometry showed that tumor-specific, interferon γ-producing CD8+ cytotoxic T lymphocytes (CTLs) were robustly activated by intradermal immunization with BLP. When BLP was administered therapeutically to tumor-bearing mice, antitumor efficacy was better compared to BL. The established tumor was completely eradicated in 50–60% of BLP-treated mice, and induction of tumor-specific CTLs was observed, suggesting that the antitumor efficacy of BLP is mediated by CD8+ T cells. Numerous CD4+ T cells infiltrated the tumors of BLP-treated mice, whereas the antitumor effect of BLP almost disappeared after removal of the tumor lysate from BLP or after depletion of BLP-immunized mice of CD4+ T cells. Thus, the combination of a peptide, lysate, and baculovirus provides stronger antitumor immunity than does a peptide plus baculovirus or a lysate plus baculovirus; effectiveness of BLP is determined by functioning of CD4+ T cells stimulated with a tumor lysate. PMID:26391871

  1. Anti-tumor Effects of Exo- and Endo-biopolymers Produced from Submerged Cultures of Three Different Mushrooms

    PubMed Central

    Jeong, Yong-Tae; Yang, Byung-Keun; Li, Chun-ru

    2008-01-01

    The anti-tumor effects of exo- (EX) and endo-biopolymers (EN) produced from submerged mycelial cultures of Ganoderma applanatum (GA), Collybia confluens (CC), and Pleurotus eryngii (PE) were studied using Sarcoma 180 bearing mice. Solid tumor growth was inhibited most effectively when 40 mg/kg body weight (BW) of GA-EX or PE-EN was administered to the intraperitoneal (i.p.) cavity of BALB/c mice. The spleen and liver indexes were increased in mice following i.p. administration of GA-EX and PE-EN fractions. GA-EX and PE-EN reduced the tumor formation by 30.7% and 29.4%, respectively. GA-EX and PE-EN increased the natural killer (NK) cell activity of splenocytes by 41.3% and 28.9%, respectively. PMID:23990743

  2. Endostatin enhances antitumor effect of tumor antigen-pulsed dendritic cell therapy in mouse xenograft model of lung carcinoma

    PubMed Central

    Liang, Jing; Liu, Xiaolin; Xie, Qi; Chen, Guoling; Li, Xingyu; Jia, Yanrui; Yin, Beibei; Qu, Xun; Li, Yan

    2016-01-01

    Objective To investigate the antitumor effect of endostatin combined with tumor antigen-pulsed dendritic cell (DC)-T cell therapy on lung cancer. Methods Transplanted Lewis lung cancer (LLC) models of C57BL/6 mice were established by subcutaneous injection of LLC cells in left extremity axillary. Tumor antigen-pulsed DC-T cells from spleen cells and bone of mice were cultured in vitro. Tumor-bearing mice were randomly divided into three groups, including DC-T+endostatin group, DC-T group, and phosphate-buffered saline (PBS) control group. Microvessel density (MVD) of tumor tissue in tumor-bearing mice was determined by immunohistochemistry (IHC). The expressions of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) were determined by Western blotting and IHC staining. The proportions of CD8+ T cells, mature dendritic cells (mDC), tumor-associated macrophages [TAM (M1/M2)], and myeloid-derived suppressor cells (MDSC) in suspended cells of tumor tissue were determined by flow cytometry. The expressions of interleukin (IL)-6, IL-10, IL-17, transforming growth factor-β (TGF-β) and interferon-γ (IFN-γ) in suspended cells of tumor tissue were detected by enzyme-linked immune sorbent assay (ELISA). Results DC-T cells combined with endostatin remarkably suppressed tumor growth. MVD of mice in DC-T+endostatin group was significantly lower than that of the control group and DC-T monotherapy group. The expressions of VEGF, IL-6 and IL-17 in tumors were markedly decreased, but IFN-γ and HIF-1α increased after treating with DC-T cells combined with endostatin, compared to control group and DC-T group. In the DC-T+endostatin group, the proportions of MDSC and TAM (M2 type) were significantly decreased, mDC and TAM (M1 type) were up-regulated, and CD8+ T cells were recruited to infiltrate tumors, in contrast to PBS control and DC-T monotherapy. DC-T cells combined with endostatin potently reduced the expressions of IL-6, IL-10, TGF-β and

  3. Differential Antitumor Effects of IgG and IgM Monoclonal Antibodies and Their Synthetic Complementarity-Determining Regions Directed to New Targets of B16F10-Nex2 Melanoma Cells.

    PubMed

    Dobroff, Andrey S; Rodrigues, Elaine G; Juliano, Maria A; Friaça, Dayson M; Nakayasu, Ernesto S; Almeida, Igor C; Mortara, Renato A; Jacysyn, Jacqueline F; Amarante-Mendes, Gustavo P; Magliani, Walter; Conti, Stefania; Polonelli, Luciano; Travassos, Luiz R

    2010-01-01

    Malignant melanoma has increased incidence worldwide and causes most skin cancer-related deaths. A few cell surface antigens that can be targets of antitumor immunotherapy have been characterized in melanoma. This is an expanding field because of the ineffectiveness of conventional cancer therapy for the metastatic form of melanoma. In the present work, antimelanoma monoclonal antibodies (mAbs) were raised against B16F10 cells (subclone Nex4, grown in murine serum), with novel specificities and antitumor effects in vitro and in vivo. MAb A4 (IgG2ak) recognizes a surface antigen on B16F10-Nex2 cells identified as protocadherin beta(13). It is cytotoxic in vitro and in vivo to B16F10-Nex2 cells as well as in vitro to human melanoma cell lines. MAb A4M (IgM) strongly reacted with nuclei of permeabilized murine tumor cells, recognizing histone 1. Although it is not cytotoxic in vitro, similarly with mAb A4, mAb A4M significantly reduced the number of lung nodules in mice challenged intravenously with B16F10-Nex2 cells. The V(H) CDR3 peptide from mAb A4 and V(L) CDR1 and CDR2 from mAb A4M showed significant cytotoxic activities in vitro, leading tumor cells to apoptosis. A cyclic peptide representing A4 CDR H3 competed with mAb A4 for binding to melanoma cells. MAb A4M CDRs L1 and L2 in addition to the antitumor effect also inhibited angiogenesis of human umbilical vein endothelial cells in vitro. As shown in the present work, mAbs A4 and A4M and selected CDR peptides are strong candidates to be developed as drugs for antitumor therapy for invasive melanoma.

  4. Artificial cytokine storm combined with hyperthermia induces significant anti-tumor effect in mice inoculated with lewis lung carcinoma and B16 melanoma cells.

    PubMed

    Kushida, Shigeki; Ohmae, Hiroshi; Kamma, Hiroshi; Totsuka, Rumiko; Matsumura, Masayuki; Takeuchi, Akira; Saiki, Ikuo; Yanagawa, Toru; Onizawa, Kojiro; Ishii, Tetsuro; Ohn, Tadao

    2006-12-01

    In cancer immunotherapies combined with hyperthermia, one or two cytokines have been tested to augment the anti-tumor effect. However, the therapies have not shown sufficient improvement. The aim of this study is to find a new potent tumor immunotherapy in order to augment antitumor effect of hyperthermia by the cytokine cocktails in vivo. We used a combination therapy of local hyperthermia (LH) and various cytokine cocktails composed of IFNs (IFN-alpha, -beta, and -gamma), Thl cytokines (IL-2, -12, -15, and -18), a Th2 cytokine (IL-4), inflammatory cytokines (IL-lalpha and TNF-alpha), and dendritic cell-inducible cytokines (IL-3 and GM-CSF). These cytokines in a proper combination augmented the anti-tumor effect of LH and prolonged survival time in Lewis lung carcinoma or B16 melanoma significantly. Moreover, the 12-cytokine cocktail suppressed B 16 metastasis to the lung and lymph nodes, and complete regression of the tumors without regrowth occurred in 3 of 5 mice. In the cured three B16 mice, there was hyperplasia of lymphatic organs with many CD3-positive T lymphocytes. The most effective cytokine combination should be able to augment the anti-tumor effect of other therapies besides hyperthermia that induce the necrosis of tumor cells.

  5. 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

  6. 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

  7. 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

  8. Mechanism of antitumor effect on mouse hepatocellular carcinoma by intratumoral injection of OK-432, a streptococcal preparation.

    PubMed

    Homma, Sadamu; Sagawa, Yukiko; Komita, Hideo; Koido, Shigeo; Nagasaki, Eijiro; Ryoma, Yoshiki; Okamoto, Masato

    2007-08-01

    Intratumoral (i.t.) injection of OK-432, a streptococcal preparation, into implanted tumors of mouse hepatocellular carcinoma (MIH-2) showed antitumor effect including tumor eradication. Intraperitoneal administration of same dose OK-432 did not exhibit tumor suppressive effect. In vitro cytotoxic test suggested that direct cytotoxic effect of OK-432 was not associated with antitumor activity by i.t.-OK-432 treatment. It was also found that Toll-like receptor 4 signaling was not involved in i.t.-OK-432 treatment. Three mice out of five, which had shown tumor eradication by i.t.-OK-432 treatment did not reject re-challenge of MIH-2 cells. Splenocytes from i.t.-OK-432 treated mice did not produce IFN-gamma by stimulation with MIH-2 cells in vitro, but produced abundant IFN-gamma by stimulation with OK-432. Immunofluorescence microscopy demonstrated that CD4+T cells, but not CD8+T cells, infiltrated to i.t.-OK-432 treated tumor tissue produced IFN-gamma. Tumor-infiltrating CD4+T cells from i.t.-OK-432 treated tumor tissue produced IFN-gamma by in vitro stimulation with OK-432 higher than those from untreated tumor tissue. IFN-gamma directly induced apoptosis of MIH-2 cells in vitro. Collectively, i.t.-OK-432 treatment induced priming of CD4+T cells to antigenecity of OK-432, and repetitive i.t.-OK-432 treatment induced IFN-gamma production from OK-432-sensitized CD4+T cells in tumor site, leading to apoptosis of MIH-2 cells susceptible to IFN-gamma.

  9. 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

  10. Anti-inflammatory and antitumor promotional effects of a novel urinary metabolite, 3',4'-didemethylnobiletin, derived from nobiletin.

    PubMed

    Lai, Ching-Shu; Li, Shiming; Chai, Chee-Yin; Lo, Chih-Yu; Dushenkov, Slavik; Ho, Chi-Tang; Pan, Min-Hsiung; Wang, Ying-Jan

    2008-12-01

    We reported previously that 3',4'-didemethylnobiletin (DDMN) is the major metabolite of nobiletin in mouse urine. In this study, we examined DDMN's molecular mechanism of action and its anti-inflammatory and antitumor properties. We demonstrated that topical application of DDMN effectively inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated transcription of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and ornithine decarboxylase (ODC) messenger RNA and protein expression in mouse skin. Pretreatment with DDMN has resulted in the reduction of TPA-induced nuclear translocation of the nuclear factor-kappa B (NF-kappaB) subunit. DDMN also reduced DNA binding by blocking phosphorylation of inhibitor kappaB (IkappaB) alpha and p65 and caused subsequent degradation of IkappaBalpha. DDMN inhibited TPA-induced phosphorylation and nuclear translocation of the signal transducer and activator of transcription 3. Moreover, DDMN suppressed TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt and protein kinase C that are upstream of NF-kappaB and activator protien-1. We also found that DDMN significantly inhibited TPA-induced mouse skin inflammation by decreasing inflammatory parameters. Furthermore, DDMN significantly inhibited 7,12-dimethylbenz[a]anthracene/TPA-induced skin tumor formation measured by the tumor multiplicity of papillomas at 20 weeks. Presented data for the first time reveal that DDMN is an effective antitumor agent that functions by downregulating inflammatory iNOS, COX-2 and ODC gene expression in mouse skin. It is suggested that DDMN is a novel functional agent capable of preventing inflammation-associated tumorigenesis.

  11. 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.

  12. 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

  13. 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

    2015-07-21

    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.

  14. 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

  15. 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

  16. Synergistic antitumor effect of puerarin combined with 5-fluorouracil on gastric carcinoma

    PubMed Central

    GUO, XU-FENG; YANG, ZI-RONG; WANG, JUN; LEI, XIAO-FEI; LV, XIAO-GUANG; DONG, WEI-GUO

    2015-01-01

    Combination chemotherapy is a crucial method in the treatment of gastric cancer. The aim of the present study was to investigate the inhibitory effects of puerarin and 5-fluorouracil (5-FU) on BGC-823 gastric cancer cells in vitro and in vivo. The in vitro growth inhibition of puerarin or 5-FU alone or combined on BGC-823 cells was determined using a cell counting kit 8 (CCK-8) on living cells. Apoptotic morphological features and proteins expression levels were detected by Hoechst 33258 staining, an Annexin V/propidium iodide apoptosis kit and western blot analysis, respectively. Tumor xenografts were established in nude mice and the inhibitory effects and side effects were detected. Results of the CCK-8, Hoechst 33258 staining and flow cytometry revealed that the combined treatment was more effective than the separate treatments. The tumor volume was 90.65% of that of the controls and the mean tumor weight was only 0.125 g at the end of the experiment in the combination group compared with the control group (0.822 g). In addition, it was determined that liver and renal toxicity did not increase in combined treatment. These findings showed that puerarin and 5-FU produced a significant synergic effect on gastric cancer cells, while there was no increase in side effects. PMID:25434307

  17. Hepatoprotective and anti-tumor effects of targeting MMP-9 in hepatocellular carcinoma and its relation to vascular invasion markers.

    PubMed

    Elewa, Mohammed A F; Al-Gayyar, Mohammed M; Schaalan, Mona F; Abd El Galil, Khaled H; Ebrahim, Mohamed A; El-Shishtawy, Mamdouh M

    2015-06-01

    The current study aims to evaluate the hepatoprotective and antitumor efficacy of doxycycline, as an matrix metalloproteases-9 (MMP-9) inhibitor, in an in vivo model of hepatocellular carcinoma (HCC). HCC was induced experimentally by thiocetamide (200 mg/kg) in rats that were treated with doxycycline (5 mg/kg for 16 weeks). Tumor severity was evaluated by measuring α-fetoprotein (AFP) levels, histopathologically by investigating liver sections stained with hematoxylin/eosin and assessing the survival rate. Liver homogenates were used for the measurements of MMP-9, fascin and hepatic heparan sulfate proteoglycan (HSPG) levels. Oxidative stress markers [malonaldehyde (MDA) and glutathione] as well as fibroblast growth factor-2 (FGF-2) gene expression were also among the assessed indicators. HCC in human and animal samples showed significant elevation in the levels of MMP-9 (231.7, 90 %), fascin (33.17, 140 %), as well as FGF-2 gene expression (342 % in animal samples; all respectively), associated with a significant decrease in hepatic HSPG level. Treatment of rats with doxycycline increased the animal survival rate (90 %) and decreased serum AFP level. Moreover, doxycycline ameliorated fibrosis and the induced massive hepatic tissue breakdown. It also restored the integrity of hepatic HSPGs and showed a magnificent inhibitory effect of tumor invasion cascade by significantly reducing the activities of MMP-9 (42 %) and fascin (50 %), as well as reducing the gene expression of FGF-2 (85.7 %). Furthermore, the antioxidant impact of doxycycline was evidenced by the significant elevation in glutathione level and depressing MDA level. To this end, doxycycline, proved promising hepatoprotective and antitumor activity and opens, thereby, a new horizon against vascular migration ability of the tumor cells.

  18. 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

  19. 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.

  20. Structural characterization and anti-tumor effects of an inulin-type fructan from Atractylodes chinensis.

    PubMed

    Xu, Jing; Chen, Dan; Liu, Chang; Wu, Xiong-Zhi; Dong, Cai-Xia; Zhou, Jing

    2016-01-01

    A fructan (ACPS-1) with a molecular weight of 11.2 kDa was isolated from Atractylodes chinensis rhizome and characterized by chemical derivatization, HPLC, GC-MS, FT-IR, and NMR. Structural analyses revealed that ACPS-1 is predominately composed of fructose and a small amount of glucose and a polymerization degree of about 53. The fructan was deduced to be an inulin-type fructan containing a linear backbone composed of (2→1)-linked β-d-Fruf residues. The in vitro antitumor activity of ACPS-1 was evaluated on four human cancer cell lines, including a cervical cancer cell line (Hela), two liver hepatocellular carcinoma cell lines (HepG2 and 7721), and an ovarian carcinoma cell line (Skov3). Results showed that ACPS-1 could significantly inhibit Hela, HepG2, and 7721 cell proliferation, especially HepG2, for which the fructan showed a proliferative inhibition rate as high as 87.40%. This result suggests that ACPS-1 may have anticancer potentiality against hepatocellular carcinoma and warrants further investigation.

  1. 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

  2. Synergistic antitumor effect of a human papillomavirus DNA vaccine harboring E6E7 fusion gene and vascular endothelial growth factor receptor 2 gene.

    PubMed

    Gao, Jie; Fan, Lei; Ma, Wei; Xiao, Huan

    2016-09-01

    Human papillomavirus (HPV) has been identified as the primary etiological factor in cervical cancer as well as in subsets of anogenital and oropharyngeal cancers. The two HPV viral oncoproteins, E6 and E7, are uniquely and consistently expressed in all HPV-infected cells and are therefore promising targets for therapeutic vaccination. In order to achieve a synergistic antitumor and anti-angiogenesis effect, we designed and constructed a novel DNA vaccine that can express the HPV 16 E6E7 fusion protein and VEGFR2 in the same reading frame. A series of DNA plasmids encoding E6E7, VEGFR2 and their conjugates were constructed and injected into mice. The resultant humoral and cellular immune responses were detected by ELISA and enzyme-linked immunospot (ELISPOT), respectively. To evaluate the antitumor efficacy of these plasmids, tumor-bearing mice expressing the E6E7 fusion protein were constructed. After injection into the tumor-bearing mouse model, the plasmid harboring the E6E7 fusion gene and VEGFR2 showed stronger inhibition of tumor growth than the plasmid expressing E6E7 or VEGFR2 alone, which indicated that the combination of E6E7 and VEGFR2 could exert a synergistic antitumor effect. These observations emphasize the potential of a synergistic antitumor and anti-angiogenesis strategy using a DNA vaccine, which could be a promising approach for tumor immunotherapy. PMID:27515281

  3. 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

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

    PubMed

    Yi, Canhui; Zhang, Yong; 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.

  5. 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

  6. 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

  7. 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

  8. MiRNA-Embedded ShRNAs for Radiation-Inducible LGMN Knockdown and the Antitumor Effects on Breast Cancer

    PubMed Central

    Zhang, Zhi-Qiang; Cao, Zhi; Liu, Cong; Li, Rong; Wang, Wei-Dong; Wang, Xing-Yong

    2016-01-01

    Legumain (LGMN) is highly expressed in breast cancer (BC) and other solid tumors and is a potential anticancer target. Here we investigate the anti-tumor effects of short hairpin RNAs (shRNAs) targeting LGMN embedded in a microRNA-155 (miR-155) architecture, which is driven by a radiation-inducible chimeric RNA polymerase II (Pol II) promoter. Lentiviral vectors were generated with the chimeric promoter which controlled the expression of downstream shRNA-miR-155 cassette. Fluorescence was observed by using confocal microscopy. Real-time quantitative PCR and Western blotting were used to determine the expression level of LGMN, MMP2, and MMP9. Furthermore, the proliferation and invasive ability of BC cells was analyzed via plate colony formation and invasion assays. Here we demonstrated that the chimeric promoter could be effectively induced by radiation treatment. Furthermore, the shRNA-miR-155 cassette targeting LGMN could be effectively activated by the chimeric promoter. Radiation plus knockdown of LGMN impairs colony formation and dampens cell migration and invasion in BC cells. Inhibition of LGMN downregulates MMP2 and MMP9 expression in BC cells. Pol II-driven shRNA-miR-155 could effectively suppress the growth and invasiveness of BC cells, and that the interference effects could be regulated by radiation doses. Moreover, knockdown of LGMN alleviates the aggressive phenotype of BC cells through modulating MMPs expression. PMID:27656894

  9. In vitro and in vivo antitumoral effects of combinations of polyphenols, or polyphenols and anticancer drugs: perspectives on cancer treatment.

    PubMed

    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

  10. Antitumor effects of minodronate, a third-generation nitrogen-containing bisphosphonate, in synergy with γδT cells in human glioblastoma in vitro and in vivo.

    PubMed

    Nakazawa, Tsutomu; Nakamura, Mitsutoshi; Matsuda, Ryosuke; Nishimura, Fumihiko; Park, Young Soo; Motoyama, Yasushi; Hironaka, Yasuo; Nakagawa, Ichiro; Yokota, Hiroshi; Yamada, Shuichi; Tamura, Kentaro; Takeshima, Yasuhiro; Omoto, Kouji; Tanaka, Yoshitaka; Ouji, Yukiteru; Yoshikawa, Masahide; Tsujimura, Takahiro; Nakase, Hiroyuki

    2016-09-01

    Nitrogen-containing bisphosphonates (N-BPs), which prevent bone resorption, exert direct and γδT cell (GDT)-mediated antitumor effects against several tumor cell types, including glioblastoma (GBM). However, limited information is available regarding the antitumor effects of N-BPs in GBM. Specifically, the antitumor effects of minodronate (MDA), a third-generation N-BP, in GBM are yet unclear. This study aimed to investigate the antitumor effects of MDA in GBM in vitro and in vivo. We performed growth inhibition and apoptosis detection assays using the GBM cell lines U87MG and U138MG. Apoptosis inhibition assays were also conducted. In vivo xenograft assays were performed in highly immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Sug)/Jic mice subcutaneously implanted with U87MG and U138MG cells. Growth inhibition and apoptosis detection assays demonstrated that MDA inhibited GBM cell growth via apoptosis, which was markedly enhanced by ex vivo expanded GDT. A pan-caspase inhibitor, z-VAD-fmk, inhibited MDA-induced U138MG apoptosis and MDA/GDT-induced U87MG and U138MG apoptosis. But z-VAD-fmk increased MDA-induced U87MG apoptosis. MDA/GDT-mediated apoptosis was blocked by the anti-T cell receptor (TCR) Vγ9, mevalonate pathway inhibitor, granzyme B inhibitor, and antitumor necrosis factor (TNF)-α. In vivo xenograft assays showed that combined intraperitoneal administration of MDA/GDT induced antitumor effects on unestablished U87MG-derived subcutaneous tumors. MDA exerted direct and GDT-mediated anti-GBM apoptotic effects in a caspase-dependent manner. GDT recognized MDA-exposed GBM cells via TCRVγ9 and induced apoptosis via granzyme B and TNF-α release. Because MDA elicited anti-GBM effects in synergy with GDT in vivo, a combination of MDA and ex vivo-generated GDT could be an effective treatment in patients with GBM. PMID:27393349

  11. 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

  12. 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

  13. 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

  14. 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

  15. Poly-S-Nitrosated Albumin as a Safe and Effective Multifunctional Antitumor Agent: Characterization, Biochemistry and Possible Future Therapeutic Applications

    PubMed Central

    Ishima, Yu; Kragh-Hansen, Ulrich; Maruyama, Toru; Otagiri, Masaki

    2013-01-01

    Nitric oxide (NO) is a ubiquitous molecule involved in multiple cellular functions. Inappropriate production of NO may lead to disease states. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated human serum albumin (Mono-SNO-HSA), and that is why we are testing whether this albumin form can be therapeutically useful. Recently, we developed SNO-HSA analogs such as SNO-HSA with many conjugated SNO groups (Poly-SNO-HSA) which were prepared using chemical modification. Unexpectedly, we found striking inverse effects between Poly-SNO-HSA and Mono-SNO-HSA. Despite the fact that Mono-SNO-HSA inhibits apoptosis, Poly-SNO-HSA possesses very strong proapoptotic effects against tumor cells. Furthermore, Poly-SNO-HSA can reduce or perhaps completely eliminate the multidrug resistance often developed by cancer cells. In this review, we forward the possibility that Poly-SNO-HSA can be used as a safe and effective multifunctional antitumor agent. PMID:24490156

  16. 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

  17. The antitumor effect of TIG3 in liver cancer cells is involved in ERK1/2 inhibition.

    PubMed

    Xu, Yan; Chen, Ting; Liao, Degui; Wu, Xiaoqin; Zhong, Yun; Liu, Shiming; Yang, Hui; Nie, Yuqiang

    2016-08-01

    Tazarotene-induced gene 3 (TIG3) was first characterized in tazarotene-treated human keratinocytes and identified as a retinoic acid responder gene, an important mediator of antitumor effects by retinoids. In this study, we aim to investigate the inhibitory effect of TIG3 on the growth of liver cancer and explore its underlying mechanism. Human hepatocellular carcinoma (HCC) Hep3B cells were transfected with plasmid GV141 carrying full-length TIG3 complementary DNA (cDNA). The effects of TIG3 on cell proliferation, apoptosis, and migration were determined in vitro. The suppressor effect of TIG3 on tumor growth was evaluated in vivo in a nude mouse HCC model. We observed that TIG3 expression is decreased in the Hep3B cell line as well as primary HCC tumors, and TIG3 expression inversely correlates with Ki-67 expression. Overexpression of TIG3 suppresses tumor growth in HCC both in vitro and in vivo via ERK1/2 inhibition by promoting apoptosis and inhibiting proliferation and migration. These findings identify TIG3 as an attractive therapeutic target for HCC.

  18. Preparation and antitumor effect of a toxin-linked conjugate targeting vascular endothelial growth factor receptor and urokinase plasminogen activator

    PubMed Central

    Xiang, Ying; Li, Qiying; Huang, Dehong; Tang, Xianjun; Wang, Li; Shi, Yang; Zhang, Wenjun; Yang, Tao; Xiao, Chunyan

    2015-01-01

    The aberrant signaling activation of vascular endothelial growth factor receptor (VEGFR) and urokinase plasminogen activator (uPA) is a common characteristic of many tumors, including lung cancer. Accordingly, VEGFR and uPA have emerged as attractive targets for tumor. KDR (Flk-1/VEGFR-2), a member of the VEGFR family, has been recognized as an important target for antiangiogenesis in tumor. In this study, a recombinant immunotoxin was produced to specifically target KDR-expressing tumor vascular endothelial cells and uPA-expressing tumor cells and mediate antitumor angiogenesis and antitumor effect. Based on its potent inhibitory effect on protein synthesis, Luffin-beta (Lβ) ribosome-inactivating protein was selected as part of a recombinant fusion protein, a single-chain variable fragment against KDR (KDRscFv)-uPA cleavage site (uPAcs)-Lβ-KDEL (named as KPLK). The KDRscFv-uPAcs-Lβ-KDEL (KPLK) contained a single-chain variable fragment (scFv) against KDR, uPAcs, Lβ, and the retention signal for endoplasmic reticulum proteins KDEL (Lys-Asp-Glu-Leu). The KPLK-expressing vector was expressed in Escherichia coli, and the KPLK protein was isolated with nickel affinity chromatography and gel filtration chromatography. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis test demonstrated KPLK was effectively expressed. Result of in vitro cell viability assay on non-small cell lung cancer (NSCLC) H460 cell line (uPA-positive cell) revealed that KPLK significantly inhibited cell proliferation, induced apoptosis, and accumulated cells in S and G2/M phases, but the normal cell line (human submandibular gland cell) was unaffected. These effects were enhanced when uPA was added to digest KPLK to release Lβ. For in vivo assay of KPLK, subcutaneous xenograft tumor model of nude mice were established with H460 cells. Growth of solid tumors was significantly inhibited in animals treated with KPLK up to 21 days, tumor weights were decreased, and the expression of

  19. Effect of ajoene, a natural antitumor small molecule, on human 20S proteasome activity in vitro and in human leukemic HL60 cells.

    PubMed

    Xu, Bo; Monsarrat, Bernard; Gairin, Jean Edouard; Girbal-Neuhauser, Elisabeth

    2004-04-01

    The pharmacologic properties of ajoene, the major sulfur-containing compound purified from garlic, and its possible role in the prevention and treatment of cancer has received increasing attention. Several studies demonstrated that induction of apoptosis and cell cycle blockade are typical biologic effects observed in tumor cells after proteasome inhibition. The proteasome is responsible for the degradation of a variety of intracellular proteins and plays a key role in the regulation of many cellular processes. The aim of the present work was therefore to explore the effects of ajoene on the proteasome activities. In vitro activities of 20S proteasome purified from human erythrocytes on fluorogenic peptide substrates specific for trypsin-like, chymotrypsin-like and peptidylglutamyl peptide hydrolyzing activities revealed that ajoene inhibited the trypsin-like activity in a dose- and time-dependent manner. Further, the ability of 20S proteasome to degrade the OVA(51-71) peptide, a model proteasomal substrate, was partially but significantly inhibited by ajoene. In addition, when human leukemia cell line HL60 was treated with ajoene, both trypsin- and chymotrypsin-like activities were affected, cells arrested in G2/M phase and total amount of cytosolic proteasome increased. All these data clearly indicate that ajoene may affect proteasome function and activity both in vitro and in the living cell. This is a novel aspect in the biologic profile of this garlic compound giving new insights into the understanding of the molecular mechanisms of its potential antitumor action.

  20. 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

  1. 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

  2. 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

  3. Autocrine expression of both endostatin and green fluorescent protein provides a synergistic antitumor effect in a murine neuroblastoma model.

    PubMed

    Davidoff, A M; Leary, M A; Ng, C Y; Spurbeck, W W; Frare, P; Vanhove, M; Nienhuis, A W; Vanin, E F

    2001-07-01

    Modalities that act through different mechanisms can often provide synergistic antitumor activity for the treatment of refractory tumors when used in combination. Here we report a gene therapy approach in which the genes for the angiogenesis inhibitor, endostatin, and the marker protein and potent immunogen, green fluorescent protein (GFP), were delivered to murine neuroblastoma cells prior to inoculation of the tumor cells into syngeneic immunocompetent mice. Although the effect of either angiogenesis inhibition or immunomodulation alone resulted in only a modest delay in tumor growth, when these approaches were used in combination, prevention of the formation of appreciable tumors was effected in 15 of 24 (63%) mice. The combination of endostatin and GFP expression elicited a strong immune response that was T cell-mediated and was reactive against both GFP and tumor cell line-specific antigens. This afforded treated mice protection against subsequent tumor challenge with unmodified tumor cells. These results suggest that antiangiogenic and immunotherapy strategies, when used in a gene therapy-mediated approach, can act synergistically in an effective multimodality anticancer approach.

  4. 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.

  5. Construction of recombinant human IFNα-2b BCG and its antitumor effects on bladder cancer cells in vitro.

    PubMed

    Sun, E; Nian, X; Liu, C; Fan, X; Han, R

    2015-04-15

    We constructed recombinant Bacille Calmette-Guérin (rBCG) that secreted human interferon alpha 2b (hIFNα-2b), and investigated its antitumor effects on bladder cancer cells in vitro. The recombinant plasmid phIFN-α-2b was constructed using pMAO-4 and transformed into BCG. The supernatant was collected at various times and IFN-γ, interleukin (IL)-12, and tumor necrosis factor (TNF)-α were detected using an enzyme-linked immunosorbent assay. EJ cells were cultivated for 24, 48, and 72 h, together with rBCG, wild-type BCG (wBCG), or wBCG+IFN-α-2b. rBCG capable of secreting cytokine IFNα-2b was constructed. On the 4th day of culture, the IFNα-2b secreted by rBCG reached a maximum. wBCG and rBCG showed no significant difference on cell growth rate over 7 days of incubation in 7H9 medium. wBCG and rBCG were both positive for acid-fast staining, and showed mycobacterial characteristics of intercellular connection in clusters with no clear abnormalities. Higher levels of IFN-γ, TNF-α, and IL-12 were induced by rBCG compared with wBCG or MAO4-rBCG (P < 0.05). rBCG may induce lymphocyte proliferation; the proliferation ratio was higher than those induced by wBCG and wBCG+IFN. rBCG had direct anti-proliferative effects on EJ cells. An MTT assay showed that rBCG inhibited the proliferation of bladder cancer cells and had more activity compared with wBCG (P < 0.05). The highest anti-tumor activity of lymphocytes was stimulated by rBCG (20.31-51.22%). rBCG-IFNα-2b induces enhanced cytotoxicity against bladder cancer cells in vitro and may be used as an alternative to BCG for bladder cancer patients.

  6. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor.

    PubMed

    Dumble, Melissa; Crouthamel, Ming-Chih; Zhang, Shu-Yun; Schaber, Michael; Levy, Dana; Robell, Kimberly; Liu, Qi; Figueroa, David J; Minthorn, Elisabeth A; Seefeld, Mark A; Rouse, Meagan B; Rabindran, Sridhar K; Heerding, Dirk A; Kumar, Rakesh

    2014-01-01

    Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.

  7. 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.

  8. 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.

  9. In vivo antitumoral effect of Plantago major L. extract on Balb/C mouse with Ehrlich ascites tumor.

    PubMed

    Ozaslan, Mehmet; Didem Karagöz, I; Kalender, M Emin; Kilic, I Halil; Sari, Ibrahim; Karagöz, Alper

    2007-01-01

    The aim of this study is to investigate the antitumor activity of Plantago major L. extract in Ehrlich ascites tumor (EAT) bearing Balb/C mice in vivo. Thirty male Balb/C mice were divided into 5 groups: 3 treatment groups and 2 control groups (6 per group). Treatment groups and the negative control group were injected with EAT (1 x 10(6) cells) intraperitoneally to develop ascites tumor. P. major L. extract (1%, 2% and 3% concentration extracts, 0.1 ml/day/mouse) were given p.o. for 10 alternate days. The control group was treated with 0.9% NaCl solution (0.1 ml/day/mouse). The changes of body weight in animals were recorded. On the 11th day, all of the mice were sacrified and their tissues were stained with haematoxylen and eosin for pathological studies. Body weights of in 3 treatment groups and the negative control group were elevated because of tumor burden. The maximal weight gain was recorded in the negative control group and the minimal weight gain was recorded in Group I. Pathological studies showed that P. major L. extract (especially 1% concentration) has inhibitive effect on EAT. P. major has an inhibitory effect on EAT in a dose dependent manner.

  10. 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

  11. 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

  12. 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.

  13. 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

  14. Intravaginal HPV DNA vaccination with electroporation induces local CD8+ T-cell immune responses and antitumor effects against cervicovaginal tumors.

    PubMed

    Sun, Y; Peng, S; Qiu, J; Miao, J; Yang, B; Jeang, J; Hung, C-F; Wu, T-C

    2015-07-01

    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.

  15. 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

  16. Antitumor effect of OK-432-derived DNA: one of the active constituents of OK-432, a streptococcal immunotherapeutic agent.

    PubMed

    Oshikawa, Tetsuya; Okamoto, Masato; Tano, Tomoyuki; Sasai, Akiko; Kan, Shin; Moriya, Yoichiro; Ryoma, Yoshiki; Saito, Motoo; Akira, Shizuo; Sato, Mitsunobu

    2006-01-01

    OK-432 is a Streptococcus-derived immunotherapeutic agent for malignancies. Our group has tried to identify the effective components of OK-432 and has succeeded in isolating a lipoteichoic acid-related preparation designated as OK-PSA, which is a strong inducer of T helper 1 (T(H)1) cells, and elicits an anticancer effect via Toll-like receptor (TLR) 4. Conversely, bacterial DNA with unmethylated CpG motifs can stimulate a T(H)1-type host response via TLR9. The unmethylated CpG DNA contained in OK-432 may play a role in its anticancer effect. In the current study, we investigated the effect of OK-432-derived DNA (OK-DNA) in augmenting the anticancer immune response. Analysis of OK-DNA with the restriction enzymes Hpa II and MspI revealed that OK-DNA contained unmethylated CpG motifs. OK-DNA induced TH1-type cytokines such as interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-12, and IL-18 and augmented killer cell activities in vitro on human peripheral blood mononuclear cells, whereas the methylated OK-DNA did not. Cytokines were also produced by OK-DNA-stimulated splenocytes derived from wild-type mice but not from TLR9-deficient mice. In the in vivo study, peritumoral administration of OK-DNA resulted in a significant inhibition of tumor growth in syngeneic tumor-bearing wild-type and TLR4-deficient mice but not in TLR9-deficient mice. The antitumor effect of OK-432 in TLR9-deficient mice was significantly but partially reduced compared with that in wild-type mice, whereas the effect of OK-432 was almost completely eliminated in TLR4-deficient mice. These findings suggest that unmethylated CpG DNA in OK-432 functions as an active component in OK-432-induced anticancer immunity via TLR9.

  17. Gold Nanoshells: Combined Near Infrared Photothermal Therapy and Chemotherapy Using Gold Nanoshells Coated Liposomes to Enhance Antitumor Effect (Small 30/2016).

    PubMed

    Luo, Liyao; Bian, Yanhong; Liu, Yanping; Zhang, Xuwu; Wang, Meili; Xing, Shanshan; Li, Lei; Gao, Dawei

    2016-08-01

    Gold nanoshell coated oleanolic acid liposomes mediating by chitosan (GNOLs), are designed and successfully synthesized for the first time by D. Gao and co-workers on page number 4103. An excellent near infrared (NIR) photothermal effect, pH-responsive drug controlled release and tumor targeting properties are demonstrated. By combining NIR photothermal therapy and chemotherapy, the smart drug delivery system exhibits a superior antitumor property in vitro and in vivo. PMID:27492497

  18. 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

  19. Enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA on human brain metastatic breast cancer.

    PubMed

    Fu, Bo; Long, Wei; Zhang, Ying; Zhang, Aifeng; Miao, Fengqin; Shen, Yuqing; Pan, Ning; Gan, Guangming; Nie, Fang; He, Youji; Zhang, Jianqiong; Teng, Gaojun

    2015-01-26

    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.

  20. Anti-tumoral effect of the mitochondrial target domain of Noxa delivered by an engineered Salmonella typhimurium.

    PubMed

    Jeong, Jae-Ho; Kim, Kwangsoo; Lim, Daejin; Jeong, Kwangjoon; Hong, Yeongjin; Nguyen, Vu H; Kim, Tae-Hyoung; Ryu, Sangryeol; Lim, Jeong-A; Kim, Jae Il; Kim, Geun-Joong; Kim, Sun Chang; Min, Jung-Joon; Choy, Hyon E

    2014-01-01

    Bacterial cancer therapy relies on the fact that several bacterial species are capable of targeting tumor tissue and that bacteria can be genetically engineered to selectively deliver therapeutic proteins of interest to the targeted tumors. However, the challenge of bacterial cancer therapy is the release of the therapeutic proteins from the bacteria and entry of the proteins into tumor cells. This study employed an attenuated Salmonella typhimurium to selectively deliver the mitochondrial targeting domain of Noxa (MTD) as a potential therapeutic cargo protein, and examined its anti-cancer effect. To release MTD from the bacteria, a novel bacterial lysis system of phage origin was deployed. To facilitate the entry of MTD into the tumor cells, the MTD was fused to DS4.3, a novel cell-penetrating peptide (CPP) derived from a voltage-gated potassium channel (Kv2.1). The gene encoding DS4.3-MTD and the phage lysis genes were placed under the control of PBAD , a promoter activated by L-arabinose. We demonstrated that DS4.3-MTD chimeric molecules expressed by the Salmonellae were anti-tumoral in cultured tumor cells and in mice with CT26 colon carcinoma.

  1. Endo-polysaccharide of Phellinus igniarius exhibited anti-tumor effect through enhancement of cell mediated immunity.

    PubMed

    Chen, Li; Pan, Jingzhi; Li, Xue; Zhou, Yong; Meng, Qinglong; Wang, Qi

    2011-02-01

    The purpose of this study was to assess the anti-tumor and immunomodulatory effects of PIE on tumor cells Sarcoma 180 and Hepatoma 22 in implanted mice. The monosaccharide composition of PIE was analyzed by GC. The results demonstrated that PIE monosaccharide composition was n(Xyl): n(Man): n(Fuc): n(Glc): n(Gal)=2.3: 1: 6.4: 22.1: 19.83. The oral administration of PIE characteristically inhibited the growth of S180 and H22 cells and increased the life span. The concentrations of serum IL-2 and IL-18 were significantly increased in the S180 implanted mice fed with PIE in the doses of 500 mg/kg and 250 mg/kg compared with those in control (p<0.01). The concentrations of serum IL-2 were significantly increased in H22 implanted mice in the doses of 500 mg/kg and 250 mg/kg compared with those in control (p<0.01). PMID:21145997

  2. Th17 Cells Exhibit Antitumor Effects in MDS Possibly through Augmenting Functions of CD8+ T Cells

    PubMed Central

    Wang, Huaquan; Liu, Chunyan; Tao, Jinglian; Qi, Weiwei

    2016-01-01

    Th17 cells are a newly found subset of distinct CD4+ Th effector cells' family and are found to play an important role in cancers. Myelodysplastic syndromes (MDS) are a common malignant hematological disease. Here, we showed that both the percentage and the function of Th17 cells were elevated in low-risk MDS while being decreased in high-risk MDS. Levels of upstream molecules of Th17 cells, IL-6 and IL-23, were higher in low-risk MDS but lower in high-risk MDS patients. The abnormal percentage of Th17 cells was closely related to clinical parameters including karyotype, morphologic blast percentage of bone marrow, peripheral absolute neutrophil count, and hemoglobin concentration. Furthermore, expression rates of perforin and granzyme B in BM CD3+CD8+ cells (cytotoxic T lymphocyte, CTL) positively correlated with levels of IL-17 but negatively correlated with BM blast percentage and could be significantly increased after stimulation with human recombinant IL-17 (rhIL-17). Our results suggested that Th17 cells might play an antitumor effect in the pathogenesis of MDS through IL-17/CTL pathway. PMID:27722177

  3. 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

  4. The Effect of Antitumor Glycosides on Glioma Cells and Tissues as Studied by Proton HR-MAS NMR Spectroscopy

    PubMed Central

    García-Álvarez, Isabel; Garrido, Leoncio; Romero-Ramírez, Lorenzo; Nieto-Sampedro, Manuel; Fernández-Mayoralas, Alfonso; Campos-Olivas, Ramón

    2013-01-01

    The effect of the treatment with glycolipid derivatives on the metabolic profile of intact glioma cells and tumor tissues, investigated using proton high resolution magic angle spinning (1H HR-MAS) nuclear magnetic resonance (NMR) spectroscopy, is reported here. Two compounds were used, a glycoside and its thioglycoside analogue, both showing anti-proliferative activity on glioma C6 cell cultures; however, only the thioglycoside exhibited antitumor activity in vivo. At the drug concentrations showing anti-proliferative activity in cell culture (20 and 40 µM), significant increases in choline containing metabolites were observed in the 1H NMR spectra of the same intact cells. In vivo experiments in nude mice bearing tumors derived from implanted C6 glioma cells, showed that reduction of tumor volume was associated with significant changes in the metabolic profile of the same intact tumor tissues; and were similar to those observed in cell culture. Specifically, the activity of the compounds is mainly associated with an increase in choline and phosphocholine, in both the cell cultures and tumoral tissues. Taurine, a metabolite that has been considered a biomarker of apoptosis, correlated with the reduction of tumor volume. Thus, the results indicate that the mode of action of the glycoside involves, at least in part, alteration of phospholipid metabolism, resulting in cell death. PMID:24194925

  5. 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

  6. 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

    2016-04-28

    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.

  7. 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

  8. [Antitumor effect of mIFN-λ3 in C57BL/6 mice model for papilloma tumors].

    PubMed

    Choobin, H; Bamdad, T; Soleimanjahi, H; Razavinikoo, H

    2015-01-01

    Although several years have passed since the determination of the human papilloma virus (HPV) as the causative agent for cervical cancer, a definitive treatment has not yet been found. Interferon-alpha (IFN-α) immunotherapy is one of the promising methods for tumor treatment, although numerous side effects were observed in clinical trials. Recently, a new type of interferon, lambda-interferon (IFN-λ), has been discovered with fewer side effects than IFN-α since its receptor repertoire is limited. IFN-λ has a series of activities including antiviral, anti-proliferative and anti-tumor actions. In the present study, the effects of IFN-α and IFN-λ on the TC1 papilloma tumor model in C57BL/6 mice were evaluated. TC1 cells were injected into the mice subcutaneously. Upon tumor formation, murine IFN, mIFN-α and mIFN-λ, expression plasmids were injected intratumorally in combination or alone. The survival time and tumor size as well as apoptosis in tumors and NK cytoxicity were measured after three injections. As compared with the control group, the remarkable results especially in the group which received mIFN-α and mIFN-λ together were obtained for all of the measured parameters. Although IFN-λ is a new member of the interferon family and its properties should be studied in detail, the data obtained suggests that the use of IFN-λ especially in combination with IFN-α could be considered as an effective strategy for papilloma cervical cancer immunotherapy. PMID:26510595

  9. Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus.

    PubMed

    Diaconu, Iulia; Cerullo, Vincenzo; Hirvinen, Mari L M; Escutenaire, Sophie; Ugolini, Matteo; Pesonen, Saila K; Bramante, Simona; Parviainen, Suvi; Kanerva, Anna; Loskog, Angelica S I; Eliopoulos, Aristides G; Pesonen, Sari; Hemminki, Akseli

    2012-05-01

    Oncolytic adenovirus is an attractive platform for immunotherapy because virus replication is highly immunogenic and not subject to tolerance. Although oncolysis releases tumor epitopes and provides costimulatory danger signals, arming the virus with immunostimulatory molecules can further improve efficacy. CD40 ligand (CD40L, CD154) induces apoptosis of tumor cells and triggers several immune mechanisms, including a T-helper type 1 (T(H)1) response, which leads to activation of cytotoxic T cells and reduction of immunosuppression. In this study, we constructed a novel oncolytic adenovirus, Ad5/3-hTERT-E1A-hCD40L, which features a chimeric Ad5/3 capsid for enhanced tumor transduction, a human telomerase reverse transcriptase (hTERT) promoter for tumor selectivity, and human CD40L for increased efficacy. Ad5/3-hTERT-E1A-hCD40L significantly inhibited tumor growth in vivo via oncolytic and apoptotic effects, and (Ad5/3-hTERT-E1A-hCD40L)-mediated oncolysis resulted in enhanced calreticulin exposure and HMGB1 and ATP release, which were suggestive of immunogenicity. In two syngeneic mouse models, murine CD40L induced recruitment and activation of antigen-presenting cells, leading to increased interleukin-12 production in splenocytes. This effect was associated with induction of the T(H)1 cytokines IFN-γ, RANTES, and TNF-α. Tumors treated with Ad5/3-CMV-mCD40L also displayed an enhanced presence of macrophages and cytotoxic CD8(+) T cells but not B cells. Together, our findings show that adenoviruses coding for CD40L mediate multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of T(H)1 cytokines.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. 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).

  18. Antitumor effects of 32P-chromic-poly (L-lactide) brachytherapy in nude mice with human prostate cancer

    PubMed Central

    SUN, LIUJING; ZHU, XISHAN; XU, LONGBAO; WANG, ZIZHENG; SHAO, GUOQIANG; ZHAO, JUN

    2013-01-01

    The aim of the present study was to investigate the antitumor effects and tissue distribution of 32P-chromic-poly (L-lactide) (32P-CP-PLLA) in nude mice with human prostate cancer. Tumor models were obtained by transplantation of PC-3M tumor cells into male BALB/c nude mice. Animals were randomly divided into control, 32P-chromic phosphate (32P-CP) colloid and 32P-CP-PLLA groups (all n=20). A series of indices were investigated, including apoptosis of tumor cells, rate of apoptosis, expression of caspase 3 and 8, biodistribution and intratumoral concentration of 32P-CP-PLLA, intensity of radioactivity, tumor volume and microvessel density (MVD). Highly concentrated radioactivity of 32P-CP-PLLA in the tumor mass was detected by single photon emission computed tomography (SPECT) scanning. The residual activities of the 32P-CP-PLLA and 32P-CP colloid groups were 3.02±0.32 and 1.76±0.31 MBq, respectively, on day 14 following treatment. The tumor inhibition rates were 67.24±3.55 and 55.92±7.65%, respectively (P<0.01). Necrotic changes, in conjunction with apoptosis, were observed in the treatment group. MVD values for the 32P-CP-PLLA and 32P-CP colloid groups were 28.24±10.07 and 36.15±11.06, respectively. 32P-CP-PLLA showed an excellent capacity for killing tumor cells, inducing apoptosis and inhibiting angiogenesis. PMID:24137391

  19. Synthesis, crystal structure and antitumor effect of a novel copper(II) complex bearing zoledronic acid derivative.

    PubMed

    Qiu, Ling; Lv, Gaochao; Guo, Liubin; Chen, Liping; Luo, Shineng; Zou, Meifen; Lin, Jianguo

    2015-01-01

    A great majority of Cu(II) complexes currently studied in the anticancer research field exert their antiproliferative activities through ligand exchange. In this work, we present the synthesis and structural characterization of two novel Cu(II) complexes, {[Cu3(ZL)2(H2O)6]·6H2O}n (1) (ZL = 1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyldiphosphonic acid) and [Cu(IPrDP)2]·3H2O (2) (IPrDP = 1-hydroxy-3-(1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid). Due to the insolubility of polymer 1 in common solvents, only the biological activities of complex 2 were investigated. The antitumor activity of complex 2 was evaluated against a panel of human cancer cell lines, including U2OS, A549, HCT116, MDA-MB-231 and HepG2. Complex 2 exhibited comparable cytotoxic effect to cisplatin (CDDP) against the human colon carcinoma cells HCT116, and superior selectivity for inhibiting human hepatocarcinoma cells rather than normal liver cells. The cell cycle distribution analysis indicates that complex 2 inhibits human carcinoma cells by inducing the cell cycle arrest at the G2/M phase, showing a similar mechanism of action to that of CDDP. The binding interaction of complex 2 with calf thymus DNA (CT-DNA) has been explored by UV-vis absorption and circular dichroism (CD), demonstrating complex 2 has a moderate binding affinity for DNA through intercalation.

  20. 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

  1. Arsenic Trioxide Overcomes Rapamycin-Induced Feedback Activation of AKT and ERK Signaling to Enhance the Anti-Tumor Effects in Breast Cancer

    PubMed Central

    Guilbert, Cynthia; Annis, Matthew G.; Dong, Zhifeng; Siegel, Peter M.; Miller, Wilson H.; Mann, Koren K.

    2013-01-01

    Inhibitors of the mammalian target of rapamycin (mTORi) have clinical activity; however, the benefits of mTOR inhibition by rapamycin and rapamycin-derivatives (rapalogs) may be limited by a feedback mechanism that results in AKT activation. Increased AKT activity resulting from mTOR inhibition can be a result of increased signaling via the mTOR complex, TORC2. Previously, we published that arsenic trioxide (ATO) inhibits AKT activity and in some cases, decreases AKT protein expression. Therefore, we propose that combining ATO and rapamycin may circumvent the AKT feedback loop and increase the anti-tumor effects. Using a panel of breast cancer cell lines, we find that ATO, at clinically-achievable doses, can enhance the inhibitory activity of the mTORi temsirolimus. In all cell lines, temsirolimus treatment resulted in AKT activation, which was decreased by concomitant ATO treatment only in those cell lines where ATO enhanced growth inhibition. Treatment with rapalog also results in activated ERK signaling, which is decreased with ATO co-treatment in all cell lines tested. We next tested the toxicity and efficacy of rapamycin plus ATO combination therapy in a MDA-MB-468 breast cancer xenograft model. The drug combination was well-tolerated, and rapamycin did not increase ATO-induced liver enzyme levels. In addition, combination of these drugs was significantly more effective at inhibiting tumor growth compared to individual drug treatments, which corresponded with diminished phospho-Akt and phospho-ERK levels when compared with rapamycin-treated tumors. Therefore, we propose that combining ATO and mTORi may overcome the feedback loop by decreasing activation of the MAPK and AKT signaling pathways. PMID:24392034

  2. 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

  3. 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.

  4. In vitro and in vivo anti-tumoral effect of curcumin against melanoma cells.

    PubMed

    Odot, Johann; Albert, Philippe; Carlier, Annie; Tarpin, Michel; Devy, Jérôme; Madoulet, Claudie

    2004-09-01

    Curcumin, the active ingredient from the spice turmeric (Curcuma longa Linn), is known to be an anti-oxidant and an anti-inflammatory agent. It has been demonstrated recently to possess anti-angiogenic effects and pro-apoptotic activities against Ehrlich ascites tumor cells. In the current study, curcumin was found to be cytotoxic in vitro for B16-R melanoma cells resistant to doxorubicin either cultivated as monolayers or grown in three-dimensional (3-D) cultures (spheroids). We have demonstrated that the cytotoxic effect observed in the 2 culture types can be related to the induction of programmed cell death. In our in vivo studies, we examined the effectiveness of a prophylactic immune preparation of soluble proteins from B16-R cells, or a treatment with curcumin as soon as tumoral appearance, alone or in combination, on the murine melanoma B16-R. The combination treatment resulted in substantial inhibition of growth of B16-R melanoma, whereas each treatment by itself showed little effect. Moreover, animals receiving the combination therapy exhibited an enhancement of their humoral anti-soluble B16-R protein immune response and a significant increase in their median survival time (> 82.8% vs. 48.6% and 45.7% respectively for the immunized group and the curcumin-treated group). Our study shows that curcumin may provide a valuable tool for the development of a therapeutic combination against the melanoma. PMID:15221965

  5. 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

  6. 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.

  7. The effects of narrow-band middle infrared radiation in enhancing the antitumor activity of paclitaxel.

    PubMed

    Tsai, Shang-Ru; Sheu, Bor-Ching; Huang, Pei-Shen; Lee, Si-Chen

    2016-01-01

    Paclitaxel is used as an adjuvant to enhance the effectiveness of ionization radiation therapy; however, high-energy radiation often damages the healthy cells surrounding cancer cells. Low-energy, middle-infrared radiation (MIR) has been shown to prevent tissue damage, and recent studies have begun combining MIR with paclitaxel. However, the cytotoxic effects of this treatment combination remain unclear, and the mechanism underlying its effects on HeLa cells has yet to be elucidated. This study investigated the effectiveness of treating HeLa human cervical cancer cells with a combination of paclitaxel for 48 h in conjunction with narrow-band MIR from 3.0 to 5.0 μm. This combined treatment significantly inhibited the growth of HeLa cells. Specifically, results from Annexin V-FITC/PI apoptosis detection and cell mitochondrial membrane potential analyses revealed an increase in apoptotic cell death and a collapse of mitochondrial membrane potential. One possible mechanism underlying cellular apoptosis is an increase in oxidative stress. These preliminary findings provide evidence to support the combination of narrow-band MIR with paclitaxel as an alternative approach in the treatment of human cervical cancer.

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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.

  13. Anti-tumor effect of estrogen-related receptor alpha knockdown on uterine endometrial cancer

    PubMed Central

    Matsushima, Hiroshi; Mori, Taisuke; Ito, Fumitake; Yamamoto, Takuro; Akiyama, Makoto; Kokabu, Tetsuya; Yoriki, Kaori; Umemura, Shiori; Akashi, Kyoko; Kitawaki, Jo

    2016-01-01

    Estrogen-related receptor (ERR)α presents structural similarities with estrogen receptor (ER)α. However, it is an orphan receptor not binding to naturally occurring estrogens. This study was designed to investigate the role of ERRα in endometrial cancer progression. Immunohistochemistry analysis on 50 specimens from patients with endometrial cancer showed that ERRα was expressed in all examined tissues and the elevated expression levels of ERRα were associated with advanced clinical stages and serous histological type (p < 0.01 for each). ERRα knockdown with siRNA suppressed angiogenesis via VEGF and cell proliferation in vitro (p < 0.01). Cell cycle and apoptosis assays using flow cytometry and western blot revealed that ERRα knockdown induced cell cycle arrest during the mitotic phase followed by apoptosis initiated by caspase-3. Additionally, ERRα knockdown sensitized cells to paclitaxel. A significant reduction of tumor growth and angiogenesis was also observed in ERRα knockdown xenografts (p < 0.01). These findings indicate that ERRα may serve as a novel molecular target for the treatment of endometrial cancer. PMID:27153547

  14. 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

  15. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

    PubMed

    Ingersoll, Matthew A; Lyons, Anastesia S; 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

  16. Edelfosine and miltefosine effects on lipid raft properties: membrane biophysics in cell death by antitumor lipids.

    PubMed

    Castro, Bruno M; Fedorov, Aleksander; Hornillos, Valentin; Delgado, Javier; Acuña, A Ulises; Mollinedo, Faustino; Prieto, Manuel

    2013-07-01

    Edelfosine (1-O-octadecyl-2-O-methyl-sn-glycero-phosphocholine) and miltefosine (hexadecylphosphocholine) are synthetic alkylphospholipids (ALPs) that are reported to selectively accumulate in tumor cell membranes, inducing Fas clustering and activation on lipid rafts, triggering apoptosis. However, the exact mechanism by which these lipids elicit these events is still not fully understood. Recent studies propose that their mode of action might be related with alterations of lipid rafts biophysical properties caused by these lipid drugs. To achieve a clear understanding of this mechanism, we studied the effects of pharmacologically relevant amounts of edelfosine and miltefosine in the properties of model and cellular membranes. The influence of these molecules on membrane order, lateral organization, and lipid rafts molar fraction and size were studied by steady-state and time-resolved fluorescence methods, Förster resonance energy transfer (FRET), confocal and fluorescence lifetime imaging microscopy (FLIM). We found that the global membrane and lipid rafts biophysical properties of both model and cellular membranes were not significantly affected by both the ALPs. Nonetheless, in model membranes, a mild increase in membrane fluidity induced by both alkyl lipids was detected, although this effect was more noticeable for edelfosine than miltefosine. This absence of drastic alterations shows for the first time that ALPs mode of action is unlikely to be directly linked to alterations of lipid rafts biophysical properties caused by these drugs. The biological implications of this result are discussed in the context of ALPs effects on lipid metabolism, mitochondria homeostasis modulation, and their relationship with tumor cell death.

  17. Antitumor effects of the hyaluronan inhibitor 4-methylumbelliferone on pancreatic cancer

    PubMed Central

    Yoshida, Eri; Kudo, Daisuke; Nagase, Hayato; Shimoda, Hiroshi; Suto, Shinichiro; Negishi, Mika; Kakizaki, Ikuko; Endo, Masahiko; Hakamada, Kenichi

    2016-01-01

    Hyaluronan (HA) is a major component of the extracellular matrix (ECM), and influences tumor invasion and metastasis. In a previous study, the present authors reported for the first time that 4-methylumbelliferone (MU) inhibited HA synthesis and suppressed tumor growth. However, the localization of HA and the changes in ECM morphology caused by MU in pancreatic cancer remain to be examined in detail. In the present study, the cytotoxicity of MU and its effect on cellular proliferation was evaluated in the human pancreatic cancer cell line MIA PaCa-2. The amount of HA synthesized and the retention of HA around the cells were quantitatively and immunohistochemically analyzed in vitro and in vivo. Structural changes in the ECM in the tumor tissue were investigated using an electron microscope. MU treatment led to a decrease in extracellular HA retention, as evidenced by a particle exclusion assay and immunohistochemical staining. Cell proliferation was suppressed by MU in a dose-dependent manner. The release of lactate dehydrogenase into the culture medium due to damage to the cellular membrane did not increase following MU administration. In tumor-inoculated mice, MU suppressed any increase in tumor volume and decreased the quantity of HA. Electron microscopy revealed that MU attenuated the intercellular space and caused it to be less cohesive. These data indicate that MU inhibits HA synthesis and reduces the amount of HA in the ECM while exhibiting no obvious cytotoxic effect. These findings suggest that MU has potential as a novel therapeutic agent for pancreatic cancer.

  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. Apoptosis-induced anti-tumor effect of Curcuma kwangsiensis polysaccharides against human nasopharyngeal carcinoma cells.

    PubMed

    Zeng, Jianhong; Dai, Ping; Ren, Lingyun; Song, Bo; Chen, Xu; Wang, Xiaohua; Wang, Jianhong; Zhang, Tiecheng; Zhu, Weiguo

    2012-08-01

    This study aimed to investigate the effect of Curcuma kwangsiensis polysaccharides on the viability of human nasopharyngeal carcinoma cell line CNE-2 cells, and explore the possible mechanisms. CNE-2 cells were treated with various concentrations of C. kwangsiensis polysaccharides, then the proliferation, apoptosis and the protein expression of apoptosis-related regulators p53 and Bcl-2 were assessed. The results demonstrated that C. kwangsiensis polysaccharides can significantly inhibit the proliferation of CNE-2 cells, which was possibly through the induction of apoptosis mediated by attenuating Bcl-2 expression and promoting p53 expression. The present study therefore indicates that C. kwangsiensis polysaccharides could be developed into potential drugs for nasopharyngeal carcinoma treatment.

  20. Antitumor effects of the hyaluronan inhibitor 4-methylumbelliferone on pancreatic cancer

    PubMed Central

    Yoshida, Eri; Kudo, Daisuke; Nagase, Hayato; Shimoda, Hiroshi; Suto, Shinichiro; Negishi, Mika; Kakizaki, Ikuko; Endo, Masahiko; Hakamada, Kenichi

    2016-01-01

    Hyaluronan (HA) is a major component of the extracellular matrix (ECM), and influences tumor invasion and metastasis. In a previous study, the present authors reported for the first time that 4-methylumbelliferone (MU) inhibited HA synthesis and suppressed tumor growth. However, the localization of HA and the changes in ECM morphology caused by MU in pancreatic cancer remain to be examined in detail. In the present study, the cytotoxicity of MU and its effect on cellular proliferation was evaluated in the human pancreatic cancer cell line MIA PaCa-2. The amount of HA synthesized and the retention of HA around the cells were quantitatively and immunohistochemically analyzed in vitro and in vivo. Structural changes in the ECM in the tumor tissue were investigated using an electron microscope. MU treatment led to a decrease in extracellular HA retention, as evidenced by a particle exclusion assay and immunohistochemical staining. Cell proliferation was suppressed by MU in a dose-dependent manner. The release of lactate dehydrogenase into the culture medium due to damage to the cellular membrane did not increase following MU administration. In tumor-inoculated mice, MU suppressed any increase in tumor volume and decreased the quantity of HA. Electron microscopy revealed that MU attenuated the intercellular space and caused it to be less cohesive. These data indicate that MU inhibits HA synthesis and reduces the amount of HA in the ECM while exhibiting no obvious cytotoxic effect. These findings suggest that MU has potential as a novel therapeutic agent for pancreatic cancer. PMID:27698797

  1. 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.

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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)

  7. 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

  8. Cisplatin-induced antitumor immunomodulation: a review of preclinical and clinical evidence.

    PubMed

    de Biasi, Andreas R; Villena-Vargas, Jonathan; Adusumilli, Prasad S

    2014-11-01

    Contrary to the long held belief that chemotherapy is immunosuppressive, emerging evidence indicates that the anticancer activity of cisplatin is not limited to its ability to inhibit mitosis, but that cisplatin also has important immunomodulatory effects. We therefore methodically examined the relevant preclinical literature and identified four main mechanisms of cisplatin-induced antitumor immunomodulation: (i) MHC class I expression upregulation; (ii) recruitment and proliferation of effector cells; (iii) upregulation of the lytic activity of cytotoxic effectors; and (iv) downregulation of the immunosuppressive microenvironment. Cisplatin-based combination chemotherapy's antitumor immunomodulatory effects are also beginning to be harnessed in the clinic; we therefore additionally reviewed the applicable clinical literature and discussed how monitoring various components of the immune system (and their responses to cisplatin) can add new levels of sophistication to disease monitoring and prognostication. In summation, this growing body of literature on cisplatin-induced antitumor immunomodulation ultimately highlights the therapeutic potential of synergistic strategies that combine traditional chemotherapy with immunotherapy.

  9. 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

  10. 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.

  11. 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

  12. In vivo pharmacokinetics, biodistribution and antitumor effect of amphiphilic poly(L-amino acids) micelles loaded with a novel all-trans retinoic acid derivative.

    PubMed

    Tang, Jihui; Wang, Xinqun; Wang, Ting; Chen, Feihu; Zhou, Jianping

    2014-01-23

    Poly(amino acid)s are well-known as biodegradable and environmentally acceptable materials. In this study, a series of poly(L-aspartic acid)-b-poly(L-phenylalanine) (PAA-PPA) compounds with different degrees of polymerization were used to prepare copolymer micelles for a poorly water-soluble drug 4-amino-2-trifluoromethyl-phenyl retinate (ATPR, a novel all-trans retinoic acid derivative) and in vivo pharmacokinetics, biodistribution and antitumor efficacy of ATPR delivered by PAA-PPA micelles were evaluated. The area under the plasma concentration time curve AUC0→∞ of ATPR-loaded PAA20PPA20 micelles was 2.23 and 1.97 times higher than that of ATPR solution and ATPR CrmEL solution, respectively; In addition, the mean residence time (MRT) was increased 1.67 and 1.97-fold, respectively and the total body clearance (CL) was reduced 2.25 and 1.98-fold, respectively. The biodistribution study indicated that most of the ATPR in the ATPR-M group was distributed in the liver and there was delayed liver aggregation compared with the ATPR solution and ATPR CrmEL solution groups. Furthermore, the antitumor efficacy of ATPR-loaded PAA20PPA20 micelles was demonstrated in in vivo antitumor models involving mice inoculated with the human gastric cancer cell line SGC-7901. At the same dose of 7mg/kg, the ATPR-loaded micelles group demonstrated a better tumor growth inhibition and induced differentiation than the groups given ATPR solution and ATPR CrmEL solution. Therefore, the ATPR-loaded PAA-PPA micelles appear to be a potentially useful drug delivery system for ATPR and suitable for the chemotherapy of gastric cancer.

  13. Interactive effects of nutrient additions and predation on infaunal communities

    USGS Publications Warehouse

    Posey, M.H.; Alphin, T.D.; Cahoon, L.; Lindquist, D.; Becker, M.E.

    1999-01-01

    Nutrient additions represent an important anthropogenic stress on coastal ecosystems. At moderate levels, increased nutrients may lead to increased primary production and, possibly, to increased biomass of consumers although complex trophic interactions may modify or mask these effects. We examined the influence of nutrient additions and interactive effects of trophic interactions (predation) on benthic infaunal composition and abundances through small-scale field experiments in 2 estuaries that differed in ambient nutrient conditions. A blocked experimental design was used that allowed an assessment of direct nutrient effects in the presence and absence of predation by epibenthic predators as well as an assessment of the independent effects of predation. Benthic microalgal production increased with experimental nutrient additions and was greater when infaunal abundances were lower, but there were no significant interactions between these factors. Increased abundances of one infaunal taxa, Laeonereis culveri, as well as the grazer feeding guild were observed with nutrient additions and a number of taxa exhibited higher abundances with predator exclusion. In contrast to results from freshwater systems there were no significant interactive effects between nutrient additions and predator exclusion as was predicted. The infaunal responses observed here emphasize the importance of both bottom-up (nutrient addition and primary producer driven) and top-down (predation) controls in structuring benthic communities. These processes may work at different spatial and temporal scales, and affect different taxa, making observation of potential interactive effects difficult.

  14. [Kinetic analysis of additive effect on desulfurization activity].

    PubMed

    Han, Kui-hua; Zhao, Jian-li; Lu, Chun-mei; Wang, Yong-zheng; Zhao, Gai-ju; Cheng, Shi-qing

    2006-02-01

    The additive effects of A12O3, Fe2O3 and MnCO3 on CaO sulfation kinetics were investigated by thermogravimetic analysis method and modified grain model. The activation energy (Ea) and the pre-exponential factor (k0) of surface reaction, the activation energy (Ep) and the pre-exponential factor (D0) of product layer diffusion reaction were calculated according to the model. Additions of MnCO3 can enhance the initial reaction rate, product layer diffusion and the final CaO conversion of sorbents, the effect mechanism of which is similar to that of Fe2O3. The method based isokinetic temperature Ts and activation energy can not estimate the contribution of additive to the sulfation reactivity, the rate constant of the surface reaction (k), and the effective diffusivity of reactant in the product layer (Ds) under certain experimental conditions can reflect the effect of additives on the activation. Unstoichiometric metal oxide may catalyze the surface reaction and promote the diffusivity of reactant in the product layer by the crystal defect and distinct diffusion of cation and anion. According to the mechanism and effect of additive on the sulfation, the effective temperature and the stoichiometric relation of reaction, it is possible to improve the utilization of sorbent by compounding more additives to the calcium-based sorbent.

  15. 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.

  16. Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB.

    PubMed

    Liu, An; Chen, Hui; Tong, Hongfei; Ye, Sheng; Qiu, Maixuan; Wang, Zhaohong; Tan, Wei; Liu, Jinxiang; Lin, Shengzhang

    2011-01-01

    Many studies have demonstrated that emodin inhibits the growth and induces the apoptosis and chemo-sensitization of various cancer cells in animal models. The aim of this study was to investigate the molecular mechanism of the chemo-sensitization potential of emodin on gemcitabine in pancreatic cancer cell lines via inhibition of nuclear factor-κB (NF-κB). SW1990 and SW1990/GZ cells were treated with: i) emodin (20 µmol/l), ii) NF-κB inhibitor Bay 11-7082 (5 µmol/l), iii) gemcitabine (20 µmol/l), iv) pre-treated with emodin for 24 h followed by coincubation with gemcitabine for 24 h, or v) pre-treated with Bay 11-7082 for 1 h followed by treatment with gemcitabine for 24 h. SW1990 and SW1990/GZ cells were also treated with emodin (20, 40 and 80 µmol/l). Cellular proliferation and apoptosis were detected by the Cell Counting Kit-8 (CCK-8) assay and flow cytometry. NF-κB protein was detected by Western blotting. SW1990/GZ cell morphological changes were observed under optical and fluorescence microscopes. Emodin strongly inhibited the proliferation and induced the apoptosis of both pancreatic cancer cell lines. Furthermore, emodin combined with gemcitabine induced a higher percentage of growth inhibition and apoptosis in both pancreatic cancer cell lines compared to gemcitabine alone. Pre-treatment of SW1990/GZ cells with Bay 11-7082 for 1 h followed by gemcitabine resulted in greater inhibitory and apoptosis rates compared to gemcitabine alone. The resistant pancreatic cell line SW1990/GZ presented higher constitutive NF-κB protein expression compared to the SW1990 cells. Emodin not only down-regulated NF-κB in a dose-dependent manner in SW1990 and SW1990/GZ cells under unstimulated conditions, but also inhibited gemcitabine-induced NF-κB protein expression. Emodin potentiated the antitumor effects of gemcitabine in pancreatic cancer, which was related to the down-regulation of NF-κB.

  17. 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.

  18. 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

  19. Antitumor effect of free rhodium (II) citrate and rhodium (II) citrate-loaded maghemite nanoparticles on mice bearing breast cancer: a systemic toxicity assay.

    PubMed

    Peixoto, Raphael Cândido Apolinário; Miranda-Vilela, Ana Luisa; de Souza Filho, José; Carneiro, Marcella Lemos' Brettas; Oliveira, Ricardo G S; da Silva, Matheus Oliveira; de Souza, Aparecido R; Báo, Sônia Nair

    2015-05-01

    Breast cancer is one of the most prevalent cancer types among women. The use of magnetic fluids for specific delivery of drugs represents an attractive platform for chemotherapy. In our previous studies, it was demonstrated that maghemite nanoparticles coated with rhodium (II) citrate (Magh-Rh2Cit) induced in vitro cytotoxicity and in vivo antitumor activity, followed by intratumoral administration in breast carcinoma cells. In this study, our aim was to follow intravenous treatment to evaluate the systemic antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. Female Balb/c mice were evaluated with regard to toxicity of intravenous treatments through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine and liver, kidney, and lung histology. The antitumor activity of rhodium (II) citrate (Rh2Cit), Magh-Rh2Cit, and maghemite nanoparticles coated with citrate (Magh-Cit), used as control, was evaluated by tumor volume reduction, histology, and morphometric analysis. Magh-Rh2Cit and Magh-Cit promoted a significant decrease in tumor area, and no experimental groups presented hematotoxic effects or increased levels of serum ALT and creatinine. This observation was corroborated by the histopathological examination of the liver and kidney of mice. Furthermore, the presence of nanoparticles was verified in lung tissue with no morphological changes, supporting the idea that our nanoformulations did not induce toxicity effects. No studies about the systemic action of rhodium (II) citrate-loaded maghemite nanoparticles have been carried out, making this report a suitable starting point for exploring the therapeutic potential of these compounds in treating breast cancer.

  20. HER-3 peptide vaccines/mimics: Combined therapy with IGF-1R, HER-2, and HER-1 peptides induces synergistic antitumor effects against breast and pancreatic cancer cells

    PubMed Central

    Miller, Megan Jo; Foy, Kevin C; Overholser, Jay P; Nahta, Rita; Kaumaya, Pravin TP

    2014-01-01

    The human epidermal growth factor receptor 3 (HER-3/ErbB3) is a unique member of the human epidermal growth factor family of receptors, because it lacks intrinsic kinase activity and ability to heterodimerize with other members. HER-3 is frequently upregulated in cancers with epidermal growth factor receptor (EGFR/HER-1/ErbB1) or human epidermal growth factor receptor 2 (HER-2/ErBB2) overexpression, and targeting HER-3 may provide a route for overcoming resistance to agents that target EGFR or HER-2. We have previously developed vaccines and peptide mimics for HER-1, HER-2 and vascular endothelial growth factor (VEGF). In this study, we extend our studies by identifying and evaluating novel HER-3 peptide epitopes encompassing residues 99–122, 140–162, 237–269 and 461–479 of the HER-3 extracellular domain as putative B-cell epitopes for active immunotherapy against HER-3 positive cancers. We show that the HER-3 vaccine antibodies and HER-3 peptide mimics induced antitumor responses: inhibition of cancer cell proliferation, inhibition of receptor phosphorylation, induction of apoptosis and antibody dependent cellular cytotoxicity (ADCC). Two of the HER-3 epitopes 237–269 (domain II) and 461–479 (domain III) significantly inhibited growth of xenografts originating from both pancreatic (BxPC3) and breast (JIMT-1) cancers. Combined therapy of HER-3 (461–471) epitope with HER-2 (266–296), HER-2 (597–626), HER-1 (418–435) and insulin-like growth factor receptor type I (IGF-1R) (56–81) vaccine antibodies and peptide mimics show enhanced antitumor effects in breast and pancreatic cancer cells. This study establishes the hypothesis that combination immunotherapy targeting different signal transduction pathways can provide effective antitumor immunity and long-term control of HER-1 and HER-2 overexpressing cancers. PMID:25941588

  1. Antitumor effects in vitro and in vivo and mechanisms of protection against melanoma B16F10-Nex2 cells by fastuosain, a cysteine proteinase from Bromelia fastuosa.

    PubMed

    Guimarães-Ferreira, Carla A; Rodrigues, Elaine G; Mortara, Renato A; Cabral, Hamilton; Serrano, Fabiana A; Ribeiro-dos-Santos, Ricardo; Travassos, Luiz R

    2007-09-01

    In the present work, the antitumor effect of fastuosain, a cysteine proteinase from Bromelia fastuosa, was investigated. In the intravenous model of lung colonization in C57Bl/6 mice, fastuosain and bromelain injected intraperitoneally were protective, and very few nodules of B16F10-Nex2 melanoma cells were detected. Tumor cells treated with fastuosain showed reduced expression of CD44 and decreased invasion through Matrigel, lost their cytoplasmic extensions and substrate adherence, and became round and detached, forming strongly bound cell clusters in suspension. Peritoneal cells recruited and activated by fastuosain treatment (mainly monocytic cells and lymphocytes) migrated to the lung, where pulmonary melanoma metastases grew. Adoptive transference of peritoneal cells recruited by fastuosain had no protective effect against lung metastases in recipient mice. Treatment of green fluorescent protein-chimeric animals with fastuosain did not change the number of cells that migrated to the lung, compared to PBS-injected control mice, but the number of positive major histocompatibility complex class II cells increased with fastuosain treatment. Murine antibodies against fastuosain, bromelain, and cathepsins B and L cross-reacted in ELISA and recognized surface and cytoplasmic components expressed on B16F10-Nex2 cells. Anti-fastuosain antibodies were cytotoxic/lytic to B16F10-Nex2 cells. Antitumor effects of fastuosain involve mainly the direct effect of the enzyme and elicitation of protective antibodies.

  2. Systemic antitumor immunity in experimental brain tumor therapy using a multimutated, replication-competent herpes simplex virus.

    PubMed

    Todo, T; Rabkin, S D; Sundaresan, P; Wu, A; Meehan, K R; Herscowitz, H B; Martuza, R L

    1999-11-20

    Replication-competent, attenuated herpes simplex virus (HSV) vectors have been developed for viral oncolytic therapy of primary and metastatic malignant brain tumors. However, the role of the host immune responses in the brain has not been elucidated. N18 neuroblastoma cells were used as a tumor model in syngeneic A/J mice to test the therapeutic efficacy of G207, a conditionally replicating HSV vector, in an immunocompetent condition. G207 inoculated intraneoplastically exhibited a prominent oncolytic antitumor effect in mice harboring N18 tumors in the brain or subcutaneously, and, in addition, elicited a systemic antitumor immune response. Subcutaneous tumor therapy with G207 caused regression of a remote, established tumor in the brain or in the periphery, which was potentially mediated by the systemic antitumor immune response, and provided persistent tumor-specific protection against N18 tumor rechallenge in the brain as well as in the periphery. Antitumor immunity was associated with an elevation of specific CTL activity against N18 tumor cells that persisted for at least 13 months. The results suggest that the oncolytic antitumor action of replication-competent HSV may be augmented by induction of specific and systemic antitumor immunity effective both in the periphery and in the brain.

  3. Antitumor effect of beta2-microglobulin in leukemic cell-bearing mice via apoptosis-inducing activity: activation of caspase-3 and nuclear factor-kappaB.

    PubMed

    Mori, M; Terui, Y; Tanaka, M; Tomizuka, H; Mishima, Y; Ikeda, M; Kasahara, T; Uwai, M; Ueda, M; Inoue, R; Itoh, T; Yamada, M; Hayasawa, H; Furukawa, Y; Ishizaka, Y; Ozawa, K; Hatake, K

    2001-06-01

    We have reported previously that beta2-microglobulin (beta2m) induces apoptosis in leukemic cells in vitro, and that an interaction between beta2m and HLA class I antigen induces apoptosis. Here we examined whether beta2m can induce apoptosis in leukemic cells in vivo and whether it has an antitumor effect in tumor-bearing mice. Daily administration of 50 or 250 microg of beta2m induced apoptosis and an antitumor effect on K562 leukemia cell-bearing mice in the same manner as tumor necrosis factor-alpha. In tumor tissues in beta2m-treated mice, both caspase-3 and nuclear factor-kappaB (NF-kappaB) were stained more strongly than in control mice by anti-caspase-3 and anti-NF-kappaB p65/Rel A polyclonal antibodies. We also observed the in vivo immunological effects of beta2m on lymphoid and hematopoietic organs, such as thymus, bone marrow, Peyer's patches, liver, and spleen in normal mice. Using antibodies against caspase-3 and NF-kappaB, immunohistochemical staining showed that no specific tissues were damaged or stained in normal mice. We conclude that beta2m stimulates caspase-3 and NF-kappaB pathways to induce apoptosis, making it a useful approach to a new therapy for leukemia.

  4. 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

  5. Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells.

    PubMed

    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

    2016-04-12

    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

  6. 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

  7. 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.

  8. 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)

  9. 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.

  10. Effects of additives on alum hematoxylin staining solutions.

    PubMed

    Clark, G

    1975-03-01

    All additives tested (ethyl alcohol, glycerine, chloral hydrate, ethylene and propylene glycol, and citric, malonic and maleic acids) in varying degrees limited the conversion of hematein to insoluble compounds. Peak absorbances increased slightly in hematoxylin solutions containing citric, malonic and maleic acids, but decreased with other additives, and in controls. After four months storage the absorbance in all solutions increased about 50%, acidity increased and staining effectiveness increased.

  11. 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

  12. 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

  13. 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

  14. Study on thermal effects & sulfurized additives, in lubricating greases

    NASA Astrophysics Data System (ADS)

    Shah, Ami Atul

    Lithium Base grease constitutes about 50% of market. The greases are developed to be able to work in multiple working conditions and have longer working life. Greases with extreme pressure additives and anti-wear additives have been developed as a solution to many of the applications. These developed greases are tested under ASTM D2266 testing conditions to meet the requirements. The actual working conditions, although, differ than the real testing conditions. The loading, speed and temperature conditions can be more harsh, or fluctuating in nature. The cyclic nature of the parameters cannot be directly related to the test performance. For this purpose studies on the performance under spectrum loading, variable speed and fluctuating temperature must be performed. This study includes tests to understand the effect of thermal variation on some of the most commonly used grease additives that perform well under ASTM D2266 testing conditions. The studied additives include most widely used industrial extreme pressure additive MoS2. Performance of ZDDP which is trying to replace MoS2 in its industrial applications has also been studied. The tests cover study of extreme pressure, anti-wear and friction modifier additives to get a general idea on the effects of thermal variation in three areas. Sulphur is the most common extreme pressure additive. Sulphur based MoS 2 is extensively used grease additive. Study to understand the tribological performance of this additive through wear testing and SEM/EDX studies has been done. This performance is also studied for other metallic sulfides like WS2 and sulphur based organic compound. The aim is to study the importance of the type of bond that sulphur shares in its additive's structure on its performance. The MoS2 film formation is found to be on the basis of the FeS formation on the substrate and protection through sacrificial monolayer deposition of the MoS2 sheared structure. The free Mo then tends to oxidise. An attempt to

  15. 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 ± 0.18 nM) and formed nanoparticles with an average diameter (~12 nm) above the threshold (~7 nm) 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 ± 0.87 h vs 0.32 ± 0.14 h). Tumor uptake of ABD-hTRAIL 8-48 h 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.

  16. Absolute Configuration of Dihydro-β-agarofuran Sesquiterpenes from Maytenus jelskii and Their Potential Antitumor-Promoting Effects.

    PubMed

    Perestelo, Nayra R; Jiménez, Ignacio A; Tokuda, Harukuni; Vázquez, Jesús T; Ichiishi, Eiichiro; Bazzocchi, Isabel L

    2016-09-23

    Chemoprevention of human cancer appears to be a feasible strategy for cancer control, especially when chemopreventive intervention is involved during early stages of the carcinogenesis process. As a part of our ongoing research program into new chemopreventive agents, herein are reported the isolation, structural elucidation, and biological evaluation of 10 new (1-10) and three known (11-13) sesquiterpenes with a dihydro-β-agarofuran skeleton from the leaves of Maytenus jelskii Zahlbr. Their stereostructures have been elucidated by means of spectroscopic analysis, including 1D and 2D NMR techniques, ECD studies, and biogenetic considerations. The isolated metabolites and eight previously reported sesquiterpenes (14-21) were screened for their antitumor-promoting activity using a short-term in vitro assay for Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Six compounds from this series (4, 5, 11, and 13-15) were found to exhibit higher efficacies than β-carotene, used as reference inhibitor for EBV-EA activation. In particular, promising antitumor activity was observed for compound 5, exhibiting inhibition even at the lowest concentration assayed (10 mol ratio/TPA). Preliminary structure-activity relationship analysis revealed that the acetate, benzoate, and hydroxy groups are the most desirable substituents on the sesquiterpene scaffold for activity in the EBV-EA activation assay. PMID:27541714

  17. In vivo antitumor and antioxidative effects of a rapeseed meal protein hydrolysate on an S180 tumor-bearing murine model.

    PubMed

    Xue, Zhaohui; Yu, Wancong; Wu, Moucheng; Wang, Jiehua

    2009-11-01

    The antitumor and antioxidative activities of a rapeseed protein hydrolysate (RSCH) obtained from rapeseed meal were evaluated by using an in vivo S180 tumor-bearing Kunming mice model. Tumor-bearing female mice were given RSCH for 10 at doses of 0, 50, 100, and 150 mg/kg/d by gastric perfusion. RSCH significantly decreased the tumor weight by 44% and 53% in the 100 and 150 mg/kg/d groups, respectively, without causing mortality or growth retardation. The thymus and spleen indices (organ weight relative to body weight) were increased significantly in the 150 mg/kg/d group. The phagocytic capability of coeliac macrophages and delayed-type hypersensitivity (DTH) were significantly increased in tumor-bearing mice treated with RSCH at 150 mg/kg/d. RSCH administration also enhanced the superoxide dismutase activity and reduced the serum level of thiobarbituric acid reactive substances. Our results show that an oral RSCH administration had an antitumor protective effect and may improve immune function by reducing free radical formation and oxidative stress in a murine model.

  18. Folic Acid-Metabolizing Enzymes Regulate the Antitumor Effect of 5-Fluoro-2′-Deoxyuridine in Colorectal Cancer Cell Lines

    PubMed Central

    Tsukihara, Hiroshi; Tsunekuni, Kenta; Takechi, Teiji

    2016-01-01

    In colorectal cancer chemotherapy, the current standard of care includes combination therapy with 5-fluorouracil (5-FU) and leucovorin (LV). However, the factors that determine the LV-mediated enhancement of 5-FU antitumor activity are not fully understood. Therefore, we investigated the roles of thymidine synthase (TYMS), folate receptor 1 (FOLR1), dihydrofolate reductase (DHFR), phosphoribosylglycinamide formyltransferase (GART), methylenetetrahydrofolate dehydrogenase (MTHFD1), and methylenetetrahydrofolate reductase (MTHFR) in LV-mediated enhancement of 5-fluoro-2′-deoxyuridine (FdUrd) cytotoxicity in vitro as a model of 5-FU antitumor activity. These genes were downregulated in DLD-1 and HCT116 human colorectal cancer cells by using small-interfering RNA. Reduced expression of TYMS mRNA significantly increased FdUrd cytotoxicity by 100- and 8.3-fold in DLD-1 and HCT116 cells, respectively. In contrast, reducing the expression of FOLR1, DHFR, GART, MTHFD1, and MTHFR decreased FdUrd cytotoxicity by 2.13- to 12.91-fold in DLD-1 cells and by 3.52- to 10.36-fold in HCT116 cells. These results demonstrate that folate metabolism is important for the efficacy of FdUrd. Overall, the results indicate that it is important to clarify the relationship between folate metabolism-related molecules and 5-FU treatment in order to improve predictions of the effectiveness of 5-FU and LV combination therapy. PMID:27685866

  19. 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

  20. Enhancement of anti-tumor effect of particulate vaccine delivery system by ‘Bacteriomimetic’ CpG functionalization of poly-lactic-co-glycolic acid nanoparticles

    PubMed Central

    Kokate, Rutika A; Thamake, Sanjay I; Chaudhary, Pankaj; Mott, Brittney; Raut, Sangram; Vishwanatha, Jamboor K; Jones, Harlan P

    2016-01-01

    Aim Low immunogenicity remains a major obstacle in realizing the full potential of cancer vaccines. In this study, we evaluated CpG-coated tumor antigen (Tag)-encapsulating ‘bacteriomimetic’ nanoparticles (CpG-nanoparticle [NP]-Tag NPs) as an approach to enhance anti-tumor immunity. Materials & methods CpG-NP-Tag NPs were synthesized, characterized for their physicochemical properties and tested in vivo. Results We found CpG predosing followed by intraperitoneal (IP) immunization with CpG-NP-Tag NPs significantly attenuated tumor growth in female BALB/c mice compared with respective controls. Histopathological and Immunofluorescence data revealed CpG-NP-Tag tumors had lower proliferation, higher apoptotic activity, greater CD4+ and CD8+ T cell infiltration as well as higher IFN-γ levels as compared with control groups. Conclusion Our findings suggest CpG-NP-Tag NPs can enhance anti-tumor effect of nanoparticulate tumor vaccination system. PMID:25867857

  1. Multitrophic effects of nutrient addition in upland grassland.

    PubMed

    Fountain, M T; Brown, V K; Gange, A C; Symondson, W O C; Murray, P J

    2008-06-01

    Although the effects of nutrient enhancement on aquatic systems are well documented, the consequences of nutritional supplements on soil food webs are poorly understood, and results of past research examining bottom-up effects are often conflicting. In addition, many studies have failed to separate the effects of nutrient enrichment and the physical effects of adding organic matter. In this field study, we hypothesised that the addition of nitrogen to soil would result in a trophic cascade, through detritivores (Collembola) to predators (spiders), increasing invertebrate numbers and diversity. Nitrogen and lime were added to plots in an upland grassland in a randomised block design. Populations of Collembola and spiders were sampled by means of pitfall traps and identified to species. Seventeen species of Collembola were identified from the nitrogen plus lime (N+L) and control plots. Species assemblage, diversity, richness, evenness and total number were not affected by nutrient additions. However, there was an increase in the number of Isotomidae juveniles and Parisotoma anglicana trapped in the N+L plots. Of the 44 spider species identified, over 80% were Linyphiidae. An effect on species assemblage from the addition of N+L to the plots was observed on two of the four sampling dates (July 2002 and June 2003). The linyphiid, Oedothorax retusus, was the only species significantly affected by the treatments and was more likely to be trapped in the control plots.The increased number of juvenile Collembola, and change in community composition of spiders, were consequences of the bottom-up effect caused by nutrient inputs. However, despite efforts to eliminate the indirect effects of nutrient inputs, a reduction in soil moisture in the N+L plots cannot be eliminated as a cause of the invertebrate population changes observed. Even so, this experiment was not confounded by the physical effects of habitat structure reported in most previous studies. It provides evidence

  2. Synergistic antitumor effect of a combination of paclitaxel and carboplatin with nobiletin from Citrus depressa on non-small-cell lung cancer cell lines.

    PubMed

    Uesato, Shinichi; Yamashita, Hirofumi; Maeda, Ryu; Hirata, Yoshiyuki; Yamamoto, Maho; Matsue, Saki; Nagaoka, Yasuo; Shibano, Makio; Taniguchi, Masahiko; Baba, Kimiye; Ju-ichi, Motoharu

    2014-04-01

    Non-small-cell lung carcinomas do not sufficiently respond to cancer chemotherapeutic drugs. Combination effects of cancer chemotherapy drugs (paclitaxel and carboplatin) with nobiletin or powdered Shiikuwasha extract from Citrus depressa were examined by isobologram and combination index analyses. It was demonstrated that the combination generated a synergistic inhibitory effect against the proliferation of the human non-small-cell lung carcinoma cell lines A549 and H460 and that of the two chemotherapy drugs, paclitaxel was responsible for this synergistic effect. Furthermore, the percentage of apoptotic cells was decreased with increasing rates of nobiletin to paclitaxel and carboplatin. These findings were considered to be attributed to the ability of nobiletin to regulate cells in the G1 phase, which escaped cell death initiated by paclitaxel and carboplatin. An antitumor activity assay showed that this combination significantly suppressed the growth of subcutaneous A549 tumor xenografts in nude mice.

  3. [RBE of neutrons from the BR-10 reactor based on their antitumor effect and on acute radiation reactions of the skin].

    PubMed

    Kuznetsova, M N; Ul'ianenko, S E

    1989-05-01

    The paper is concerned with the results of investigation of antitumor effectiveness (rats, sarcoma M-1) of neutron radiation of a BR-10 reactor with the mean energy of 0.85 MeV, correlated with the effect of 60Co gamma radiation (Luch-1). RBE in single local tumor radiation with neutrons was 4.5, being higher than RBE based on acute skin radiation reactions over a tumor (4.0). For this case FTA is over I (1.13) but slightly lower than after dose fractionated irradiation (1.18). Experimental data indicate the necessity of extending the clinical use of reactor neutrons and a profound study of the effects after neutron irradiation, particularly in dose-fractionated regimens.

  4. Redesigning nature's poisons to create anti-tumor reagents.

    PubMed

    Vitetta, E S; Fulton, R J; May, R D; Till, M; Uhr, J W

    1987-11-20

    Immunotoxins are conjugates of cell-reactive antibodies and toxins or their subunits. In this report, the chemistry, biology, pharmacokinetics, and anti-tumor effects of first generation immunotoxins; the preparation of improved second generation immunotoxins that display greater anti-tumor efficacy; and the role of genetic engineering in creating third-generation immunotoxins are discussed.

  5. Redesigning Nature's Poisons to Create Anti-Tumor Reagents

    NASA Astrophysics Data System (ADS)

    Vitetta, Ellen S.; Jerrold Fulton, R.; May, Richard D.; Till, Mark; Uhr, Jonathan W.

    1987-11-01

    Immunotoxins are conjugates of cell-reactive antibodies and toxins or their subunits. In this report, the chemistry, biology, pharmacokinetics, and anti-tumor effects of first generation immunotoxins; the preparation of improved second generation immunotoxins that display greater anti-tumor efficacy; and the role of genetic engineering in creating third-generation immunotoxins are discussed.

  6. Effects of additional cysteine in fish diet on mercury concentration.

    PubMed

    Mok, W J; Hatanaka, Y; Seoka, M; Itoh, T; Tsukamasa, Y; Ando, M

    2014-03-15

    Mercury contamination, especially of seafood, continues to attract public concern. Cysteine, NH2CH(CH2SH)COOH, is a naturally occurring hydrophobic amino acid that contains a thiol group. The purpose of our study was to investigate the use of the additive cysteine in fish diets to reduce mercury concentration in fish, and to observe the effectiveness of dietary cysteine in fish livers. Diets containing 1% and 10% cysteine successfully decreased mercury concentrations in fish compared with the 0% cysteine diet. The liver may have formed excessive lipid droplets or was unable to mobilize lipid stores during exposure to mercury; additional cysteine could help to mobilize excessive lipids in it.

  7. 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

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. Adenovirus-mediated p53 and ING4 gene co-transfer elicits synergistic antitumor effects through enhancement of p53 acetylation in breast cancer.

    PubMed

    Wu, Jie; Zhu, Yanbo; Xu, Chun; Xu, Hong; Zhou, Xiumin; Yang, Jicheng; Xie, Yufeng; Tao, Min

    2016-01-01

    Multigene-based combination therapy may be an effective practice in cancer gene therapy. Substantial studies have demonstrated that tumor suppressor p53 acetylation is indispensable for p53 activation. Inhibitor of growth 4 (ING4), as a novel tumor suppressor, is capable of remarkably enhancing p53 acetylation and its transcriptional activity. Hence, we assumed that combined treatment of p53 and ING4 double tumor suppressors would exhibit enhanced antitumor effects. The combined therapeutic efficacy of p53 and ING4 for human cancers has not been previously reported. We thus generated multiple promoter expression cassette-based recombinant adenovirus-co-expressing ING4 and p53 double tumor suppressor genes (AdVING4/p53), evaluated the combined effects of AdVING4/p53 on breast cancer using the MDA-MB-231 (mutant p53) human breast cancer cell line, and also elucidated its underlying molecular mechanisms. We demonstrated that AdVING4/p53-mediated p53 and ING4 co-expression induced synergistic growth inhibition and apoptosis as well as enhanced effects on upregulation of acetylated p53, P21, Bax, PUMA, Noxa, cleaved caspase-9, cleaved caspase-3 and cleaved PARP, and downregulation of Bcl-2, CD31 and microvessel density (MVD) in MDA-MB-231 breast cancer in vitro and/or in vivo subcutaneous (s.c.) xenografted tumors. The synergistic antitumor activity elicited by AdVING4/p53 was closely associated with the enhanced activation of the intrinsic apoptotic pathway and synergistic inhibition of tumor angiogenesis, very possibly via ING4-mediated enhancement of p53 acetylation and activity. Thus, our results indicate that cancer gene therapy combining two or more tumor suppressors such as p53 and ING4 may constitute a novel and effective therapeutic modality for human breast cancer and other cancers.

  13. 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

  14. 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

  15. 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.

  16. Survival of free and microencapsulated Bifidobacterium: effect of honey addition.

    PubMed

    Favarin, Luciana; Laureano-Melo, Roberto; Luchese, Rosa Helena

    2015-01-01

    This study evaluated the effect of honey addition on the viability of free and emulsion encapsulated cells of two strains of Bifidobacterium that underwent simulation of human upper gastrointestinal transit. In the control condition, without honey, free cells were drastically reduced after exposure to gastrointestinal conditions. The reduction was more pronounced with Bifidobacterium J7 of human origin. On the other hand, when cells were encapsulated, the viability reduction was higher for strain Bifidobacterium Bb12. The microencapsulation improved the viability maintenance of both Bifidobacterium strains, in recommended amounts for probiotic activity, after exposure to simulated gastrointestinal conditions. Moreover, suspending free cells of both Bifidobacterium strains in honey solutions resulted in a protective effect, equivalent to the plain microencapsulation with sodium alginate 3%. It is concluded that microencapsulation and the addition of honey improved the ability of Bifidobacterium to tolerate gastrointestinal conditions in vitro. PMID:25775038

  17. Effect of additives on the thermolysis of ammonia borane

    SciTech Connect

    Heldebrant, David J; Linehan, John C; Camaioni, Donald M; Rassat, Scot D; Zheng, Feng; Autrey, Thomas

    2007-08-21

    Ammonia borane (AB) is an attractive hydrogen storage material with high gravimetric and volumetric density of hydrogen. The thermolysis of solid ammonia borane follows sigmoidal kinetics with an "induction period" prior to rapid hydrogen release, generating a complex mixture of spent fuel products. We present evidence for the induction period involving isomerization of AB into the diammoniate of diborane (DADB). The induction period is substantially decreased with the addition of DADB. The induction period is also dependent on AB purity and temperature. Reducing the induction period and enhancing the rate of hydrogen release ultimately makes AB an attractive hydrogen storage material for fuel applications. This study profiles the mechanism of the thermolysis of AB, the effect of AB purity and the effect of chemical additives on the induction period and rates of dehydrogenation of AB.

  18. Antitumor effects and blood flow dynamics after photodynamic therapy using benzoporphyrin derivative monoacid ring A in KLN205 and LM8 mouse tumor models.

    PubMed

    Osaki, Tomohiro; Takagi, Satoshi; Hoshino, Yuki; Okumura, Masahiro; Fujinaga, Toru

    2007-04-01

    Photodynamic therapy (PDT) using benzoporphyrin derivative monoacid ring A (BPD-MA) induces direct tumor cell damage and microvascular injury. We administered BPD-MA at 3h or 15min before laser irradiation to KLN205 and LM8 tumors in murine models. Tumor growth delay was induced more effectively by 15-min-interval PDT than by 3-h-interval PDT. Vascularity and blood perfusion was significantly decreased by 15-min-interval PDT. We observed death of all tumor cells, except peripheral cells, in the 3-h-interval PDT group, and death of cells around the damaged tumor vasculature in the 15-min-interval PDT group. Thus, 15-min-interval PDT enhanced the antitumor effect by damaging tumor vasculature.

  19. 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

  20. 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

  1. 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

  2. Cantaloupe melon peroxidase: characterization and effects of additives on activity.

    PubMed

    Lamikanra, O; Watson, M A

    2000-06-01

    Peroxidase in cantaloupe melon (Cucumis melo L. var. reticulatus Naud.), a fruit commonly fresh cut processed, was characterized to determine reaction pathway, optimal conditions for activity and effect of some additives on enzymatic action. Mn2+, CaCl2, NaNO2 and kinetin had partial inhibitory effects on enzyme activity. Activity was effectively inhibited by compounds capable of chelating peroxidase heme iron such as diethyldithiocarbamate and tiron, but unaffected by EDTA. Free radical scavenger, superoxide dismutase, also had no effect on reaction velocity. Enzymatic action was consistent with that of ascorbate peroxidase based on the relatively higher affinity for ascorbate over guaiacol. Optimum activity temperature was 50-55 degrees C. The enzyme was stable at temperatures below 40 degrees C and at 50 degrees C for up to 10 min. Over 90% of total activity was lost at 80 degrees C within 5 min. Broad pH optima, 5.5-7.5 at 50 degrees C and 6-7 at 30 degrees C, were obtained. Peroxidase activity in cantaloupe was higher than those in strawberry (Fragaria ananassa Duch.) and lettuce (Lactuca sativa L.), suggesting a relatively high oxidative stress in fresh cut cantaloupe. The potential use of ascorbate as an additive in fresh cut cantaloupe melon was demonstrated by its ability to preserve color in minimally processed fruits for 25 days at 4 degrees C, possibly as a result of an enhanced antioxidative action of the ascorbate-peroxidase complex and trace metal ion cofactors.

  3. 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

  4. 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.

  5. Metabonomic study on the antitumor effect of flavonoid derivative 3d in HepG2 cells and its action mechanism.

    PubMed

    Gao, Dan; Jin, Feng; Liu, Hongxia; Wang, Yini; Jiang, Yuyang

    2014-01-01

    A novel flavonid derivate, 1-(3-chloro-4-(6-ethyl-4-oxo-4H-chromen-2-yl)phenyl)-3-(4-chlorophenyl)urea (3d) synthesized in our lab possesses potent antitumor activity against HepG2 cells. Our previous studies on pharmacological mechanism of 3d mostly focused on cell and gene levels, little is about its metabolomics study. 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 3d on HepG2 cells and its action mechanism. Q-TOF MS was used to identify metabolites, and tandem mass spectrometry was used to confirm their identity. Comparing 3d-treated HepG2 cells with vehicle control (dimethyl sulfoxide), 32 distinct metabolites involved in glutathione metabolism, glycerophospholipid metabolism, cysteine and methionine metabolism, fatty acid metabolism, and phenylalanine metabolism. The reduced level of glutathione (GSH) and decreased ratio of reduced/oxidized glutathione (GSH/GSSG) in 3d-treated cells indicated the increased oxidative stress after 3d treatment. The significant decrease of phosphatidylcholine (PC) levels and increase of lysophosphatidylcholine (LPC) levels suggested alterations in lipid composition which were causally related to decline in mitochondrial function. Depletion of carnitine and increase of long chain carnitines and fatty acids reflected decline in fatty acid metabolism. The further biological experiments including ROS and MMP measurements confirmed the above probabilities presumed from metabolomic results. Our findings suggested that 3d caused the perturbation of multiple cellular pathways. The increased oxidative stress and the resulting mitochondrial dysfunction resulted in the antiproliferative effect of 3d. The UPLC/Q-TOF MS based metabolomics approach provides new insights into the mechanistic studies of new compounds that distinct from traditional biological studies.

  6. Bevacizumab impairs oxidative energy metabolism and shows antitumoral effects in recurrent glioblastomas: a 31P/1H MRSI and quantitative magnetic resonance imaging study.

    PubMed

    Hattingen, Elke; Jurcoane, Alina; Bähr, Oliver; Rieger, Johannes; Magerkurth, Jörg; Anti, Sandra; Steinbach, Joachim P; Pilatus, Ulrich

    2011-12-01

    Bevacizumab shows unprecedented rates of response in recurrent glioblastomas (GBM), but the detailed mechanisms are still unclear. We employed in vivo magnetic resonance spectroscopic imaging (MRSI) and quantitative magnetic resonance imaging to investigate whether bevacizumab alters oxygen and energy metabolism and whether this effect has antitumoral activity in recurrent GBM. (31)P and (1)H MRSI, apparent diffusion coefficient (ADC), and high-resolution T2 and T2' mapping (indirect marker of oxygen extraction) were investigated in 16 patients with recurrent GBM at 3 Tesla before and 1.5-2 months after initiation of therapy with bevacizumab. Changes of metabolite concentrations and of the quantitative values in the tumor and normal appearing brain tissue were calculated. The Wilcoxon signed-ranks test was used to evaluate differences for tumor/edema versus control as well as changes before versus after commencement of therapy. Survival analyses were performed for significant parameters. Tumor T2', pH, ADC, and T2 decreased significantly in patients responding to bevacizumab therapy (n = 10). Patients with at least 25% T2' decrease during treatment showed longer progression-free and overall survival durations. Levels of high-energy metabolites were lower at baseline; these persisted under therapy. Glycerophosphoethanolamine as catabolic phospholipid metabolite increased in responders. The MRSI data support the hypothesis that bevacizumab induces relative tumor hypoxia (T2' decrease) and affects energy homeostasis in recurrent GBM, suggesting that bevacizumab impairs vascular function. The antiangiogenic effect of bevacizumab is predictive of better outcome and seems to induce antitumoral activity in the responding GBMs. PMID:21890539

  7. Pronounced effects of additional resistance in Andreev reflection spectroscopy

    NASA Astrophysics Data System (ADS)

    Chen, T. Y.; Huang, S. X.; Chien, C. L.

    2010-06-01

    We present a systematic investigation of the additional resistance (RE) , which is an unavoidable consequence of pseudo-four-probe electrical measurements, on the point-contact Andreev reflection (PCAR) spectrum by both modeling and experiments. Instead of considering the total resistance between the two voltage leads across a point contact as a sum of a contact resistance (RC) and a fixed sample resistance (RS) , it is essential to treat the total resistance as a sum of the Andreev resistance RAR and the additional resistance RE , which are, respectively, the resistances affected and unaffected by the Andreev reflection process. We show a detailed formalism of taking RE into account in modeling and demonstrate that the PCAR spectrum can be drastically affected by the presence of RE . Experimentally, we have found that not only RE cannot be readily measured or even estimated, it is in fact different for each contact, depending on the contact resistance and whether the contact is near the purely ballistic regime or the purely diffusive regime. A self-consistent process is necessary to analyze the entire PCAR spectrum, properly normalize the conductance, determine RE , and other parameters including the spin polarization and the superconducting gap for each contact. We determine RE for various contacts on specimens with different resistivity and resolve the causes of RE . For contacts close to the diffusive regime, there are two sources of RE : a dominant contribution which is linearly proportional to the total resistance and a constant value from the sample resistance. We also address the effects of additional resistance when PCAR is administered in the ballistic limit and in the diffusive limit. With the proper treatment of the additional resistance, we demonstrate that PCAR can quantitatively extract essential information of spin polarization and superconducting gap.

  8. 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

  9. 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.

  10. Effects of salinity and nutrient addition on mangrove Excoecaria agallocha.

    PubMed

    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.

  11. 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.

  12. Antitumor effects of hydroxycamptothecin-loaded poly[ethylene glycol]-poly [gamma-benzyl-L-glutamate] micelles against oral squamous cell carcinoma.

    PubMed

    Ding, Xue-Qiang; Chen, Dan; Wang, An-Xun; Li, Su; Chen, Yu; Wang, Ji

    2007-01-01

    Therapeutic use of hydroxycamptothecin (HCPT), a promising antitumor agent, is limited by its poor solubility and rapid destruction. Amphiphilic block copolymer micelle carriers possess significant potential for improving drug solubility and stability. Poly[ethylene glycol]-poly[gamma-benzyl-L-glutamate] (PEG-PBLG) micelles were prepared and loaded with the active lactone form of HCPT using an uncomplicated dialysis method. HPLC and scanning electron microscopy studies revealed an encapsulation efficiency of 56.8% and a core-shell figure with a mean diameter of 200 nm. Encapsulated HCPT lactone was compared with the less active, open ring-carboxylated HCPT-Na+ soluble form generated in vivo from the free active lactone for activity against oral squamous cell carcinoma. Cytotoxicity in vitro was measured in cultured Tca8113 cells by the MTT assay and microscopy techniques. The golden hamster cheek pouch squamous cell carcinoma model was employed for in vivo studies; encapsulated lactone and open ring-carboxylated forms of HCPT were administered intraperitoneally, followed by determinations of tumor growth rate and inhibition ratio. PEG-PBLG micelles were not cytotoxic in vitro. At 48 h of treatment, open ring-carboxylated HCPT proved significantly more cytotoxic in vitro than encapsulated HCPT lactone. At 96 h, however, the open ring-carboxylated and encapsulated drugs displayed comparable in vitro cytotoxicities. In the in vivo squamous cell carcinoma model, encapsulated HCPT lactone produced greater and more prolonged tumor suppression compared to the open ring-carboxylated form. The antitumor effects of HCPT/PEG-PBLG micelles against oral squamous cell carcinoma in vivo are concluded to be superior to those exerted by open ring-carboxylated HCPT. PMID:17518269

  13. Marine Antitumor Drugs: Status, Shortfalls and Strategies

    PubMed Central

    Bhatnagar, Ira; Kim, Se-Kwon

    2010-01-01

    Cancer is considered as one of the deadliest diseases in the medical field. Apart from the preventive therapies, it is important to find a curative measure which holds no loopholes and acts accurately and precisely to curb cancer. Over the past few decades, there have been advances in this field and there are many antitumor compounds available on the market, which are of natural as well as synthetic origin. Marine chemotherapy is well recognized nowadays and profound development has been achieved by researchers to deal with different molecular pathways of tumors. However, the marine environment has been less explored for the production of safe and novel antitumor compounds. The reason is a number of shortfalls in this field. Though ample reviews cover the importance and applications of various anticancerous compounds from marine natural products, in the present review, we have tried to bring the current status of antitumor research based on marine inhibitors of cancer signaling pathways. In addition, focus has been placed on the shortfalls and probable strategies in the arena of marine antitumor drug discovery. PMID:21116415

  14. Thermal processing of EVA encapsulants and effects of formulation additives

    SciTech Connect

    Pern, F.J.; Glick, S.H.

    1996-05-01

    The authors investigated the in-situ processing temperatures and effects of various formulation additives on the formation of ultraviolet (UV) excitable chromophores, in the thermal lamination and curing of ethylene-vinyl acetate (EVA) encapsulants. A programmable, microprocessor-controlled, double-bag vacuum laminator was used to study two commercial as formulated EVA films, A9918P and 15295P, and solution-cast films of Elvaxrm (EVX) impregnated with various curing agents and antioxidants. The results show that the actual measured temperatures of EVA lagged significantly behind the programmed profiles for the heating elements and were affected by the total thermal mass loaded inside the laminator chamber. The antioxidant Naugard P{trademark}, used in the two commercial EVA formulations, greatly enhances the formation of UV-excitable, short chromophores upon curing, whereas other tested antioxidants show little effect. A new curing agent chosen specifically for the EVA formulation modification produces little or no effect on chromophore formation, no bubbling problems in the glass/EVX/glass laminates, and a gel content of {approximately}80% when cured at programmed 155{degrees}C for 4 min. Also demonstrated is the greater discoloring effect with higher concentrations of curing-generated chromophores.

  15. Additional disinfectants effective against the amphibian chytrid fungus Batrachochytrium dendrobatidis.

    PubMed

    Webb, R; Mendez, D; Berger, L; Speare, R

    2007-02-01

    Chytridiomycosis, a disease contributing to amphibian declines worldwide, is caused by the fungus Batrachochytrium dendrobatidis. Identifying efficient and practical disinfectants effective against B. dendrobatidis is important to reduce the spread of the disease both in the wild and captivity. Previous studies identified a range of suitable disinfectant strategies. We evaluated the suitability of 3 additional disinfectants: two of these (TriGene Virucidal Disinfectant Cleaner and F10 Super Concentrate Disinfectant) are mixtures of chemicals and one (Betadine Antiseptic Liquid) contains a single active ingredient, povidone iodine. The disinfectants were tested using a range of concentrations for 1,5 and 10 min to determine their ability to kill B. dendrobatidis in vitro. The measure of effectiveness was 100% kill of zoosporangia grown in multiwell plates. All disinfectants had a 100% efficacy at concentrations recommended by the manufacturers. The lowest concentrations capable of 100% kill after exposure for 1 min were 0.1 ml l(-1) for TriGene, 0.33 ml l(-1) for F10 and 100 ml l(-1) for Betadine. TriGene is the most effective disinfectant yet to be found, and both TriGene and F10 are more effective than various disinfectants tested in previous studies. TriGene and F10 are considered suitable for use in the field, as only small amounts of concentrate are needed. PMID:17425259

  16. Additive effectiveness in minerally-enhanced slurry walls

    SciTech Connect

    Evans, J.C.; Prince, M.J.

    1997-12-31

    This study has presented evidence for improved design of soil-bentonite slurry trench cutoff walls for containment of contaminants in the subsurface. Conventional soil-bentonite vertical barriers are designed and built as hydraulic barriers. These studies show that these hydraulic barriers can be enhanced to significantly retard the transport of metals such as cadmium. The results of these laboratory studies and the associated mathematical modeling suggest that passive barrier systems can be readily transformed to active systems which effect some treatment of the ground water passing through the barrier. This study examined the effectiveness of three mineral enhancements (attapulgite, calcium chabazite and bentonite) on the retention of cadmium in barrier systems. Cadmium is chosen as the model compound because it is a common, hazardous contaminant which has been found to be among the most mobile of the heavy metals under a range of field conditions. Previous studies have predicted the migration rates of cadmium through adsorbent barrier systems by using isotherm data in conjunction with one dimensional transport models. This study extends the earlier work by examining the effect of adsorbent concentration on predicted barrier effectiveness. Enhancement of a soil-bentonite slurry wall backfill was best enhanced through the addition of attapulgite, followed by ca-chabazite and finally by increasing bentonite content. It was found that the effectiveness of barriers increases with adsorbent concentration. Increasing the bentonite content is less effective in retarding the transport of cadmium than adding attapulgite or ca-chabazite. Note that these were laboratory findings and readers are provided the usual caution regarding extrapolation to field performance.

  17. The effect of additives and substrates on nonferrous metal electrodeposition

    NASA Astrophysics Data System (ADS)

    Zhou, Zeyang

    Electrodeposits play an important role in science and industry today. Control of the quality of electrodeposits becomes more critical. One of the major factors which can lead to better products is the ability to control the electrocrystallization process to obtain smooth, dense and coherent deposits with good mechanical and physical properties, such as corrosion resistance, ductility and less internal stress. Many parameters may play a prominent role in electrodeposition. Two of the more important parameters is the control of impurities/additives present in the solution and cathode condition. In this study, the effects of small concentrations of tin additions on the composition, structure and surface morphology of Zn-Ni alloy deposits were studied. Electrochemical impedance spectroscopy (EIS) were conducted to study the role of tin in changing the charge transfer resistance of the reaction. The results obtained were promising in elucidating some basic factors which influence Zn-Ni alloy electrocrystallization mechanisms. The effects of thermal oxidation of stainless steel cathodes used in copper electrodeposition were studied. Particular emphasis was given to the initial stages of copper nucleation and growth. The copper electrocrystallization process was strongly influenced by the temperature applied in oxidizing the stainless steel. In this research, the effects of the impurities Alsp{3+} and Crsp{3+} using two stainless steels as cathodes during Ni electrowinning from a sulfate bath were studied. The current efficiency decreased in the presence of the impurities over the concentration range studied. Certain changes in the surface morphology, internal stress, crystallographic orientation and polarization behavior were observed. The changes were different for two stainless steel substrates.

  18. The effect of chemical additives on the synthesis of ethanol

    SciTech Connect

    Chuang, S.S.C.; Pien, S.I.

    1991-06-01

    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 electronegativeities. 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, reactive probing, steady state rate measurement, and transient kinetic study. CO insertion is known to be a key step to the formation of acetaldehyde and ethanol from CO hydrogenation. Reaction of ethylene with syngas is used as a probe to determine CO insertion capabilities of metal catalysts. During the sixth quarter of the project, the mechanism of CO insertion on Ni/SiO{sub 2} was investigated by in-situ infrared spectroscopy. Ni/SiO{sub 2}, a methanation catalyst, has been shown to exhibit CO insertion activity. In situ infrared studies of CO/H{sub 2} and C{sub 2}H{sub 4}/CO/H{sub 2} reactions show that the carbonylation of Ni/SiO{sub 2} to Ni(CO){sub 4} leads to an inhibition of methanation in CO hydrogenation but an enhancement of formation of propionaldehyde in C{sub 2}H{sub 4}/CO/H{sub 2} reaction. The results suggest that the sites for propionaldehyde formation is different from those for methanation.

  19. Effect of Nb addition on the microstructure of BNT ceramics

    NASA Astrophysics Data System (ADS)

    Sangsubun, Chontira

    2014-11-01

    This research studied the fabrication of bismuth-sodium-titanate (BNT) powders and the effect of Nb2O5 addition on the structure and the properties of BNT ceramics. The powders were synthesized via high-energy ball milling by using a mixed-oxide process. The results show that the perovskite structure was obtained in BNT powders at a calcination temperature of 800 °C. Particle sizes below 200 nm were observed. For the study, BNT/xNb ceramics were prepared using x = 0.01, 0.02, 0.03 and 0.05. The ceramics were sintered at a temperature of 1200 °C for 2 hours. The results showed that the relative density increased with increasing Nb2O5 from 0 to 0.03 whereas the grain size decreased with increasing Nb2O5 from 0.01 to 0.05. In addition, the dielectric constant increased with increasing Nb2O5 content.

  20. Effect of adsorbent addition on floc formation and clarification.

    PubMed

    Younker, Jessica M; Walsh, Margaret E

    2016-07-01

    Adding adsorbent into the coagulation process is an emerging treatment solution for targeting hard-to-remove dissolved organic compounds from both drinking water and industrial wastewater. The impact of adding powdered activated carbon (PAC) or organoclay (OC) adsorbents with ferric chloride (FeCl3) coagulant was investigated in terms of potential changes to the coagulated flocs formed with respect to size, structure, and breakage and regrowth properties. The ability of dissolved air flotation (DAF) and sedimentation (SED) clarification processes to remove hybrid adsorbent-coagulant flocs was also evaluated through clarified water quality analysis of samples collected in bench-scale jar test experiments. The jar tests were conducted using both a synthetic fresh water and oily wastewater test water spiked with dissolved aromatic compounds phenol and naphthalene. Results of the study demonstrated that addition of adsorbent reduced the median coagulated floc size by up to 50% but did not affect floc strength or regrowth potential after application of high shear. Experimental results in fresh water demonstrated that sedimentation was more effective than DAF for clarification of both FeCl3-PAC and FeCl3-OC floc aggregates. However, experimental tests performed on the synthetic oily wastewater showed that coagulant-adsorbent floc aggregates were effectively removed with both DAF and sedimentation treatment, with lower residual turbidity achieved in clarified water samples than with coagulation treatment alone. Addition of OC or PAC into the coagulation process resulted in removals of over half, or nearly all of the dissolved aromatics, respectively. PMID:27064206

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

    PubMed

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

    2013-01-01

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

  2. Enhanced antitumor effect and reduced vector dissemination with fiber-modified adenovirus vectors expressing herpes simplex virus thymidine kinase.

    PubMed

    Mizuguchi, Hiroyuki; Hayakawa, Takao

    2002-03-01

    There are at least two hurdles confronting the use of the adenovirus (Ad)-mediated herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) system for the treatment of cancer. One is inefficient Ad vector-mediated gene transfer into tumor cells lacking the primary receptor, i.e., the coxsackievirus and adenovirus receptor (CAR). The other is hepatotoxicity due to unwanted vector spread into the liver, even when Ad vectors are injected intratumorally. Herein, we present an attractive strategy for overcoming such limitations based on use of a fiber-modified Ad vector containing an RGD peptide motif in the fiber knob. HSVtk-expressing Ad vectors containing mutant fiber (AdRGD-tk) or wild-type fiber (Ad-tk) were injected intratumorally into CAR-negative B16 melanoma cells inoculated into mice, after which GCV was injected intraperitoneally for 10 days. AdRGD-tk showed approximately 25 times more antitumor activity than Ad-tk. Histopathological studies suggested that liver damage in mice injected with AdRGD-tk was significantly lower than that in mice injected with Ad-tk. Intratumoral administration of luciferase-expressing Ad vectors containing the mutant fiber (AdRGD-L2) resulted in nearly 40 times more luciferase production in the tumor, but 8 times less production in the liver than the conventional Ad vectors (Ad-L2). These results indicate that combination of fiber-modified vectors and a HSVtk/GCV system is a potentially useful and safe approach for the treatment of tumors lacking CAR expression, and that fiber-modified vectors could be of great utility for gene therapy and gene transfer experiments. PMID:11896439

  3. Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current

    PubMed Central

    Barbieri, Federica; Peretti, Marta; Pizzi, Erika; Pattarozzi, Alessandra; Carra, Elisa; Sirito, Rodolfo; Daga, Antonio; Curmi, Paul M.G.; Mazzanti, Michele; Florio, Tullio

    2014-01-01

    Epidemiological and preclinical studies propose that metformin, a first-line drug for type-2 diabetes, exerts direct antitumor activity. Although several clinical trials are ongoing, the molecular mechanisms of this effect are unknown. Here we show that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin exposure induces antiproliferative effects in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human glioblastomas. These effects phenocopy metformin-mediated inhibition of a chloride current specifically dependent on CLIC1 functional activity. CLIC1 ion channel is preferentially active during the G1-S transition via transient membrane insertion. Metformin inhibition of CLIC1 activity induces G1 arrest of glioblastoma stem cells. This effect was time-dependent, and prolonged treatments caused antiproliferative effects also for low, clinically significant, metformin concentrations. Furthermore, substitution of Arg29 in the putative CLIC1 pore region impairs metformin modulation of channel activity. The lack of drugs affecting cancer stem cell viability is the main cause of therapy failure and tumor relapse. We identified CLIC1 not only as a modulator of cell cycle progression in human glioblastoma stem cells but also as the main target of metformin's antiproliferative activity, paving the way for novel and needed pharmacological approaches to glioblastoma treatment. PMID:25361004

  4. Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current.

    PubMed

    Gritti, Marta; Würth, Roberto; Angelini, Marina; Barbieri, Federica; Peretti, Marta; Pizzi, Erika; Pattarozzi, Alessandra; Carra, Elisa; Sirito, Rodolfo; Daga, Antonio; Curmi, Paul M G; Mazzanti, Michele; Florio, Tullio

    2014-11-30

    Epidemiological and preclinical studies propose that metformin, a first-line drug for type-2 diabetes, exerts direct antitumor activity. Although several clinical trials are ongoing, the molecular mechanisms of this effect are unknown. Here we show that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin exposure induces antiproliferative effects in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human glioblastomas. These effects phenocopy metformin-mediated inhibition of a chloride current specifically dependent on CLIC1 functional activity. CLIC1 ion channel is preferentially active during the G1-S transition via transient membrane insertion. Metformin inhibition of CLIC1 activity induces G1 arrest of glioblastoma stem cells. This effect was time-dependent, and prolonged treatments caused antiproliferative effects also for low, clinically significant, metformin concentrations. Furthermore, substitution of Arg29 in the putative CLIC1 pore region impairs metformin modulation of channel activity. The lack of drugs affecting cancer stem cell viability is the main cause of therapy failure and tumor relapse. We identified CLIC1 not only as a modulator of cell cycle progression in human glioblastoma stem cells but also as the main target of metformin's antiproliferative activity, paving the way for novel and needed pharmacological approaches to glioblastoma treatment.

  5. Effect of salts addition on hydrogen production by C. acetobutylicum.

    PubMed

    Alshiyab, H; Kalil, M S; Hamid, A A; Wan Yusoff, W M

    2008-09-15

    The objective of this study is to investigate the effect of salts addition to fermentation medium on hydrogen production, under anaerobic batch culture system. In this study, batch experiments were conducted to investigate the inhibitory effect of both NaCl and sodium acetate on hydrogen production. The optimum pH and temperature for hydrogen production were at initial pH of 7.0 and 30 degrees C. Enhanced production of hydrogen, using glucose as substrate was achieved. In the absence of Sodium Chloride and Sodium Acetate enhanced hydrogen yield (Y(P/S)) from 350 mL g(-1) glucose utilized to 391 mL g(-1) glucose utilized with maximum hydrogen productivity of 77.5 ml/L/h. Results also show that sodium chloride and sodium acetate in the medium adversely affect growth. Hydrogen yield per biomass (Y(P/X)) of 254 ml/L/g, biomass per substrate utilized (Y(X/S)) of 0.268 and (Y(H2/S) of 0.0349. The results suggested that Sodium at any concentration resulted to inhibit the bacterial productivity of hydrogen.

  6. Constant-Pressure Combustion Charts Including Effects of Diluent Addition

    NASA Technical Reports Server (NTRS)

    Turner, L Richard; Bogart, Donald

    1949-01-01

    Charts are presented for the calculation of (a) the final temperatures and the temperature changes involved in constant-pressure combustion processes of air and in products of combustion of air and hydrocarbon fuels, and (b) the quantity of hydrocarbon fuels required in order to attain a specified combustion temperature when water, alcohol, water-alcohol mixtures, liquid ammonia, liquid carbon dioxide, liquid nitrogen, liquid oxygen, or their mixtures are added to air as diluents or refrigerants. The ideal combustion process and combustion with incomplete heat release from the primary fuel and from combustible diluents are considered. The effect of preheating the mixture of air and diluents and the effect of an initial water-vapor content in the combustion air on the required fuel quantity are also included. The charts are applicable only to processes in which the final mixture is leaner than stoichiometric and at temperatures where dissociation is unimportant. A chart is also included to permit the calculation of the stoichiometric ratio of hydrocarbon fuel to air with diluent addition. The use of the charts is illustrated by numerical examples.

  7. Possible neurologic effects of aspartame, a widely used food additive.

    PubMed

    Maher, T J; Wurtman, R J

    1987-11-01

    The artificial sweetener aspartame (L-aspartyl-L-phenylalanyl-methyl ester), is consumed, primarily in beverages, by a very large number of Americans, causing significant elevations in plasma and, probably, brain phenylalanine levels. Anecdotal reports suggest that some people suffer neurologic or behavioral reactions in association with aspartame consumption. Since phenylalanine can be neurotoxic and can affect the synthesis of inhibitory monoamine neurotransmitters, the phenylalanine in aspartame could conceiveably mediate neurologic effects. If mice are given aspartame in doses that elevate plasma phenylalanine levels more than those of tyrosine (which probably occurs after any aspartame dose in humans), the frequency of seizures following the administration of an epileptogenic drug, pentylenetetrazole, is enhanced. This effect is simulated by equimolar phenylalanine and blocked by concurrent administration of valine, which blocks phenylalanine's entry into the brain. Aspartame also potentiates the induction of seizures by inhaled fluorothyl or by electroconvulsive shock. Perhaps regulations concerning the sale of food additives should be modified to require the reporting of adverse reactions and the continuing conduct of mandated safety research.

  8. Anti-tumor effect of inflammatory neutrophils: characteristics of in vivo generation and in vitro tumor cell lysis.

    PubMed

    Lichtenstein, A; Kahle, J

    1985-01-15

    Inflammatory neutrophils elicited by intraperitoneal injection of Corynebacterium parvum, thioglycollate or proteose peptone were capable of lysing different murine and human tumor targets in a short-term chromium-release assay. A single-cell cytotoxicity assay, which evaluated effector-target cell interactions at the single-cell level, confirmed a PMN-mediated tumor-lytic effect. Optimal lysis was achieved by PMNs obtained 6 hr after injection of C. parvum and 16 hr after injection of thioglycollate. In vitro, loss of tumor cell membrane integrity occurred extremely rapidly following conjugation with inflammatory PMNs (beginning within 15 min of the binding step). By 45 min, the lytic event was completed. Addition of catalase or superoxide dismutase to the cytotoxicity assays prevented tumor lysis in a concentration-dependent fashion, indicating that hydrogen peroxide and superoxide, products of the PMN respiratory burst, are mediators of the lytic reaction. PMID:3917986

  9. Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents–A drug repurposing strategy

    PubMed Central

    Wu, Chia-Hsien; Bai, Li-Yuan; Tsai, Ming-Hsui; Chu, Po-Chen; Chiu, Chang-Fang; Chen, Michael Yuanchien; Chiu, Shih-Jiuan; Chiang, Jo-Hua; Weng, Jing-Ru

    2016-01-01

    Phenothiazines (PTZs) have been used for the antipsychotic drugs for centuries. However, some of these PTZs have been reported to exhibit antitumor effects by targeting various signaling pathways in vitro and in vivo. Thus, this study was aimed at exploiting trifluoperazine, one of PTZs, to develop potent antitumor agents. This effort culminated in A4 [10-(3-(piperazin-1-yl)propyl)-2-(trifluoromethyl)-10H-phenothiazine] which exhibited multi-fold higher apoptosis-inducing activity than the parent compound in oral cancer cells. Compared to trifluoperazine, A4 demonstrated similar regulation on the phosphorylation or expression of multiple molecular targets including Akt, p38, and ERK. In addition, A4 induced autophagy, as evidenced by increased expression of the autophagy biomarkers LC3B-II and Atg5, and autophagosomes formation. The antitumor activity of A4 also related to production of reactive oxygen species and adenosine monophosphate-activated protein kinase. Importantly, the antitumor utility of A4 was extended in vivo as it, administrated at 10 and 20 mg/kg intraperitoneally, suppressed the growth of Ca922 xenograft tumors. In conclusion, the ability of A4 to target diverse aspects of cancer cell growth suggests its value in oral cancer therapy. PMID:27277973

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

    PubMed Central

    Monteiro, Luara de Sousa; Bastos, Katherine Xavier; Barbosa-Filho, José Maria; de Athayde-Filho, Petrônio Filgueiras; Diniz, Margareth de Fátima Formiga Melo; Sobral, Marianna Vieira

    2014-01-01

    Lung cancer is a disease with high morbidity and mortality rates. As a result, it is often associated with a significant amount of suffering and a general decrease in the quality of life. Herbal medicines are recognized as an attractive approach to lung cancer therapy with little side effects and are a major source of new drugs. The aim of this work was to review the medicinal plants and other living organisms with antitumor potential against lung cancer. The assays were conducted with animals and humans, and Lewis lung carcinoma was the most used experimental model. China, Japan, South Korea, and Ethiopia were the countries that most published studies of species with antitumor activity. Of the 38 plants evaluated, 27 demonstrated antitumor activity. In addition, six other living organisms were cited for antitumor activity against lung cancer. Mechanisms of action, combination with chemotherapeutic drugs, and new technologies to increase activity and reduce the toxicity of the treatment are discussed. This review was based on the NAPRALERT databank, Web of Science, and Chemical Abstracts. This work shows that natural products from plants continue to be a rich source of herbal medicines or biologically active compounds against cancer. PMID:25147575

  11. The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1{alpha} targeted gene expression

    SciTech Connect

    Miyake, Kotaro; Nishioka, Masanori; Imura, Satoru; Batmunkh, Erdenebulgan; Uto, Yoshihiro; Nagasawa, Hideko; Hori, Hitoshi; Shimada, Mitsuo

    2012-08-01

    Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel hypoxic cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1{alpha} (HIF-1{alpha}), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P < 0.01 versus control). Quantitative real-time reverse transcription-PCR analysis revealed that TX-2098 significantly inhibited mRNA expression of the HIF-1 associated molecules, VEGF, glucose transporter 1 and Aldolase A (P < 0.01 versus control). These treatments also prolong the survival in orthotopic models. These results suggest that the effect of TX-2098 in pancreatic cancer might be correlated with the expression of VEGF and HIF-1 targeted molecules. -- Highlights: Black-Right-Pointing-Pointer We designed and synthesized novel hypoxic cytoxin, TX-2098. Black-Right-Pointing-Pointer TX-2098 inhibited the proliferation of human pancreatic cancer cells than TPZ. Black-Right-Pointing-Pointer TX-2098 reduced VEGF protein level than TPZ. Black-Right-Pointing-Pointer TX-2098

  12. [The mechanism of potentiation of the antitumor effect of 5-fluorouracil by methionine-free intravenous amino acid solution (AO-90) in rats].

    PubMed

    Hibino, Y; Kawarabayashi, Y; Kohri, H; Ueda, N; Tsukagoshi, S

    1994-09-01

    AO-90, a methionine-free intravenous amino acid solution (7.43%) showed to potentiate the antitumor effect of 5-fluorouracil (5-FU) when concomitantly used as the nitrogen source in total parenteral nutrition (TPN) in Yoshida sarcoma (YS)-bearing rats. In the present experiment, this potentiation mechanism was studied by determining the serum methionine level and tumor methylenetetrahydrofolate (CH2FH4) content in YS-bearing Donryu rats given AO-90 (nitrogen 0.73g/kg on the 1st day and 1.46g/kg for the remaining 6 days) by TPN for 1 week. The rats were subcutaneously inoculated with 10(4) YS cells in the dorsum 3 days before the start of TPN. Inhibition of thymidylate synthase activity in tumor tissue after dosing of AO-90 (nitrogen 0.68g/kg on the 1st day and 1.36 g/kg for the remaining 6 days) by TPN along with daily intraperitoneal dosing of 5-FU (10 mg/kg) was also evaluated with the inoculation of 10(6) tumor cells. The results were compared with those in tumor-bearing rats given TPN with a commercially available amino acid solution containing methionine. On day 5 of TPN, the tumor-bearing rats given AO-90 showed a significantly lower serum methionine level than the control rats: 101 +/- 11 mumol/l versus 29 +/- 14 mumol/l (p < 0.01); and a higher CH2FH4 content in tumor: 7.0 +/- 2.8 pmol/g protein versus 23.7 +/- 16.6 pmol/g protein (p < 0.05). Thymidylate synthase inhibition was 81.2 +/- 5.1% in the AO-90 group and 30.9 +/- 26.3% in the control group (p < 0.01). The results of the present study suggest that AO-90 potentiate the antitumor effect of 5-FU by biochemical modulation. AO-90 concomitantly given with 5-FU for 7 days was effective not only in the allogeneic tumor model, but also in WKAH and SHR rats previously inoculated with 10(6) of syngeneic KDH-8 hepatoma cells and SST-2 adenocarcinoma cells, respectively. Weight of SST-2 adenocarcinoma in SHR rats after the TPN period was significantly smaller in the AO-90 group than in the control rats given

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

    PubMed

    Meng, Xin; Liang, Hebin; Luo, Lixin

    2016-04-01

    Mushrooms are popular folk medicines that have attracted considerable attention because of their efficient antitumor activities. This review covers existing research achievements on the mechanisms of isolated mushroom polysaccharides, particularly (1→3)-β-D-glucans. Our review also describes the function in modulating the immune system and potential tumor-inhibitory effects of polysaccharides. The antitumor mechanisms of mushroom polysaccharides are mediated by stimulated T cells or other immune cells. These polysaccharides are able to trigger various cellular responses, such as the expression of cytokines and nitric oxide. Most polysaccharides could bind other conjugate molecules, such as polypeptides and proteins, whose conjugation always possess strong antitumor activities. The purpose of this review is to summarize available information, and to reflect the present situation of polysaccharide research filed with a view for future direction. PMID:26974354

  14. Albumin-Binding and Tumor Vasculature Determine the Antitumor Effect of 15-Deoxy-Δ12,14-Prostaglandin-J2 in vivo1

    PubMed Central

    Prakash, Jai; Bansal, Ruchi; Post, Eduard; de Jager-Krikken, Alie; Lub-de Hooge, Marjolijn N; Poelstra, Klaas

    2009-01-01

    15-Deoxy-Δ12,14-prostaglandin-J2 (15d-PGJ2), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, induces cell death in tumor cells in vitro; however, no study showed its in vivo effect on tumors. Here, we report that 15d-PGJ2 shows antitumor effects in vivo in mice. However, its effects correlate with tumor uptake of albumin, to which it reversibly binds. 15d-PGJ2 induces cell death in B16F10 melanoma and C26 colon carcinoma cells in vitro. These effects were not elicited through PPARγ-dependent pathways because an irreversible PPARγ antagonist GW9662 did not inhibit these effects. Caspase- and nuclear factor κB- (NF-κB) dependent pathways were found to be involved as determined with caspase-3/7 fluorescent assay and NF-κB containing plasmid transfection assay, respectively. Noticeably, 15d-PGJ2 had significantly stronger effects in C26 cells compared with B16 cells in all assays. However, in vivo, there was no effect on C26 tumors, yet it significantly inhibited the B16 tumor growth in mice by 75%. We found that 15d-PGJ2 rapidly bound to albumin and in vivo albumin greatly distributed to B16 tumors compared with C26 tumors, shown with γ-camera imaging and immunohistochemical staining. Albumin accumulation can be attributed to the large blood vessel diameter in B16 tumors and an enhanced permeability and retention effect. These findings suggest that 15d-PGJ2 can be an effective therapeutic agent for cancer, although its effects seem to be limited to the tumors allowing albumin penetration. PMID:20019843

  15. Enhancing the circulating half-life and the antitumor effects of a tumor-selective cytotoxic peptide by exploiting endogenous serum albumin as a drug carrier.

    PubMed

    Su, Tao; Yang, Hao; Fan, Qing; Jia, Dianlong; Tao, Ze; Wan, Lin; Lu, Xiaofeng

    2016-02-29

    The elevated expression of bombesin receptors in many of the deadliest cancers has attracted special interest in developing bombesin-directed agents for tumor imaging and therapy. Previously, we constructed the chimeric peptide BB28 by fusing bombesin to a mitochondria-disrupting peptide. BB28 selectively induced the apoptosis of various tumor cells in vitro and showed promising in vivo antitumor effects. In general, a short circulating half-life limits the in vivo effect of peptides. To prolong the half-life of BB28, here, we generated the novel peptide ABB28 by fusing an albumin-binding domain (ABD) to the N-terminus of BB28. ABB28 exhibited much higher binding affinity for albumin than BB28, and this modification extended the peptide half-life from several minutes to 2 h. Optical imaging revealed that ABB28 accumulated in xenografted tumors within 1h post-injection and persisted at an evident level for up to 24 h. ABB28 exerted stronger tumor-suppressive effects than BB28. Significant differences in the tumor volumes (P<0.001) and the tumor weights (P=0.002) were observed between ABB28- and BB28-treated mice. Moreover, ABB28 exhibited tumor suppression comparable to that of PEGylated 5K-BB28 in vivo. These results suggest that half-life extension via ABD fusion represents a useful strategy for optimizing bombesin-directed pharmaceuticals for cancer-targeted therapy.

  16. Insights on the antitumor effects of kahweol on human breast cancer: Decreased survival and increased production of reactive oxygen species and cytotoxicity

    SciTech Connect

    Cárdenas, Casimiro; Quesada, Ana R.; Medina, Miguel Ángel

    2014-05-09

    Highlights: • Kahweol inhibits growth and attachment-independent proliferation of tumor cells. • Kahweol induces apoptosis in MDA-MB231 human breast cancer cells. • Kahweol-induced apoptosis involves caspase activation and cytochrome c release. • Kahweol does not protect against hydrogen peroxide cytotoxicity. • Kahweol increases hydrogen peroxide production by human breast cancer cells. - Abstract: The present study aims to identify the modulatory effects of kahweol, an antioxidant diterpene present in coffee beans, on a panel of human tumor cell lines. Kahweol inhibits tumor cell proliferation and clonogenicity and induces apoptosis in several kinds of human tumor cells. In the estrogen receptor-negative MDA-MB231 human breast cancer, the mentioned effects are accompanied by caspases 3/7 and 9 activation and cytochrome c release. On the other hand, kahweol increases the production of reactive oxygen species and their cytotoxicity in human breast cancer cells but not in normal cells. Taken together, our data suggest that kahweol is an antitumor compound with inhibitory effects on tumor cell growth and survival, especially against MDA-MB231 breast cancer cells.

  17. Potentiation of antitumor drug action by centrophenoxine: specificity.

    PubMed

    Sladek, N E

    1977-05-01

    The cytotoxic action of certain antitumor agents is potentiated by centrophenoxine although centrophenoxine itself is not an antitumor agent. Previous investigations have suggested that centrophenoxine might potentiate the cytotoxicity produced by antitumor drugs that alkylate, and other modalities that damage, DNA, but that it would not potentiate the cytotoxicity produced by antitumor drugs that inflict cellular damage in other ways. To test this hypothesis, the antitumor effects of X-irradiation UV-irradiation, alkylating agents and antitumor drugs that are not ordinarily considered to be alkylating agents were determined in the presence and absence of centrophenoxine. Mouse P388 lymphoma cells growing in static suspension culture were used as the experimental tumor. The cytotoxic action of most alkylating agents was found to be potentiated by centrophenoxine; Included in this group were several difunctional nitrogen mustards, two ethylenimines, a nitrosourea and mitomycin C. Greatest enhancement, 7-fold, was of chlorambucil antitumor activity. Centrophenoxine did not potentiate the lethality of X- or UV-irradiation or the cytotoxicity of several antineoplastic drugs that are not alkylating agents.

  18. Lubricant and additive effects on spur gear fatigue life

    NASA Technical Reports Server (NTRS)

    Townsend, D. P.; Zaretsky, E. V.; Scibbe, H. W.

    1985-01-01

    Spur gear endurance tests were conducted with six lubricants using a single lot of consumable-electrode vacuum melted (CVM) AISI 9310 spur gears. The sixth lubricant was divided into four batches each of which had a different additive content. Lubricants tested with a phosphorus-type load carrying additive showed a statistically significant improvement in life over lubricants without this type of additive. The presence of sulfur type antiwear additives in the lubricant did not appear to affect the surface fatigue life of the gears. No statistical difference in life was produced with those lubricants of different base stocks but with similar viscosity, pressure-viscosity coefficients and antiwear additives. Gears tested with a 0.1 wt % sulfur and 0.1 wt % phosphorus EP additives in the lubricant had reactive films that were 200 to 400 (0.8 to 1.6 microns) thick.

  19. Lubricant and additive effects on spur gear fatigue life

    NASA Technical Reports Server (NTRS)

    Townsend, D. P.; Zaretsky, E. V.; Scibbe, H. W.

    1986-01-01

    Spur gear endurance tests were conducted with six lubricants using a single lot of consumable-electrode vacuum melted (CVM) AISI 9310 spur gears. The sixth lubricants was divided into four batches each of which had a different additive content. Lubricant tested with a phosphorus-type load carrying additive showed a statistically significant improvement in life over lubricants without this type of additive. The presence of sulfur type antiwear additives in the lubricant did not appear to affect the surface fatigue life of the gears. No statistical difference in life was produced with those lubricants of different base stocks but with similar viscosity, pressure-viscosity coefficients and antiwar additives. Gears tested with a 0.1 wt pct sulfur and 0.1 wt pct phosphorus EP additives in the lubricant had reactive films that were 200 to 400 (0.8 to 1.6 microns) thick.

  20. Chemistry of Food Additives: Direct and Indirect Effects.

    ERIC Educational Resources Information Center

    Pauli, George H.

    1984-01-01

    The primary component(s), impurities, and degradation products of polysorbate 80, nitrate and nitrite salts, and diethylpyrocarbonate (DEPC) are discussed. Safety considerations related to these food additives are also noted. The chick-edema factor which results from an additive in poultry feed is also discussed. (JN)

  1. Efficient anti-tumor effect of photodynamic treatment with polymeric nanoparticles composed of polyethylene glycol and polylactic acid block copolymer encapsulating hydrophobic porphyrin derivative.

    PubMed

    Ogawara, Ken-ichi; Shiraishi, Taro; Araki, Tomoya; Watanabe, Taka-ichi; Ono, Tsutomu; Higaki, Kazutaka

    2016-01-20

    To develop potent and safer formulation of photosensitizer for cancer photodynamic therapy (PDT), we tried to formulate hydrophobic porphyrin derivative, photoprotoporphyrin IX dimethyl ester (PppIX-DME), into polymeric nanoparticles composed of polyethylene glycol and polylactic acid block copolymer (PN-Por). The mean particle size of PN-Por prepared was around 80nm and the zeta potential was determined to be weakly negative. In vitro phototoxicity study for PN-Por clearly indicated the significant phototoxicity of PN-Por for three types of tumor cells tested (Colon-26 carcinoma (C26), B16BL6 melanoma and Lewis lung cancer cells) in the PppIX-DME concentration-dependent fashion. Furthermore, it was suggested that the release of PppIX-DME from PN-Por would gradually occur to provide the sustained release of PppIX-DME. In vivo pharmacokinetics of PN-Por after intravenous administration was evaluated in C26 tumor-bearing mice, and PN-Por exhibited low affinity to the liver and spleen and was therefore retained in the blood circulation for a long time, leading to the efficient tumor disposition of PN-Por. Furthermore, significant and highly effective anti-tumor effect was confirmed in C26 tumor-bearing mice with the local light irradiation onto C26 tumor tissues after PN-Por injection. These findings indicate the potency of PN-Por for the development of more efficient PDT-based cancer treatments.

  2. Role of nitric oxide in the anti-tumoral effect of retinoic acid and 1,25-dihydroxyvitamin D3 on human promonocytic leukemic cells.

    PubMed

    Dugas, N; Mossalayi, M D; Calenda, A; Léotard, A; Bécherel, P; Mentz, F; Ouaaz, F; Arock, M; Debré, P; Dornand, J; Dugas, B

    1996-11-01

    All trans retinoic acid and vitamin D3 derivatives are well known for their antileukemic activity, while the precise mechanism of this effect remains to be clarified. Using human leukemic U937 and THP-1 promonocytic cell lines, we analyzed the effect of all-trans retinoic acid (RA) and/or 1,25-dihydroxyvitamin D3 (VD) on the generation of nitric oxide (NO), a potent antitumoral mediator. U937 cell differentiation with VD or with both RA and VD (RA/VD) correlated with gene transcription and functional expression of inducible nitric oxide synthase (iNOS). Nitrites and L-citrulline were also detected in U937 cell supernatants as soon as 24 hours following cell incubation with VD or RA/VD, but not in cells treated with RA alone. Inhibition of iNOS activity by NG-monomethyl-L-arginine (LNMMA) significantly decreased in vitro U937 cell differentiation with VD and RA/VD as shown by the expression of cell differentiation markers (CD14 and CD68) and by the capacity of these cells to undergo a luminol-dependent chemiluminescence in response to opsonized zymosan. Similar results were obtained using the THP-1 cell line strengthening the role of NO in the VD- and RA/VD-induced growth arrest and terminal differentiation of promonocytic leukemia cells.

  3. Synthesis and biological evaluation of new fluorine substituted derivatives as angiotensin II receptor antagonists with anti-hypertension and anti-tumor effects.

    PubMed

    Da, Ya-jing; Yuan, Wei-dong; Xin, Ting; Nie, Yong-yan; Ye, Ying; Yan, Yi-Jia; Liang, Li-sha; Chen, Zhi-long

    2012-12-15

    The synthesis and pharmaceutical activity of new potent non-tetrazole angiotensin II (Ang II) receptor antagonists were described. These compounds were fluorine substituted derivatives of Losartan, Valsartan and Irbesartan with carboxylic acid group as replacements to the known potent tetrazole moiety at the 2'-biphenyl position. Their activities were evaluated by Ang II receptor binding assay as well as by in vivo assay. All of the synthesized compounds showed nanomolar affinity for the AT(1) receptor subtype. The vivo biological evaluation showed that compounds 1a, 2 and 4 produced a dose-dependent antihypertensive effect both in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR). Compound 4 especially showed an efficient and long-lasting effect in reducing blood pressure which can last more than 24 h at dose of 10 mg/kg in SHR, which was much better than control Losartan and Valsartan. Compound 4 can also inhibit the prostate cancer in vitro and in vivo. So compound 4 was selected for in-depth investigation as potent, novel and long-lasting non-tetrazole anti-hypertension and anti-tumor drug candidate. PMID:23122933

  4. Aerosol delivery of beclin1 enhanced the anti-tumor effect of radiation in the lungs of K-rasLA1 mice.

    PubMed

    Shin, Ji-Young; Lim, Hwang-Tae; Minai-Tehrani, Arash; Noh, Mi-Suk; Kim, Ji-Eun; Kim, Ji-Hye; Jiang, Hu-Lin; Arote, Rohidas; Kim, Doo-Yeol; Chae, Chanhee; Lee, Kee-Ho; Kim, Mi-Sook; Cho, Myung-Haing

    2012-07-01

    Radiotherapy alone has several limitations for treating lung cancer. Inhalation, a non-invasive approach for direct delivery of therapeutic agents to the lung, may help to enhance the therapeutic efficacy of radiation. Up-regulating beclin1, known as a tumor suppressor gene that plays a major role in autophagy, may sensitize tumors and lead to tumor regression in lungs of K-ras(LA1) lung cancer model mice. To minimize the side-effects of radiotherapy, fractionated exposures (five times, 24-h interval) with low dose (2 Gy) of radiation to the restricted area (thorax, 2 cm) were conducted. After sensitizing the lungs with radiation, beclin1, complexed with a nano-sized biodegradable poly(ester amine), was prepared and delivered into the murine lung via aerosol three times/week for four weeks. In a histopathological analysis, animals treated with beclin1 and radiation showed highly significant tumor regression and low progression to adenocarcinoma. An increase in the number of autophagic vacuoles and secondary lysosomes was detected. Dissociation of beclin1-bcl2 stimulated autophagy activation and showed a synergistic anti-tumor effect by inhibiting the Akt-mTOR pathway, cell proliferation and angiogenesis. The combination of radiation with non-invasive aerosol delivery of beclin1 may provide a prospect for developing novel therapy regimens applicable in clinics. PMID:22843615

  5. Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGF-IR in vitro and in vivo

    SciTech Connect

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

    2011-05-01

    Focal adhesion kinase (FAK) is a 125-kDa non-receptor type tyrosine kinase that localizes to focal adhesions. FAK overexpression is frequently found in invasive and metastatic cancers of the breast, colon, thyroid, and prostate, but its role in osteolytic metastasis is not well understood. In this study, we have analyzed anti-tumor effects of the novel FAK Tyr{sup 397} inhibitor TAE226 against bone metastasis in breast cancer by using TAE226. Oral administration of TAE226 in mice significantly decreased bone metastasis and osteoclasts involved which were induced by MDA-MB-231 breast cancer cells and increased the survival rate of the mouse models of bone metastasis. TAE226 also suppressed the growth of subcutaneous tumors in vivo and the proliferation and migration of MDA-MB-231 cells in vitro. Significantly, TAE226 inhibited the osteoclast formation in murine pre-osteoclastic RAW264.7 cells, and actin ring and pit formation in mature osteoclasts. Moreover, TAE226 inhibited the receptor activator for nuclear factor {kappa} B Ligand (RANKL) gene expression induced by parathyroid hormone-related protein (PTHrP) in bone stromal ST2 cells and blood free calcium concentration induced by PTHrP administration in vivo. These findings suggest that FAK was critically involved in osteolytic metastasis and activated in tumors, pre-osteoclasts, mature osteoclasts, and bone stromal cells and TAE226 can be effectively used for the treatment of cancer induced bone metastasis and other bone diseases.

  6. Effects of Antitumor Necrosis Factor Therapy on Osteoprotegerin, Neopterin, and sRANKL Concentrations in Patients with Rheumatoid Arthritis

    PubMed Central

    Kurz, Katharina; Herold, Manfred; Russe, Elisabeth; Klotz, Werner; Weiss, Guenter; Fuchs, Dietmar

    2015-01-01

    Background. Rheumatoid arthritis is a systemic autoimmune disease characterized by joint erosions, progressive focal bone loss, and chronic inflammation. Methods. 20 female patients with moderate-to-severe rheumatoid arthritis were treated with anti-TNF-antibody adalimumab in addition to concomitant antirheumatic therapies. Patients were assessed for overall disease activity using the DAS28 score, and neopterin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) concentrations as well as osteoprotegerin (OPG) and soluble receptor activator of NF-κB ligand (sRANKL) concentrations were determined before therapy and at week 12. Neopterin as well as OPG and sRANKL were determined by commercial ELISAs. Results. Before anti-TNF therapy patients presented with high disease activity and elevated concentrations of circulating inflammatory markers. OPG concentrations correlated with neopterin (rs = 0.494, p = 0.027), but not with DAS28. OPG concentrations and disease activity scores declined during anti-TNF-treatment (both p < 0.02). Patients who achieved remission (n = 7) or showed a good response according to EULAR criteria (n = 13) presented with initially higher baseline OPG levels, which subsequently decreased significantly during treatment (p = 0.018 for remission, p = 0.011 for good response). Conclusions. Adalimumab therapy was effective in modifying disease activity and reducing proinflammatory and bone remodelling cascades. PMID:26576067

  7. Chemo-immunotherapy using saffron and its ingredients followed by E7-NT (gp96) DNA vaccine generates different anti-tumor effects against tumors expressing the E7 protein of human papillomavirus.

    PubMed

    Khavari, Afshin; Bolhassani, Azam; Alizadeh, Fatemeh; Bathaie, S Zahra; Balaram, Prabha; Agi, Elnaz; Vahabpour, Rouhollah

    2015-02-01

    Saffron and its components have been suggested as promising candidates for cancer prevention. Carotenoids and monoterpene aldehydes are two potent ingredients of saffron. The goal of the current study was to investigate the anti-tumor effect of chemo-immunotherapy using saffron and its ingredients followed by E7-NT (gp96) DNA vaccine against tumors expressing the E7 protein of human papillomavirus. The in vitro cytotoxic and apoptotic effects of aqueous saffron extract and its components were evaluated in malignant TC-1 and non-malignant COS-7 cell lines. Then, multimodality treatments using E7-NT (gp96) DNA vaccine combined with saffron extract and its ingredients as well as single-modality treatments were tested for their efficacy in inhibiting large and bulky tumor growth. Saffron and its components exerted a considerable anti-tumor effect through prevention of cell growth and stimulation of programmed cell death. Furthermore, 100 % of mice treated with crocin were tumor-free, in contrast to DNA vaccine alone (~66.7 %) and DNA + crocin (~33.3 %) indicating the high potency of crocin as a chemotherapeutic agent. Interestingly, the multimodality treatment using DNA vaccine along with picrocrocin augmented the anti-tumor effects of picrocrocin. Thus, the combination of DNA vaccine with saffron extract and crocin at certain concentrations did not potentiate protective and therapeutic effects compared to mono-therapies for the control of TC-1 tumors. PMID:25395243

  8. Chemo-immunotherapy using saffron and its ingredients followed by E7-NT (gp96) DNA vaccine generates different anti-tumor effects against tumors expressing the E7 protein of human papillomavirus.

    PubMed

    Khavari, Afshin; Bolhassani, Azam; Alizadeh, Fatemeh; Bathaie, S Zahra; Balaram, Prabha; Agi, Elnaz; Vahabpour, Rouhollah

    2015-02-01

    Saffron and its components have been suggested as promising candidates for cancer prevention. Carotenoids and monoterpene aldehydes are two potent ingredients of saffron. The goal of the current study was to investigate the anti-tumor effect of chemo-immunotherapy using saffron and its ingredients followed by E7-NT (gp96) DNA vaccine against tumors expressing the E7 protein of human papillomavirus. The in vitro cytotoxic and apoptotic effects of aqueous saffron extract and its components were evaluated in malignant TC-1 and non-malignant COS-7 cell lines. Then, multimodality treatments using E7-NT (gp96) DNA vaccine combined with saffron extract and its ingredients as well as single-modality treatments were tested for their efficacy in inhibiting large and bulky tumor growth. Saffron and its components exerted a considerable anti-tumor effect through prevention of cell growth and stimulation of programmed cell death. Furthermore, 100 % of mice treated with crocin were tumor-free, in contrast to DNA vaccine alone (~66.7 %) and DNA + crocin (~33.3 %) indicating the high potency of crocin as a chemotherapeutic agent. Interestingly, the multimodality treatment using DNA vaccine along with picrocrocin augmented the anti-tumor effects of picrocrocin. Thus, the combination of DNA vaccine with saffron extract and crocin at certain concentrations did not potentiate protective and therapeutic effects compared to mono-therapies for the control of TC-1 tumors.

  9. The effects of atmosphere and additives of coal slag viscosity

    SciTech Connect

    Hurley, J.P.; Watne, T.M.; Nowok, J.W.

    1996-12-31

    The viscosities of a Powder River Basin slag were measured in air, air + 10% water vapor, and a reducing atmosphere. The temperature of critical viscosity (T), below which the viscosity increases dramatically, was approximately 1250{degrees}C in air and air + water vapor, but dropped to 1180{degrees}C when measured in the reducing atmosphere. Since the corrosivity of the slag is much higher when its viscosity is low, the slag will be highly corrosive at the substantially lower temperature in reducing gas. The addition of alumina increased viscosity and T{sub c} making the slag less corrosive, while magnesia additions dropped viscosity but increased T{sub c}. These changes imply that magnesia additions will make the slag slightly more corrosive in its liquid range, but that the slag will harden and become less corrosive at a higher temperature than without the magnesia addition. The changes in T{sub c} were more substantial when measured in the presence of water vapor in the case of alumina additions, but less substantial in the case of magnesia additions.

  10. In vitro and in vivo studies on antitumor effects of gossypol on human stomach adenocarcinoma (AGS) cell line and MNNG induced experimental gastric cancer

    SciTech Connect

    Gunassekaran, G.R.; Kalpana Deepa Priya, D.; Gayathri, R.; Sakthisekaran, D.

    2011-08-12

    Highlights: {yields} Gossypol is a well known polyphenolic compound used for anticancer studies but we are the first to report that gossypol has antitumor effect on MNNG induced gastric cancer in experimental animal models. {yields} Our study shows that gossypol inhibits the proliferation of AGS (human gastric adenocarcinoma) cell line. {yields} In animal models, gossypol extends the survival of cancer bearing animals and also protects the cells from carcinogenic effect. {yields} So we suggest that gossypol would be a potential chemotherapeutic and chemopreventive agent for gastric cancer. -- Abstract: The present study has evaluated the chemopreventive effects of gossypol on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis and on human gastric adenocarcinoma (AGS) cell line. Gossypol, C{sub 30}H{sub 30}O{sub 8}, is a polyphenolic compound that has anti proliferative effect and induces apoptosis in various cancer cells. The aim of this work was to delineate in vivo and in vitro anti-initiating mechanisms of orally administered gossypol in target (stomach) tissues and in human gastric adenocarcinoma (AGS) cell line. In vitro results prove that gossypol has potent cytotoxic effect and inhibit the proliferation of adenocarcinoma (AGS) cell line. In vivo results prove gossypol to be successful in prolonging the survival of MNNG induced cancer bearing animals and in delaying the onset of tumor in animals administrated with gossypol and MNNG simultaneously. Examination of the target (stomach) tissues in sacrificed experimental animals shows that administration of gossypol significantly reduces the level of tumor marker enzyme (carcino embryonic antigen) and pepsin. The level of Nucleic acid contents (DNA and RNA) significantly reduces, and the membrane damage of glycoprotein subsides, in the target tissues of cancer bearing animals, with the administration of gossypol. These data suggest that gossypol may create a beneficial effect in patients

  11. MiR-145 regulates PAK4 via the MAPK pathway and exhibits an antitumor effect in human colon cells

    SciTech Connect

    Wang, Zhigang; Zhang, Xiaoping; Yang, Zhili; Du, Hangxiang; Wu, Zhenqian; Gong, Jianfeng; Yan, Jun; Zheng, Qi

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer MiR-145 targets a putative binding site in the 3 Prime UTR of PAK4. Black-Right-Pointing-Pointer MiR-145 played an important role in inhibiting cell growth by directly targeting PAK4. Black-Right-Pointing-Pointer MiR-145 may function as tumor suppressors. -- Abstract: MicroRNAs (miRNAs) are regulators of numerous cellular events; accumulating evidence indicates that miRNAs play a key role in a wide range of biological functions, such as cellular proliferation, differentiation, and apoptosis in cancer. Down-regulated expression of miR-145 has been reported in colon cancer tissues and cell lines. The molecular mechanisms underlying miR-145 and the regulation of colon carcinogenesis remain unclear. In this study, we investigated the levels of miR-145 in human colon cancer cells using qRT-PCR and found markedly decreased levels compared to normal epithelial cells. We identified PAK4 as a novel target of miR-145 using informatics screening. Additionally, we demonstrated that miR-145 targets a putative binding site in the 3 Prime UTR of PAK4 and that its abundance is inversely associated with miR-145 expression in colon cancer cells; we confirmed this relationship using the luciferase reporter assay. Furthermore, restoration of miR-145 by mimics in SW620 cells significantly attenuated cell growth in vitro, in accordance with the inhibitory effects induced by siRNA mediated knockdown of PAK4. Taken together, these findings demonstrate that miR-145 downregulates P-ERK expression by targeting PAK4 and leads to inhibition of tumor growth.

  12. Inhibition of A20 expression in tumor microenvironment exerts anti-tumor effect through inducing myeloid-derived suppressor cells apoptosis

    PubMed Central

    Shao, Bin; Wei, Xiawei; Luo, Min; Yu, Jiayun; Tong, Aiping; Ma, Xuelei; Ye, Tinghong; Deng, Hongxin; Sang, Yaxiong; Liang, Xiao; Ma, Yu; Wu, Qinjie; Du, Wei; Du, Jing; Gao, Xiang; Wen, Yi; Fu, Ping; Shi, Huashan; Luo, Shuntao; Wei, Yuquan

    2015-01-01

    Myeloid-derived suppressor cells (MDSCs) are known to play important roles in the development of immunosuppressive tumor microenvironment. A20 is a zinc-finger protein which could negatively regulate apoptosis in several cell types. However, the role of A20 in tumor microenvironment remains largely unknown. In this study, we found that A20 was over-expressed in MDSCs. The treatment of tumor-bearing mice with small interfering RNA targeting A20 (si-A20) inhibited the growth of tumors. The infiltration of MDSCs was dramatically reduced after si-A20 treatment, as compared to control groups, whereas the numbers of dendritic cells and macrophages were not affected. Also, injection of si-A20 improved T cell mediated tumor-specific immune response. Depletion of MDSCs with anti-Gr1 antibody showed similar antitumor effect and improved T cell response. TNF-α was highly expressed after si-A20 injection. Furthermore, si-A20 induced apoptosis of MDSCs in the presence of TNF-α both in vivo and in vitro. Cleaved Caspase-3 and Caspase-8 were elevated with the activation of JNK pathway after the induction of MDSC apoptosis by si-A20. Thus, our findings suggested that knockdown of A20 in tumor site inhibited tumor growth at least through inducing the apoptosis of MDSCs. A20 might be a potential target in anticancer therapy. PMID:26561336

  13. In vivo electroporation-mediated transfer of interleukin-12 and interleukin-18 genes induces significant antitumor effects against melanoma in mice.

    PubMed

    Kishida, T; Asada, H; Satoh, E; Tanaka, S; Shinya, M; Hirai, H; Iwai, M; Tahara, H; Imanishi, J; Mazda, O

    2001-08-01

    Direct intratumoral transfection of cytokine genes was performed by means of the in vivo electroporation as a novel therapeutic strategy for cancer. Plasmid vectors carrying the firefly luciferase, interleukin (IL)-12 and IL-18 genes were injected into established subcutaneous B16-derived melanomas followed by electric pulsation. When plasmid vectors with Epstein--Barr virus (EBV) nuclear antigen 1 (EBNA1) gene were employed, the expression levels of the transgenes were significantly higher in comparison with those obtained with conventional plasmid vectors. In consequence of the transfection with IL-12 and IL-18 genes, serum concentrations of the cytokines were significantly elevated, while interferon (IFN)-gamma also increased in the sera of the animals. The IL-12 gene transfection resulted in significant suppression of tumor growth, while the therapeutic effect was further improved by co-transfection with IL-12 and IL-18 genes. Repetitive co-transfection with IL-12 and IL-18 genes resulted in significant prolongation of survival of the animals. Natural killer (NK) and cytotoxic T lymphocyte (CTL) activities were markedly enhanced in the mice transfected with the cytokine genes. The present data suggest that the cytokine gene transfer can be successfully achieved by in vivo electroporation, leading to both specific and nonspecific antitumoral immune responses and significant therapeutic outcome. PMID:11509956

  14. Protective Effect of Spin-Labeled 1-Ethyl-1-nitrosourea against Oxidative Stress in Liver Induced by Antitumor Drugs and Radiation

    PubMed Central

    Gadjeva, V.; Grigorov, B.; Nikolova, G.; Tolekova, A.; Zheleva, A.; Vasileva, M.

    2013-01-01

    This study was carried out to investigate possible protection effect of 1-ethyl-3-[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)]-1-nitrosourea (SLENU), synthesized in our laboratory, against oxidative liver injuries induced in mice treated by antitumor drugs: doxorubicin (DOX), bleomycin (BLM), or gamma irradiation (R). Specifically, alterations in some biomarkers of oxidative stress, such as lipid peroxidation products measured as malondialdehyde (MDA) levels and activities of the antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), were studied in liver homogenates isolated from tumor bearing C57 black mice after i.p. treatment with solutions of DOX (60 mg/kg), BLM (60 mg/kg), or after total body gamma-irradiation with a single dose of 5 Gy. The same biomarkers were also measured after i.p. pretreatment of mice with SLENU (100 mg/kg). Statistical significant increased MDA levels and SOD and CAT enzymes activities were found in the liver homogenates of tumor bearing mice after alone treatment with DOX or gamma-irradiation compared to the control mice, while these parameters were insignificantly increased after BLM administration compared to the same controls. PMID:24175309

  15. Two clinical drugs deubiquitinase inhibitor auranofin and aldehyde dehydrogenase inhibitor disulfiram trigger synergistic anti-tumor effects in vitro and in vivo

    PubMed Central

    Liu, Ningning; Hua, Xianliang; Cai, Jianyu; Yang, Changshan; Long, Huidan; Zhao, Chong; Chen, Xin; Lan, Xiaoying; Zang, Dan; Wu, Jinjie; Li, Xiaofen; Shi, Xianping; Wang, Xuejun; Liu, Jinbao

    2016-01-01

    Inhibition of proteasome-associated deubiquitinases (DUBs) is emerging as a novel strategy for cancer therapy. It was recently reported that auranofin (Aur), a gold (I)-containing compound used clinically to treat rheumatoid arthritis, is a proteasome-associated DUB inhibitor. Disulfiram (DSF), an inhibitor of aldehyde dehydrogenase, is currently in clinical use for treating alcoholism. Recent studies have indicated that DSF can also act as an antitumor agent. We investigated the effect of combining DSF and Aur on apoptosis induction and tumor growth in hepatoma cancer cells. Here we report that (i) the combined treatment of Aur and DSF results in synergistic cytotoxicity to hepatoma cells in vitro and in vivo; (ii) Aur and DSF in combination induces caspase activation, endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) production; (iii) pan-caspase inhibitor z-VAD-FMK could efficiently block apoptosis but not proteasome inhibition induced by Aur and DSF combined treatment, and ROS is not required for Aur+DSF to induce apoptosis. Collectively, we demonstrate a model of synergism between DSF and proteasome-associated DUB inhibitor Aur in the induction of apoptosis in hepatoma cancer cells, identifying a potential novel anticancer strategy for clinical use in the future. PMID:26625200

  16. Prodigiosin rescues deficient p53 signaling and anti-tumor effects via up-regulating p73 and disrupting its interaction with mutant p53

    PubMed Central

    Hong, Bo; Prabhu, Varun V.; Zhang, Shengliang; van den Heuvel, A. Pieter J.; Dicker, David T.; Kopelovich, Levy; El-Deiry, Wafik S.

    2015-01-01

    p53 reactivation offers a broad-based strategy for cancer therapy. In this study we report the identification of prodigiosin that can reactivate p53 family-dependent transcriptional activity in p53 deficient human colon cancer cells. Prodigiosin and its structural analogue (compound R) induced the expression of p53 target genes accompanied by cell cycle arrest and apoptosis in p53 deficient cancer cells. Prodigiosin restored p53 signaling in cancer cells harboring hotspot p53 mutations, with little to no detectable cytotoxicity in normal human fibroblasts and with no genotoxicity. Prodigiosin induced the expression of p73 and disrupted its interaction with mutant p53, thereby rescuing p53 pathway deficiency and promoting anti-tumor effects. The disruption of mutant p53/p73 interaction was specific to prodigiosin and not related to mTOR inhibition. Our findings suggest that mutant p53 needs to be targeted in the context of p73 stimulation to allow efficient restoration of the p53 pathway. In exhibiting this capability, prodigiosin and its analogue provide lead compounds to rescue deficiencies in the p53 pathway in cancer cells by up-regulating p73 and targeting mutant p53/p73 interaction there. PMID:24247721

  17. Antitumor Effects and Related Mechanisms of Penicitrinine A, a Novel Alkaloid with a Unique Spiro Skeleton from the Marine Fungus Penicillium citrinum

    PubMed Central

    Liu, Qin-Ying; Zhou, Tong; Zhao, Yang-Yang; Chen, Li; Gong, Mei-Wei; Xia, Qi-Wen; Ying, Min-Gang; Zheng, Qiu-Hong; Zhang, Qi-Qing

    2015-01-01

    Penicitrinine A, a novel alkaloid with a unique spiro skeleton, was isolated from a marine-derived fungus Penicillium citrinum. In this study, the isolation, structure and biosynthetic pathway elucidation of the new compound were described. This new compound showed anti-proliferative activity on multiple tumor types. Among them, the human malignant melanoma cell A-375 was confirmed to be the most sensitive. Morphologic evaluation, apoptosis rate analysis, Western blot and real-time quantitative PCR (RT-qPCR) results showed penicitrinine A could significantly induce A-375 cell apoptosis by decreasing the expression of Bcl-2 and increasing the expression of Bax. Moreover, we investigated the anti-metastatic effects of penicitrinine A in A-375 cells by wound healing assay, trans-well assay, Western blot and RT-qPCR. The results showed penicitrinine A significantly suppressed metastatic activity of A-375 cells by regulating the expression of MMP-9 and its specific inhibitor TIMP-1. These findings suggested that penicitrinine A might serve as a potential antitumor agent, which could inhibit the proliferation and metastasis of tumor cells. PMID:26264002