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Sample records for sulindac sulfide-mediated cytotoxicity

  1. Up-regulation of early growth response gene 1 (EGR-1) via ERK1/2 signals attenuates sulindac sulfide-mediated cytotoxicity in the human intestinal epithelial cells

    SciTech Connect

    Moon, Yuseok Yang, Hyun; Kim, Yung Bu

    2007-09-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are used to relieve pain and inflammation and have also received considerable attention because of their preventive effects against human cancer. However, the drug application is sometimes limited by the severe gastrointestinal ulcers and mucosal complications. In the present study, NSAID sulindac sulfide was investigated for the cytotoxic injury in the intestinal epithelial cells in association with an immediate inducible factor, early growth response gene 1 (EGR-1). Previously we reported that sulindac sulfide can suppress tumor cell invasion by inducing EGR-1. Extending the previous study, EGR-1 induction by sulindac sulfide was observed both in the non-transformed and transformed human intestinal epithelial cell lines. In terms of signaling pathway, ERK1/2 MAP kinases and its substrate Elk-1 transcription factor were involved in the sulindac sulfide-induced EGR-1 gene expression. Moreover, sulindac sulfide stimulated the nuclear translocation of the transcription factor EGR-1, which was also mediated by ERK1/2 signaling pathway. The roles of EGR-1 signals in the apoptotic cell death were assessed in the intestinal epithelial cells. Suppression of EGR-1 expression retarded cellular growth and colony forming activity in the intestinal epithelial cells. Moreover, induced EGR-1 ameliorated sulindac sulfide-mediated apoptotic cell death and enhanced the cellular survival. Taken all together, sulindac sulfide activated ERK1/2 MAP kinases which then mediated EGR-1 induction and nuclear translocation, all of which played important roles in the cellular survival from NSAID-mediated cytotoxicity in the human intestinal epithelial cells, implicating the protective roles of EGR-1 in the NSAID-mediated mucosal injuries.

  2. Sulindac and its metabolites: sulindac sulfide and sulindac sulfone enhance cytotoxic effects of arsenic trioxide on leukemic cell lines.

    PubMed

    Stępnik, Maciej; Ferlińska, Magdalena; Smok-Pieniążek, Anna; Gradecka-Meesters, Dobrosława; Arkusz, Joanna; Stańczyk, Małgorzata

    2011-08-01

    The effects of arsenic trioxide (ATO) in combination with sulindac (SUL), sulindac sulfide (SS) or sulindac sulfone (SF) on human (Jurkat, HL-60, K562 and HPB-ALL) and mouse (EL-4) leukemic cell lines were investigated. The cells showed different sensitivity to sulindacs (2.5-200 μM) with SS being the most cytotoxic (72 h WST-1 reduction test). The cytotoxicity of ATO was enhanced by combination with sulindacs. The combination of ATO (1 μM) with SS or SF at concentrations over 50 μM induced considerable cytotoxicity in all cell lines. Normal human lymphocytes exposed for 48 h to the combinations showed smaller decrease in viability. Measurements of Jurkat, HL-60 and K562 cells exposed to ATO (1 μM) and sulindacs (100 μM or 200 μM for K562 cells) indicated apoptosis as the main cell death mechanism. The mitochondrial membrane potential measurements (JC-1 probe) indicated an active involvement of mitochondria in the process. The results did not indicate involvement of an inhibitory effect of the combinations on NF-κB activity in Jurkat, HL-60 and K562 cells. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Synergistic cytotoxic effect of sulindac and pyrrolidine dithiocarbamate against ovarian cancer cells.

    PubMed

    Jakubowska-Mućka, Anna; Sieńko, Jacek; Zapała, Łukasz; Wolny, Rafał; Lasek, Witold

    2012-04-01

    Sulindac, a non-steroidal anti-inflammatory drug, suppresses carcinogenesis and inhibits growth of tumor cells. Pyrrolidine dithiocarbamate (PDTC), a potent NF-κB inhibitor, has been also identified as a potential anti-neoplastic agent. We hypothesized that combination of sulindac and PDTC could result in augmentation of cytotoxicity against ovarian cancer cells. The effect of sulindac and PDTC was examined on several ovarian cancer lines. Tumor cell viability was assessed using the MTT assay. Annexin-V/PI staining was used to detect apoptosis, cell cycle distribution was analyzed in FACS, and expression of cellular proteins was detected by western blotting. Incubation of OVA-14, OVP-10 and CAOV-1 ovarian cancer cells with sulindac and PDTC resulted in significantly greater inhibition of cell viability compared to either compound alone. In a model of OVA-14 cells it was evident that this effect was not related to the expression of COX enzymes since both active (sulindac sulfide) and inactive (sulindac) in vitro compounds affected the growth of tumor cells to a similar extent and synergized in cytotoxicity with PDTC. Combination of sulindac and PDTC lead to G0 arrest and massive apoptosis in co-treated cultures. Western blotting analysis argued for induction of the mitochondrial apoptotic pathway. These data demonstrate the synergistic cytotoxic effect of sulindac and PDTC on ovarian cancer cells through apoptosis and cell cycle arrest and prompt to test the efficacy of this combination in animal models.

  4. Synergistic cytotoxic effect of sulindac and pyrrolidine dithiocarbamate against ovarian cancer cells

    PubMed Central

    JAKUBOWSKA-MUĆKA, ANNA; SIEŃKO, JACEK; ZAPAŁA, ŁUKASZ; WOLNY, RAFAŁ; LASEK, WITOLD

    2012-01-01

    Sulindac, a non-steroidal anti-inflammatory drug, suppresses carcinogenesis and inhibits growth of tumor cells. Pyrrolidine dithiocarbamate (PDTC), a potent NF-κB inhibitor, has been also identified as a potential anti-neoplastic agent. We hypothesized that combination of sulindac and PDTC could result in augmentation of cytotoxicity against ovarian cancer cells. The effect of sulindac and PDTC was examined on several ovarian cancer lines. Tumor cell viability was assessed using the MTT assay. Annexin-V/PI staining was used to detect apoptosis, cell cycle distribution was analyzed in FACS, and expression of cellular proteins was detected by Western blotting. Incubation of OVA-14, OVP-10 and CAOV-1 ovarian cancer cells with sulindac and PDTC resulted in significantly greater inhibition of cell viability compared to either compound alone. In a model of OVA-14 cells it was evident that this effect was not related to the expression of COX enzymes since both active (sulindac sulfide) and inactive (sulindac) in vitro compounds affected the growth of tumor cells to a similar extent and synergized in cytotoxicity with PDTC. Combination of sulindac and PDTC lead to G0 arrest and massive apoptosis in co-treated cultures. Western blotting analysis argued for induction of the mitochondrial apoptotic pathway. These data demonstrate the synergistic cytotoxic effect of sulindac and PDTC on ovarian cancer cells through apoptosis and cell cycle arrest and prompt to test the efficacy of this combination in animal models. PMID:22266802

  5. Assessment of the involvement of oxidative stress and Mitogen-Activated Protein Kinase signaling pathways in the cytotoxic effects of arsenic trioxide and its combination with sulindac or its metabolites: sulindac sulfide and sulindac sulfone on human leukemic cell lines.

    PubMed

    Stępnik, M; Ferlińska, M; Smok-Pieniążek, A; Gradecka-Meesters, D; Arkusz, J; Stańczyk, M

    2012-06-01

    The purpose of the study was to characterize the involvement of reactive oxygen species (ROS) in mediating the cytotoxic effects of arsenic trioxide (ATO) in combination with sulindac or its metabolites: sulfide (SS) and sulfone (SF) on human leukemic cell lines. Jurkat, HL-60, K562, and HPB-ALL cells were exposed to the drugs alone or in combinations. Cell viability was measured using WST-1 or XTT reduction tests and ROS production by dichlorodihydrofluorescein diacetate staining (flow cytometry). Modulation of (a) intracellular glutathione (GSH) level was done by using L: -buthionine sulfoximine (BSO) or diethylmaleate (DEM), (b) NADPH oxidase by using diphenyleneiodonium (DPI), and (c) MAP kinases by using SB202190 (p38), SP600125 (JNK), and U0126 (ERK) inhibitors. ATO cytotoxicity (0.5 or 1 μM) was enhanced by sulindacs, with higher activity showed by the metabolites. Strong cytotoxic effects appeared at SS and SF concentrations starting from 50 μM. The induction of ROS production seemed not to be the major mechanism responsible for the cytotoxicity of the combinations. A strong potentiating effect of BSO on ATO cytotoxicity was demonstrated; DEM (10-300 μM) and DPI (0.0025-0.1 μM; 72 h) did not influence the effects of ATO. Some significant decreases in the viability of the cells exposed to ATO in the presence of MAPK inhibitors comparing with the cells exposed to ATO alone were observed; however, the effects likely resulted from a simple additive cytotoxicity of the drugs. The combinations of ATO with sulindacs offer potential therapeutic usefulness.

  6. Sulindac Compounds Facilitate the Cytotoxicity of β-Lapachone by Up-Regulation of NAD(P)H Quinone Oxidoreductase in Human Lung Cancer Cells

    PubMed Central

    Kung, Hsiu-Ni; Lu, Kuo-Shyan; Chau, Yat-Pang

    2014-01-01

    β-lapachone, a major component in an ethanol extract of Tabebuia avellanedae bark, is a promising potential therapeutic drug for various tumors, including lung cancer, the leading cause of cancer-related deaths worldwide. In the first part of this study, we found that apoptotic cell death induced in lung cancer cells by high concentrations of β-lapachone was mediated by increased activation of the pro-apoptotic factor JNK and decreased activation of the cell survival/proliferation factors PI3K, AKT, and ERK. In addition, β-lapachone toxicity was positively correlated with the expression and activity of NAD(P)H quinone oxidoreductase 1 (NQO1) in the tumor cells. In the second part, we found that the FDA-approved non-steroidal anti-inflammatory drug sulindac and its metabolites, sulindac sulfide and sulindac sulfone, increased NQO1 expression and activity in the lung adenocarcinoma cell lines CL1-1 and CL1-5, which have lower NQO1 levels and lower sensitivity to β-lapachone treatment than the A549 cell lines, and that inhibition of NQO1 by either dicoumarol treatment or NQO1 siRNA knockdown inhibited this sulindac-induced increase in β-lapachone cytotoxicity. In conclusion, sulindac and its metabolites synergistically increase the anticancer effects of β-lapachone primarily by increasing NQO1 activity and expression, and these two drugs may provide a novel combination therapy for lung cancers. PMID:24505400

  7. Sulindac compounds facilitate the cytotoxicity of β-lapachone by up-regulation of NAD(P)H quinone oxidoreductase in human lung cancer cells.

    PubMed

    Kung, Hsiu-Ni; Weng, Tsai-Yun; Liu, Yu-Lin; Lu, Kuo-Shyan; Chau, Yat-Pang

    2014-01-01

    β-lapachone, a major component in an ethanol extract of Tabebuia avellanedae bark, is a promising potential therapeutic drug for various tumors, including lung cancer, the leading cause of cancer-related deaths worldwide. In the first part of this study, we found that apoptotic cell death induced in lung cancer cells by high concentrations of β-lapachone was mediated by increased activation of the pro-apoptotic factor JNK and decreased activation of the cell survival/proliferation factors PI3K, AKT, and ERK. In addition, β-lapachone toxicity was positively correlated with the expression and activity of NAD(P)H quinone oxidoreductase 1 (NQO1) in the tumor cells. In the second part, we found that the FDA-approved non-steroidal anti-inflammatory drug sulindac and its metabolites, sulindac sulfide and sulindac sulfone, increased NQO1 expression and activity in the lung adenocarcinoma cell lines CL1-1 and CL1-5, which have lower NQO1 levels and lower sensitivity to β-lapachone treatment than the A549 cell lines, and that inhibition of NQO1 by either dicoumarol treatment or NQO1 siRNA knockdown inhibited this sulindac-induced increase in β-lapachone cytotoxicity. In conclusion, sulindac and its metabolites synergistically increase the anticancer effects of β-lapachone primarily by increasing NQO1 activity and expression, and these two drugs may provide a novel combination therapy for lung cancers.

  8. [Antitumor effects of sulindac in ovarian cell cultures].

    PubMed

    Jakubowska-Mućka, Anna; Sieńko, Jacek; Switaj, Tomasz; Gołab, Jakub; Lasek, Witold

    2011-03-01

    The purpose of our study was to assess susceptibility of cells of various ovarian cell lines on different nonsteroidal anti-inflammatory drugs (NSAIDs). Cytotoxic effect of NSAIDs was tested using MTT colorimetric assay. Amongst 6 NSAIDs tested: sulindac, sulindac sulfide, sulindac sulfone, acetylsalicylic acid, nimesulide, and rofecoxib, viability of ovarian carcinoma cells was compromised most strongly by sulindac and sulindac sulfide and concerned all the cell lines tested: SKOV-3, MDAH 2774, OVCA-1, and OVP-10. Sulindac sulfone and rofecoxib also displayed some cytotoxic effect during prolonged 72-hour incubation. Other NSAIDs tested: nimesulide and acetylsalicylic acid were devoid of cytotoxic effect on ovarian cancer cells. Our results are encourage enough to conduct clinical trials that could allow to draw conclusions regarding potential application of sulindac in the adjuvant treatment of a standard chemotherapy of ovarian cancer.

  9. Sulindac Sulfide, but Not Sulindac Sulfone, Inhibits Colorectal Cancer Growth

    PubMed Central

    Williams, Christopher S; Goldman, Angela P; Sheng, Hongmiao; Morrow, Jason D; DuBois, Raymond N

    1999-01-01

    Abstract Sulindac sulfide, a metabolite of the nonsteroidal antiinflammatory drug (NSAID) sulindac sulfoxide, is effective at reducing tumor burden in both familial adenomatous polyposis patients and in animals with colorectal cancer. Another sulindac sulfoxide metabolite, sulindac sulfone, has been reported to have antitumor properties without inhibiting cyclooxygenase activity. Here we report the effect of sulindac sulfone treatment on the growth of colorectal carcinoma cells. We observed that sulindac sulfide or sulfone treatment of HCA-7 cells led to inhibition of prostaglandin E2 production. Both sulindac sulfide and sulfone inhibited HCA-7 and HCT-116 cell growth in vitro. Sulindac sulfone had no effect on the growth of either HCA-7 or HCT-116 xenografts, whereas the sulfide derivative inhibited HCA-7 growth in vivo. Both sulindac sulfide and sulfone inhibited colon carcinoma cell growth and prostaglandin production in vitro, but sulindac sulfone had no effect on the growth of colon cancer cell xenografts in nude mice. PMID:10933052

  10. Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion.

    PubMed

    Whitt, Jason D; Keeton, Adam B; Gary, Bernard D; Sklar, Larry A; Sodani, Kamlesh; Chen, Zhe-Sheng; Piazza, Gary A

    2016-03-01

    ATP-binding cassette (ABC) transporters ABCC1 (MRP1), ABCB1 (P-gp), and ABCG2 (BCRP) contribute to chemotherapy failure. The primary goals of this study were to characterize the efficacy and mechanism of the nonsteroidal anti-inflammatory drug (NSAID), sulindac sulfide, to reverse ABCC1 mediated resistance to chemotherapeutic drugs and to determine if sulindac sulfide can influence sensitivity to chemotherapeutic drugs independently of drug efflux. Cytotoxicity assays were performed to measure resistance of ABC-expressing cell lines to doxorubicin and other chemotherapeutic drugs. NSAIDs were tested for the ability to restore sensitivity to resistance selected tumor cell lines, as well as a large panel of standard tumor cell lines. Other experiments characterized the mechanism by which sulindac sulfide inhibits ABCC1 substrate and co-substrate (GSH) transport in isolated membrane vesicles and intact cells. Selective reversal of multi-drug resistance (MDR), decreased efflux of doxorubicin, and fluorescent substrates were demonstrated by sulindac sulfide and a related NSAID, indomethacin, in resistance selected and engineered cell lines expressing ABCC1, but not ABCB1 or ABCG2. Sulindac sulfide also inhibited transport of leukotriene C4 into membrane vesicles. Sulindac sulfide enhanced the sensitivity to doxorubicin in 24 of 47 tumor cell lines, including all melanoma lines tested (7-7). Sulindac sulfide also decreased intracellular GSH in ABCC1 expressing cells, while the glutathione synthesis inhibitor, BSO, selectively increased sensitivity to sulindac sulfide induced cytotoxicity. Sulindac sulfide potently and selectively reverses ABCC1-mediated MDR at clinically achievable concentrations. ABCC1 expressing tumors may be highly sensitive to the direct cytotoxicity of sulindac sulfide, and in combination with chemotherapeutic drugs that induce oxidative stress.

  11. Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion

    PubMed Central

    Whitt, Jason D.; Keeton, Adam B.; Gary, Bernard D.; Sklar, Larry A.; Sodani, Kamlesh; Chen, Zhe-Sheng; Piazza, Gary A.

    2016-01-01

    Abstract ATP-binding cassette (ABC) transpo rters ABCC1 (MRP1), ABCB1 (P-gp), and ABCG2 (BCRP) contribute to chemotherapy failure. The primary goals of this study were to characterize the efficacy and mechanism of the non­steroidal anti-inflammatory drug (NSAID), sulindac sulfide, to reverse ABCC1 mediated resistance to chemother­apeutic drugs and to determine if sulindac sulfide can influence sensitivity to chemotherapeutic drugs independently of drug efflux. Cytotoxicity assays were performed to measure resistance of ABC-expressing cell lines to doxoru­bicin and other chemotherapeutic drugs. NSAIDs were tested for the ability to restore sensitivity to resistance selected tumor cell lines, as well as a large panel of standard tumor cell lines. Other experiments characterized the mechanism by which sulindac sulfide inhibits ABCC1 substrate and co-substrate (GSH) transport in isolated membrane vesicles and intact cells. Selective reversal of multi-drug resistance (MDR), decreased efflux of doxor­ubicin, and fluorescent substrates were demonstrated by sulindac sulfide and a related NSAID, indomethacin, in resistance selected and engineered cell lines expressing ABCC1, but not ABCB1 or ABCG2. Sulindac sulfide also inhibited transport of leukotriene C4 into membrane vesicles. Sulindac sulfide enhanced the sensitivity to doxoru­bicin in 24 of 47 tumor cell lines, including all melanoma lines tested (7-7). Sulindac sulfide also decreased intra­cellular GSH in ABCC1 expressing cells, while the glutathione synthesis inhibitor, BSO, selectively increased sensitivity to sulindac sulfide induced cytotoxicity. Sulindac sulfide potently and selectively reverses ABCC1-mediated MDR at clinically achievable concentrations. ABCC1 expressing tumors may be highly sensitive to the direct cytotoxicity of sulindac sulfide, and in combination with chemotherapeutic drugs that induce oxidative stress. PMID:28276667

  12. Synergistic induction of apoptosis by sulindac and simvastatin in A549 human lung cancer cells via reactive oxygen species-dependent mitochondrial dysfunction.

    PubMed

    Hwang, Ki-Eun; Park, Chul; Kwon, Su-Jin; Kim, Young-Suk; Park, Do-Sim; Lee, Mi-Kyung; Kim, Byoung-Ryun; Park, Seong-Hoon; Yoon, Kwon-Ha; Jeong, Eun-Taik; Kim, Hak-Ryul

    2013-07-01

    Prevention of lung cancer is more feasible and holds greater promise when different agents are used in combination to target multiple processes during carcinogenesis. The mechanisms by which non-steroidal anti-inflammatory drugs and statins inhibit cancer cell growth and induce apoptosis are not fully understood. This study was designed to investigate lung cancer chemoprevention through a mechanism-based approach using sulindac at low doses in combination with simvastatin. We found that sulindac-induced cytotoxicity was significantly enhanced in the presence of simvastatin. The combination of sulindac and simvastatin induced more extensive caspase-dependent apoptosis in A549 cells compared to that induced with either drug alone. The combination of sulindac and simvastatin also increased the loss of mitochondrial transmembrane potential (∆Ψm) and the cytosolic release of cytochrome c. In addition, ROS generation in cells treated with both sulindac and simvastatin was markedly increased compared to cells treated with either sulindac or simvastatin alone. The enhancement of ROS generation by sulindac and simvastatin was abrogated by pretreatment with NAC, which also prevented apoptosis and mitochondrial dysfunction induced by sulindac and simvastatin. These results suggest that sulindac and simvastatin-induced ROS generation in A549 lung cancer cells causes their accumulation in mitochondria, triggering the release of apoptogenic molecules from the mitochondria to the cytosol, and thus leading to caspase activation and cell death.

  13. Synthesis and biological evaluation of nitric oxide-donating analogues of sulindac for prostate cancer treatment.

    PubMed

    Nortcliffe, Andrew; Ekstrom, Alexander G; Black, James R; Ross, James A; Habib, Fouad K; Botting, Nigel P; O'Hagan, David

    2014-01-15

    A series of analogues of the non-steroidal anti-inflammatory drug (NSAID) sulindac 1 were synthesised tethered to nitric oxide (NO) donating functional groups. Sulindac shows antiproliterative effects against immortal PC3 cell lines. It was previously demonstrated that the effect can be enhanced when tethered to NO releasing groups such as nitrate esters, furoxans and sydnonimines. To explore this approach further, a total of fifty-six sulindac-NO analogues were prepared and they were evaluated as NO-releasing cytotoxic agents against prostate cancer (PCa) cell lines. Compounds 1k and 1n exhibited significant cytotoxic with IC50 values of 6.1±4.1 and 12.1±3.2μM, respectively, coupled with observed nitric oxide release. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Dimethyl sulfoxide inhibits bioactivation of sulindac.

    PubMed

    Swanson, B N; Boppana, V K; Vlasses, P H; Rotmensch, H H; Ferguson, R K

    1983-07-01

    Sulindac, a nonsteroidal anti-inflammatory agent, is converted to a bioactive sulfide metabolite via reversible reduction of its sulfoxide moiety. To test whether DMSO can inhibit conversion of sulindac to its active form, eight healthy men received, in a randomized, crossover manner, 400 mg of sulindac, orally, either alone or 60 min after an oral dose of DMSO (30 ml, 70% solution). After the drug combination, mean plasma concentrations of the sulfide metabolite were significantly lower than in controls at 1.5, 2, 3, 4, and 8 hr after sulindac administration. The mean area under the plasma sulfide concentration-time curve for 0 to 12 hr was 30% (range 7% to 56%) lower after DMSO treatment. This study suggests that DMSO can inhibit metabolism of other sulfoxides in man and may antagonize the therapeutic efficacy of sulindac.

  15. Effects of intervention with sulindac and inulin/VSL#3 on mucosal and luminal factors in the pouch of patients with familial adenomatous polyposis.

    PubMed

    Friederich, Pieter; Verschuur, Jelle; van Heumen, Bjorn W H; Roelofs, Hennie M J; Berkhout, Marloes; Nagtegaal, Iris D; van Oijen, Martijn G H; van Krieken, Johannes H J M; Peters, Wilbert H M; Nagengast, Fokko M

    2011-05-01

    In order to define future chemoprevention strategies for adenomas or carcinomas in the pouch of patients with familial adenomatous polyposis (FAP), a 4-weeks intervention with (1) sulindac, (2) inulin/VSL#3, and (3) sulindac/inulin/VSL#3 was performed on 17 patients with FAP in a single center intervention study. Primary endpoints were the risk parameters cell proliferation and glutathione S-transferase (GST) detoxification capacity in the pouch mucosa; secondary endpoints were the short chain fatty acid (SCFA) contents, pH, and cytotoxicity of fecal water. Before the start and at the end of each 4-week intervention period, six biopsies of the pouch were taken and feces was collected during 24 h. Cell proliferation and GST enzyme activity was assessed in the biopsies and pH, SCFA contents, and cytotoxicity were assessed in the fecal water fraction. The three interventions (sulindac, inulin/VSL#3, sulindac/inulin/VSL#3) were compared with the Mann-Whitney U test. Cell proliferation was lower after sulindac or VSL#3/inulin, the combination treatment with sulindac/inulin/VSL#3 showed the opposite. GST enzyme activity was increased after sulindac or VSL#3/inulin, the combination treatment showed the opposite effect. However, no significance was reached in all these measures. Cytotoxicity, pH, and SCFA content of fecal water showed no differences at all among the three treatment groups. Our study revealed non-significant decreased cell proliferation and increased detoxification capacity after treatment with sulindac or VSL#3/inulin; however, combining both regimens did not show an additional effect.

  16. Sulindac sulfide--induced stimulation of eryptosis.

    PubMed

    Zbidah, Mohanad; Lupescu, Adrian; Yang, Wenting; Bosc, Anastasia; Jilani, Kashif; Shaik, Nazneen; Lang, Florian

    2012-01-01

    Sulindac sulfide, a non-steroidal anti-inflammatory drug (NSAID), stimulates apoptosis of tumor cells and is thus effective against malignancy. In analogy to apoptosis of nucleated cells, erythrocytes may undergo eryptosis, an apoptosis-like suicidal erythrocyte death, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine-exposure at the cell surface. Stimulators of eryptosis include increase of cytosolic Ca(2+)-activity ([Ca(2+)](i)) and ceramide formation. The present study explored, whether sulindac sulfide stimulates eryptosis. [Ca(2+)](i) was estimated from Fluo-3 fluorescence, cell volume from forward scatter, phosphatidylserine-exposure from binding of fluorescent annexin-V, hemolysis from hemoglobin release, and ceramide abundance utilizing fluorescent antibodies. A 48 h exposure to sulindac sulfide (≤ 20 µM) was followed by significant increase of [Ca(2+)](i), enhanced ceramide abundance, decreased forward scatter and increased percentage of annexin-V-binding erythrocytes. Sulindac sulfide triggered slight but significant hemolysis. Removal of extracellular Ca(2+) significantly blunted, but did not abrogate the effect of sulindac sulfide (20 µM) on annexin-V-binding. Sulindac sulfide stimulates the suicidal death of erythrocytes or eryptosis, an effect paralleled by Ca(2+)-entry, ceramide formation, cell shrinkage and phosphatidylserine-exposure. Copyright © 2012 S. Karger AG, Basel.

  17. Mechanisms of sulindac-induced apoptosis and cell cycle arrest.

    PubMed

    Jung, Barbara; Barbier, Valerie; Brickner, Howard; Welsh, John; Fotedar, Arun; McClelland, Michael

    2005-02-28

    The mechanism underlying the chemopreventive effects of the non-steroidal anti-inflammatory drug sulindac remains unclear. Its active metabolite, sulindac sulfide, induces cell cycle arrest as well as apoptosis in mammalian cell lines. We now show that in murine thymocytes, sulindac sulfide-induced cell death is p53, bax, Fas, and FasL independent. In contrast, bcl2 transgenic thymocytes are resistant to sulindac sulfide-induced apoptosis. In addition, we demonstrate that sulindac sulfide-induced cell cycle arrest in mouse embryonic fibroblasts (MEFs) is partly mediated by the retinoblastoma tumor suppressor protein (Rb) and the cyclin kinase inhibitor p21waf1/cip1. Furthermore, MEFs deficient in p21 or Rb are more susceptible to sulindac sulfide-induced cell death. These results suggest that sulindac may selectively target premalignant cells with cell cycle checkpoint deficits.

  18. Sulindac

    MedlinePlus

    ... osteoarthritis (arthritis caused by a breakdown of the lining of the joints), rheumatoid arthritis (arthritis caused by swelling of the lining of the joints), and ankylosing spondylitis (arthritis that ...

  19. Aerosol administration of phospho-sulindac inhibits lung tumorigenesis.

    PubMed

    Cheng, Ka Wing; Wong, Chi C; Alston, Ninche; Mackenzie, Gerardo G; Huang, Liqun; Ouyang, Nengtai; Xie, Gang; Wiedmann, Timothy; Rigas, Basil

    2013-08-01

    Phospho-sulindac is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of phospho-sulindac and evaluated the antitumor efficacy of inhaled phospho-sulindac in an orthotopic model of human non-small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of phospho-sulindac to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled phospho-sulindac (6.5 mg/kg) was highly effective in inhibiting lung tumorigenesis (75%; P < 0.01) and significantly improved the survival of mice bearing orthotopic A549 xenografts. Mechanistically, phospho-sulindac suppressed lung tumorigenesis by (i) inhibiting EGF receptor (EGFR) activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; (ii) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and (iii) inducing autophagic cell death. Our data establish that inhalation delivery of phospho-sulindac is an efficacious approach to the control of lung cancer, which merits further evaluation.

  20. Effect of dimethyl sulfoxide on sulindac disposition in rats.

    PubMed

    Swanson, B N; Mojaverian, P; Boppana, V K; Dudash, M R

    1981-01-01

    Sulindac and dimethyl sulfoxide (DMSO) are both effective antiinflammatory agents in man. Since the sulfoxide moiety in these compounds is metabolized similarly, a biochemical interaction between the two drugs in vivo was thought to be possible. After iv injections of sulindac (5 mg/kg), plasma concentrations of sulindac, and its sulfide and sulfone metabolites, were measured in normal rats and in rats that had received, 30 min earlier, a single ip dose of DMSO (0.1, 0.5, or 1.0 ml). The half-life of sulindac (normally 94 min) was increased significantly by DMSO (0.1, 0.5, or 1.0 ml). The half-life of sulindac (normally 94 min) was increased significantly by DMSO (408 min after 1.0 ml of DMSO). Plasma sulfide metabolite levels were reduced in a dose-related manner by DMSO (93% reduction in peak concentration after 1.0 ml of DMSO). Sulfone metabolite concentration was also significantly diminished by the highest dose of DMSO. Similarly, DMSO was shown to decrease conversion of sulindac to sulfide and sulfone metabolites by rat liver enzymes in vitro. Sulfoxide reductase was more sensitive to DMSO inhibition than was sulfoxide oxidase both in vivo and in vitro. These data demonstrate that DMSO can significantly alter in vivo the formation of the pharmacologically active, sulfide metabolite of sulindac; therefore, concurrent use of DMSO and sulindac should be approached with caution.

  1. [Effect of sulindac on improving autistic behaviors in rats].

    PubMed

    Qin, Liyan; Dai, Xufang

    2015-08-01

    To test the effect of sulindac on autistic behaviors in a rat model and explore the possible mechanisms. Autistic rat models were established by a single intraperitoneal injection of sodium valproate (VPA) at 12.5 days of pregnancy. The pregnant rats were treated with oral sulindac at a daily dose of 80 mg/kg until weaning of the newborn rats (23 days after being born), which were divided into control, VPA treatment, sulindac treatment, and VPA+ sulindac treatment groups. The social interaction and neuroethology of the newborn rats were evaluated at 35 days, and the levels of β-catenin and phosphorylated Gsk3β in the brain tissues were investigated by Western blotting. Compared with the control rats, the rats treated with VPA showed lower social interaction, longer moving time in central area, and reduced standing times. Treatment with sulindac alone resulted in no obvious changes in the social interaction or neuroethology of the newborn rats, but sulindac treatment corrected VPA-induced autistic-like behaviors. Sulindac also attenuated VPA-triggered p-Gsk3β downregulation and β-catenin upregulation in the prefrontal lobe, seahorse and cerebellum. Sulindac can improve the behaviors of autistic rats possibly by suppressing Wnt signaling pathway.

  2. Sulindac and Sulindac Metabolites in Nipple Aspirate Fluid and Effect on Drug Targets in a Phase I Trial

    PubMed Central

    Thompson, Patricia A.; Hsu, Chiu-Hsieh; Green, Sylvan; Stopeck, Alison T.; Johnson, Karen; Alberts, David S.; Chow, H.-H. Sherry

    2014-01-01

    Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of breast cancer. Sulindac, a non-selective NSAID with both cyclooxygenase 2 (COX2) dependent and independent activities, is a candidate for breast chemoprevention. We conducted a Phase Ib trial in 30 women at increased risk for breast cancer to evaluate the breast tissue distribution of sulindac at two dose levels (150 mg q.d. and 150 mg b.i.d. for 6 weeks), using nipple aspirate fluid (NAF) as a surrogate of breast tissue drug exposure. We also explored the effect of sulindac on drug-induced biomarkers in NAF. We show that sulindac and its metabolites partition to human breast as measured by NAF levels. Sulindac intervention did not decrease 13,14-dihydro-15-keto prostaglandin A2 (PGEM), a stable derivative of prostaglandin E2, in NAF, but exposure was associated with a significant trend towards higher levels of growth differentiation factor 15 (GDF15) in NAF in women receiving 150 mg b.i.d. (p = 0.038). These results are the first to demonstrate partitioning of sulindac and metabolites to human breast tissue and the first evidence for a potential dose dependent effect of sulindac on GDF15 levels in NAF. PMID:20051377

  3. Inhibition of sulindac metabolism by dimethyl sulfoxide in the rat.

    PubMed

    Swanson, B N; Mojaverian, P; Boppana, V K

    1983-01-01

    Dimethyl sulfoxide (DMSO) suppresses conversion of the prodrug sulindac to its bioactive sulfide metabolite (SD) by competitively inhibiting sulfoxide reductase. During continuous iv infusions of sulindac (1 mg/kg X h), plasma concentrations of SD at steady-state equilibrium were 80% lower when DMSO was infused concomitantly at 0.34 ml/kg X h, whereas sulindac plasma concentrations were not significantly affected by DMSO. Dermal application and intragastric administration of DMSO also inhibited SD accumulation in plasma. DMSO was only a weak inhibitor of SD oxidation in vitro and did not affect the rate of SD elimination in vivo. In contrast, dimethyl sulfide, a metabolite of DMSO, was a potent inhibitor of SD oxidase in vitro. These data suggest that DMSO can inhibit bioactivation and, hence, the antiinflammatory effects of sulindac.

  4. Drug-associated cholelithiasis: a case of sulindac stone formation and the incorporation of sulindac metabolites into the gallstones.

    PubMed

    Tokumine, F; Sunagawa, T; Shiohira, Y; Nakamoto, T; Miyazato, F; Muto, Y

    1999-08-01

    A case of drug-associated cholelithiasis (sulindac chlecystohepatolithiasis) in a 63-yr-old woman is reported. The patient was admitted to our hospital to undergo treatment for rheumatoid arthritis of 20 yr duration. She was treated with nonsteroidal anti-inflammatory drugs (NSAID: sulindac). Two months later, she presented with right upper quadrant pain. Diagnostic studies including ultrasonography (US), computed tomography (CT) and endoscopic retrograde cholangiography (ERC), led to the diagnosis of cholecystohepatolithiasis. She underwent cholecystectomy and choledochotomy with an extraction of intrahepatic stones. The intrahepatic stones were light yellow in color with a claylike appearance. Unexpectedly, an infrared spectroscopic analysis of the stone showed it to consist of sulindac metabolites. In addition, the dilated segment of the intrahepatic bile duct naturally returned to its normal size after the discontinuation of the drug administration. This is the first reported case of sulindac stone formation in the bile duct. No similar problems with other NSAIDs have been reported previously.

  5. The role of NAG-1/GDF15 in the inhibition of intestinal polyps in APC/Min mice by sulindac.

    PubMed

    Wang, Xingya; Kingsley, Philip J; Marnett, Larry J; Eling, Thomas E

    2011-01-01

    The antitumor effects of nonsteroidal anti-inflammatory drugs (NSAID) are assumed to be due to the inhibition of COX activity, but COX-independent mechanisms may also play an important role. NSAID-activated gene (NAG-1/GDF15) is induced by NSAIDs and has antitumorigenic activities. To determine the contribution of COX-2 inhibition and NAG-1/GDF15 expression to the prevention of colon carcinogenesis by NSAIDs, we evaluated several sulindac derivatives [des-methyl (DM)-sulindac sulfide and its prodrug DM-sulindac] that do not inhibit COX-2 activity. Sulindac sulfide and DM-sulindac induced the expression of NAG-1/GDF15 in HCT116 cells as determined by quantitative real-time PCR and Western blot. We fed APC/Min mice with 320 ppm of sulindac and doses of DM-sulindac. Only sulindac significantly inhibited tumor formation inAPC/Min mice. To determine the pharmacokinetic properties of sulindac and DM-sulindac in vivo, wild-type C57/B6 mice were fed with sulindac and DM-sulindac at 80, 160, and 320 ppm. High-performance liquid chromatography analysis revealed that the conversion of DM-sulindac to DM-sulindac sulfide (active form) was less efficient than the conversion of sulindac to sulindac sulfide (active form) in the mice. Lower levels of DM-sulindac sulfide accumulated in intestinal and colon tissues in comparison with sulindac sulfide. In addition, NAG-1/GDF15 was induced in the liver of sulindac-fed mice but not in the DM-sulindac-fed mice. Collectively, our results suggest that the tumor-inhibitory effects of sulindac in APC/Min mice may be due to, in part, NAG-1/GDF15 induction in the liver. Our study also suggests that pharmacologic properties should be carefully evaluated when developing drug candidates. ©2011 AACR.

  6. Randomized Phase II Trial of Sulindac for Lung Cancer Chemoprevention

    PubMed Central

    Limburg, Paul J.; Mandrekar, Sumithra J.; Aubry, Marie Christine; Ziegler, Katie L. Allen; Zhang, Jun; Yi, Joanne E.; Henry, Michael; Tazelaar, Henry D.; Lam, Stephen; McWilliams, Annette; Midthun, David E.; Edell, Eric S.; Rickman, Otis B.; Mazzone, Peter; Tockman, Melvyn; Beamis, John F.; Lamb, Carla; Simoff, Michael; Loprinzi, Charles; Szabo, Eva; Jett, James

    2012-01-01

    Introduction Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥ 30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN). Methods At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150 mg bid or an identical placebo bid for six months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index. Results Slower than anticipated recruitment led to trial closure after randomizing participants (n = 31 and n = 30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p = 0.0005) and sulindac (30 versus 10; p = 0.0003) arms, but the difference between arms was not statistically significant (p = 0.92). Conclusions Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150 mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention

  7. Randomized phase II trial of sulindac for lung cancer chemoprevention.

    PubMed

    Limburg, Paul J; Mandrekar, Sumithra J; Aubry, Marie Christine; Ziegler, Katie L Allen; Zhang, Jun; Yi, Joanne E; Henry, Michael; Tazelaar, Henry D; Lam, Stephen; McWilliams, Annette; Midthun, David E; Edell, Eric S; Rickman, Otis B; Mazzone, Peter; Tockman, Melvyn; Beamis, John F; Lamb, Carla; Simoff, Michael; Loprinzi, Charles; Szabo, Eva; Jett, James

    2013-03-01

    Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN). At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150mg bid or an identical placebo bid for 6 months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index. Slower than anticipated recruitment led to trial closure after randomizing participants (n=31 and n=30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p=0.0005) and sulindac (30 versus 10; p=0.0003) arms, but the difference between arms was not statistically significant (p=0.92). Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention. Copyright © 2012 Elsevier Ireland Ltd. All rights

  8. The Role of NAG-1/GDF15 in the Inhibition of Intestinal Polyps in APC/Min Mice by Sulindac

    PubMed Central

    Wang, Xingya; Kingsley, Philip J.; Marnett, Larry J.; Eling, Thomas E.

    2014-01-01

    The antitumor effects of nonsteroidal anti-inflammatory drugs (NSAID) are assumed to be due to the inhibition of COX activity, but COX-independent mechanisms may also play an important role. NSAID-activated gene (NAG-1/GDF15) is induced by NSAIDs and has antitumorigenic activities. To determine the contribution of COX-2 inhibition and NAG-1/GDF15 expression to the prevention of colon carcinogenesis by NSAIDs, we evaluated several sulindac derivatives [des-methyl (DM)-sulindac sulfide and its prodrug DM-sulindac] that do not inhibit COX-2 activity. Sulindac sulfide and DM-sulindac induced the expression of NAG-1/GDF15 in HCT116 cells as determined by quantitative real-time PCR and Western blot. We fed APC/Min mice with 320 ppm of sulindac and doses of DM-sulindac. Only sulindac significantly inhibited tumor formation in APC/Min mice. To determine the pharmacokinetic properties of sulindac and DM-sulindac in vivo, wild-type C57/B6 mice were fed with sulindac and DM-sulindac at 80, 160, and 320 ppm. High-performance liquid chromatography analysis revealed that the conversion of DM-sulindac to DM-sulindac sulfide (active form) was less efficient than the conversion of sulindac to sulindac sulfide (active form) in the mice. Lower levels of DM-sulindac sulfide accumulated in intestinal and colon tissues in comparison with sulindac sulfide. In addition, NAG-1/GDF15 was induced in the liver of sulindac-fed mice but not in the DM-sulindac–fed mice. Collectively, our results suggest that the tumor-inhibitory effects of sulindac in APC/Min mice may be due to, in part, NAG-1/GDF15 induction in the liver. Our study also suggests that pharmacologic properties should be carefully evaluated when developing drug candidates. PMID:21205743

  9. Single dose oral sulindac for acute postoperative pain in adults

    PubMed Central

    Moore, R Andrew; Derry, Sheena; McQuay, Henry J

    2014-01-01

    Background Sulindac is a non-steroidal anti-inflammatory drug (NSAID) licensed for use in rheumatic disease and other musculoskeletal disorders in the UK, and widely available in other countries worldwide. This review sought to evaluate the efficacy and safety of oral sulindac in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. Objectives To assess the efficacy of single dose oral sulindac in acute postoperative pain, and any associated adverse events. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies up to June 2009. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of oral sulindac for relief of acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We planned to use area under the “pain relief versus time” curve to derive the proportion of participants with meloxicam experiencing least 50% pain relief over 4 to 6 hours, using validated equations; to use number needed to treat to benefit (NNT); the proportion of participants using rescue analgesia over a specified time period; time to use of rescue analgesia; information on adverse events and withdrawals. Main results No studies were identified by the searches that examined oral sulindac in patients with established postoperative pain. Authors’ conclusions In the absence of evidence of efficacy, at present, for oral sulindac in acute postoperative pain, its use in this indication is not justified. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies is lacking, use in other indications should be evaluated carefully. Given the large number of available drugs of this and similar classes

  10. Population Pharmacokinetic Model for Cancer Chemoprevention With Sulindac in Healthy Subjects

    PubMed Central

    Berg, Alexander K.; Mandrekar, Sumithra J.; Ziegler, Katie L. Allen; Carlson, Elsa C.; Szabo, Eva; Ames, Mathew M.; Boring, Daniel; Limburg, Paul J.; Reid, Joel M.

    2014-01-01

    Sulindac is a prescription-based non-steroidal anti-inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study comparing two formulations of sulindac. The complex disposition of sulindac and its metabolites was described by a seven-compartment model featuring enterohepatic recirculation and is the first reported population pharmacokinetic model for sulindac. The derived model was used to explore effects of clinical variables on sulindac pharmacokinetics and revealed that body weight, creatinine clearance, and gender were significantly correlated with pharmacokinetic parameters. Moreover, the model quantifies the relative bioavailability of the sulindac formulations and illustrates the utility of population pharmacokinetics in bioequivalence assessment. This novel population pharmacokinetic model provides new insights regarding the factors that may affect the pharmacokinetics of sulindac and the exisulind and sulindac sulfide metabolites in generally healthy subjects, which have implications for future chemoprevention trial design for this widely available agent. PMID:23436338

  11. Population pharmacokinetic model for cancer chemoprevention with sulindac in healthy subjects.

    PubMed

    Berg, Alexander K; Mandrekar, Sumithra J; Ziegler, Katie L Allen; Carlson, Elsa C; Szabo, Eva; Ames, Mathew M; Boring, Daniel; Limburg, Paul J; Reid, Joel M

    2013-04-01

    Sulindac is a prescription-based non-steroidal anti-inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study comparing two formulations of sulindac. The complex disposition of sulindac and its metabolites was described by a seven-compartment model featuring enterohepatic recirculation and is the first reported population pharmacokinetic model for sulindac. The derived model was used to explore effects of clinical variables on sulindac pharmacokinetics and revealed that body weight, creatinine clearance, and gender were significantly correlated with pharmacokinetic parameters. Moreover, the model quantifies the relative bioavailability of the sulindac formulations and illustrates the utility of population pharmacokinetics in bioequivalence assessment. This novel population pharmacokinetic model provides new insights regarding the factors that may affect the pharmacokinetics of sulindac and the exisulind and sulindac sulfide metabolites in generally healthy subjects, which have implications for future chemoprevention trial design for this widely available agent. © The Author(s) 2013.

  12. Sulindac sulfide inhibits colon cancer cell growth and downregulates specificity protein transcription factors.

    PubMed

    Li, Xi; Pathi, Satya S; Safe, Stephen

    2015-12-16

    Specificity protein (Sp) transcription factors play pivotal roles in maintaining the phenotypes of many cancers. We hypothesized that the antineoplastic effects of sulindac and its metabolites were due, in part, to targeting downregulation of Sp transcription factors. The functional effects of sulindac, sulindac sulfone and sulindac sulfide on colon cancer cell proliferation were determined by cell counting. Effects of these compounds on expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes were determined by western blot analysis of whole cell lysates and in transient transfection assays using GC-rich constructs. Sulindac and its metabolites inhibited RKO and SW480 colon cancer cell growth and the order of growth inhibitory potency was sulindac sulfide>sulindac sulfone>sulindac. Treatment of SW480 and RKO cells with sulindac sulfide downregulated expression of Sp1, Sp3 and Sp4 proteins. Sulindac sulfide also decreased expression of several Sp-regulated genes that are critical for cancer cell survival, proliferation and angiogenesis and these include survivin, bcl-2, epidermal growth factor receptor (EGFR), cyclin D1, p65 subunit of NFκB and vascular endothelial growth factor (VEGF). Sulindac sulfide also induced reactive oxygen species (ROS) and decreased the level of microRNA-27a in colon cancer cells, which resulted in the upregulation of the Sp-repressor ZBTB10 and this resulted in downregulation of Sp proteins. The results suggest that the cancer chemotherapeutic effects of sulindac in colon cancer cells are due, in part, to its metabolite sulindac sulfide which downregulates Sp transcription factors and Sp-regulated pro-oncogenic gene products.

  13. Effect of sulindac sulfide on metallohydrolases in the human colon cancer cell line HT-29.

    PubMed

    Guillen-Ahlers, Hector; Tan, Jiangning; Castellino, Francis J; Ploplis, Victoria A

    2011-01-01

    Matrix metalloproteinase 7 (MMP7), a metallohydrolase involved in the development of several cancers, is downregulated in the Apc(Min/+) colon cancer mouse model following sulindac treatment. To determine whether this effect is relevant to the human condition, HT-29 human colon cancer cells were treated with sulindac and its metabolites, and compared to results obtained from in vivo mouse studies. The expression of MMP7 was monitored. The results demonstrated that sulindac sulfide effectively downregulated both MMP7 expression and activity. Furthermore, activity-based proteomics demonstrated that sulindac sulfide dramatically decreased the activity of leukotriene A4 hydrolase in HT-29 cells as reflected by a decrease in the level of its product, leukotriene B4. This study demonstrates that the effect of sulindac treatment in a mouse model of colon cancer may be relevant to the human counterpart and highlights the effect of sulindac treatment on metallohydrolases.

  14. Effect of Sulindac Sulfide on Metallohydrolases in the Human Colon Cancer Cell Line HT-29

    PubMed Central

    Guillen-Ahlers, Hector; Tan, Jiangning; Castellino, Francis J.; Ploplis, Victoria A.

    2011-01-01

    Matrix metalloproteinase 7 (MMP7), a metallohydrolase involved in the development of several cancers, is downregulated in the ApcMin/+ colon cancer mouse model following sulindac treatment. To determine whether this effect is relevant to the human condition, HT-29 human colon cancer cells were treated with sulindac and its metabolites, and compared to results obtained from in vivo mouse studies. The expression of MMP7 was monitored. The results demonstrated that sulindac sulfide effectively downregulated both MMP7 expression and activity. Furthermore, activity-based proteomics demonstrated that sulindac sulfide dramatically decreased the activity of leukotriene A4 hydrolase in HT-29 cells as reflected by a decrease in the level of its product, leukotriene B4. This study demonstrates that the effect of sulindac treatment in a mouse model of colon cancer may be relevant to the human counterpart and highlights the effect of sulindac treatment on metallohydrolases. PMID:21991341

  15. Antenatal exposure to sulindac and risk of necrotizing enterocolitis.

    PubMed

    Kamath-Rayne, Beena D; Habli, Mounira; Rodriguez, Zahidee; Wu, Malcolm; Gresh, James; DeFranco, Emily A

    2015-01-01

    Most studies of tocolytics are underpowered to assess drug effects on rare adverse neonatal outcomes. Our aim was to optimize statistical power to assess the influence of sulindac on the rare but severe outcome of necrotizing enterocolitis (NEC) by performing a case-control study. A priori sample size of 78 in each group was estimated to detect a 2.5-fold increase in nonsteroidal antiinflammatory drug exposure in NEC cases. Maternal-neonatal charts were reviewed from 2007 through 2012 to yield 110 NEC cases: 68 patients with confirmed NEC by Bell's stage II criteria, and 42 with suspected NEC. Cases and controls (N = 131, matched according to gestational age at delivery, plurality, and delivery date) were compared in rates of antenatal exposures to nonsteroidal antiinflammatory drugs, other tocolytics, and maternal-neonatal characteristics and complications. Cases and controls were delivered at a mean of 28 weeks. Approximately 52% of the total cohort received tocolytics (26% indomethacin, 15% sulindac, 32% calcium channel blockers, 32% beta-sympathomimetics), with no differences in frequency of use between cases and controls. While there was no difference in indomethacin exposure between cases and controls, antenatal exposure to sulindac was independently associated with increased risk of NEC (adjusted odds ratio, 5.33; 95% confidence interval, 1.38-20.57; P = .02), even after adjustment for other factors significantly associated with NEC. Our data demonstrate an adverse association of sulindac with NEC. These findings deserve further investigation and using sulindac as a tocolytic agent requires caution. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Structural analysis of sulindac as an inhibitor of aldose reductase and AKR1B10.

    PubMed

    Cousido-Siah, Alexandra; Ruiz, Francesc X; Crespo, Isidro; Porté, Sergio; Mitschler, André; Parés, Xavier; Podjarny, Alberto; Farrés, Jaume

    2015-06-05

    Aldose reductase (AR, AKR1B1) and AKR1B10 are enzymes implicated in important pathologies (diabetes and cancer) and therefore they have been proposed as suitable targets for drug development. Sulindac is the metabolic precursor of the potent non-steroidal anti-inflammatory drug (NSAID) sulindac sulfide, which suppresses prostaglandin production by inhibition of cyclooxygenases (COX). In addition, sulindac has been found to be one of the NSAIDs with higher antitumoral activity, presumably through COX inhibition. However, sulindac anticancer activity could be partially mediated through COX-independent mechanisms, including the participation of AR and AKR1B10. Previously, it had been shown that sulindac and sulindac sulfone were good AR inhibitors and the structure of the ternary complex with NADP(+) and sulindac was described (PDB ID 3U2C). In this work, we determined the three-dimensional structure of AKR1B10 with sulindac and established structure-activity relationships (SAR) of sulindac and their derivatives with AR and AKR1B10. The difference in the IC50 values for sulindac between AR (0.36 μM) and AKR1B10 (2.7 μM) might be explained by the different positioning and stacking interaction given by Phe122/Phe123, and by the presence of two buried and ordered water molecules in AKR1B10 but not in AR. Moreover, SAR analysis shows that the substitution of the sulfinyl group is structurally allowed in sulindac derivatives. Hence, sulindac and its derivatives emerge as lead compounds for the design of more potent and selective AR and AKR1B10 inhibitors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. Phospho-sulindac (OXT-328), a novel sulindac derivative, is safe and effective in colon cancer prevention in mice

    PubMed Central

    Mackenzie, Gerardo G.; Sun, Yu; Huang, Liqun; Xie, Gang; Ouyang, Nengtai; Gupta, Ramesh C.; Johnson, Francis; Komninou, Despina; Kopelovich, Levy; Rigas, Basil

    2010-01-01

    Background & Aims Non-steroidal anti-inflammatory drugs (NSAIDs) are effective cancer chemopreventive agents. However, chronic administration of NSAIDs is associated with significant side effects, mainly gastrointestinal. Given these limitations, we synthesized phospho-sulindac (P-S; OXT-328), a novel sulindac derivative. Methods Here, we evaluated the safety and efficacy of P-S in preclinical models, including its mechanism of action using human colon cancer cell (HCCC) lines and animal tumor models. Results a) Compared to sulindac, P-S is much more potent in inhibiting the growth of cultured HCCC and more efficacious in preventing the growth of HT-29 xenografts in nude mice. P-S also prevents the growth of intestinal tumors in Apc/Min mice, b) in combination with difluoromethylornithine (DFMO), P-S reduced tumor multiplicity in Apc/Min mice by 90%; and c) P-S is much safer than sulindac as evidenced by its in vitro toxicological evaluation and animal toxicity studies. Mechanistically, P-S increases the intracellular levels of reactive oxygen and nitrogen species, which are key early mediators of its chemopreventive effect. Moreover, P-S induces spermidine/spermine N1-acetyltransferase enzymatic activity, and together with DFMO it reduces polyamine levels in vitro and in vivo. Conclusions P-S displays considerable safety and efficacy, two pharmacological properties that are essential for a potential cancer chemopreventive agent, and thus merits further evaluation. PMID:20600034

  18. Phospho-sulindac (OXT-328), a novel sulindac derivative, is safe and effective in colon cancer prevention in mice.

    PubMed

    Mackenzie, Gerardo G; Sun, Yu; Huang, Liqun; Xie, Gang; Ouyang, Nengtai; Gupta, Ramesh C; Johnson, Francis; Komninou, Despina; Kopelovich, Levy; Rigas, Basil

    2010-10-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective cancer chemopreventive agents. However, chronic administration of NSAIDs is associated with significant side effects, mainly of the gastrointestinal tract. Given these limitations, we synthesized phospho-sulindac (P-S; OXT-328), a novel sulindac derivative. Here, we evaluated the safety and efficacy of P-S in preclinical models, including its mechanism of action with human colon cancer cell (HCCC) lines and animal tumor models. (1) Compared with sulindac, P-S is much more potent in inhibiting the growth of cultured HCCCs and more efficacious in preventing the growth of HT-29 xenografts in nude mice. P-S also prevents the growth of intestinal tumors in Apc/Min mice. (2) In combination with difluoromethylornithine (DFMO), P-S reduced tumor multiplicity in Apc/Min mice by 90%. (3) P-S is much safer than sulindac as evidenced by its in vitro toxicologic evaluation and animal toxicity studies. Mechanistically, P-S increases the intracellular levels of reactive oxygen and nitrogen species, which are key early mediators of its chemopreventive effect. Moreover, P-S induces spermidine/spermine N(1)-acetyltransferase enzymatic activity, and together with DFMO it reduces polyamine levels in vitro and in vivo. P-S displays considerable safety and efficacy, two pharmacologic properties that are essential for a potential cancer chemopreventive agent, and thus merits further evaluation. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  19. Inhibition of breast cancer cell motility with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGFβ/miR-21 signaling

    PubMed Central

    Ma, Ruixia; Feng, Xiangling; Li, Wei; Piazza, Gary A.; Xi, Yaguang

    2016-01-01

    Compelling efficacy on intervention of tumorigenesis by nonsteroidal anti-inflammatory drugs (NSAIDs) has been documented intensively. However, the toxicities related to cyclooxygenase (COX) inhibition resulting in suppression of physiologically important prostaglandins limit their clinical use for human cancer chemoprevention. A novel derivative of the NSAID sulindac sulfide (SS), referred as sulindac sulfide amide (SSA), was recently developed, which lacks COX inhibitory activity, yet shows greater suppressive effect than SS on growth of various cancer cells. In this study, we focus on the inhibitory activity of SSA on breast tumor cell motility, which has not been studied previously. Our results show that SSA treatment at non-cytotoxic concentrations can specifically reduce breast tumor cell motility without influencing tumor cell growth, and the mechanism of action involves the suppression of TGFβ signaling by directly blocking Smad2/3 phosphorylation. Moreover, miR-21, a well-documented oncogenic miRNA for promoting tumor cell metastasis, was also found to be involved in inhibitory activity of SSA in breast tumor cell motility through the modulation of TGFβ pathway. In conclusion, we demonstrate that a non-COX inhibitory derivative of sulindac can inhibit breast tumor metastasis by a mechanism involving the TGFβ/miR-21 signaling axis. PMID:26769851

  20. Combined treatment with vitamin C and sulindac synergistically induces p53- and ROS-dependent apoptosis in human colon cancer cells.

    PubMed

    Gong, Eun-Yeung; Shin, Yu Jin; Hwang, Ih-Yeon; Kim, Jeong Hee; Kim, Seung-Mi; Moon, Jai-Hee; Shin, Jae-Sik; Lee, Dae-Hee; Hur, Dae Young; Jin, Dong-Hoon; Hong, Seung-Woo; Lee, Won Keun; Lee, Wang-Jae

    2016-09-06

    Sulindac has anti-neoplastic properties against colorectal cancers; however, its use as a chemopreventive agent has been limited due to toxicity and efficacy concerns. Combinatorial treatment of colorectal cancers has been attempted to maximize anti-cancer efficacy with minimal side effects by administrating NSAIDs in combination with other inhibitory compounds or drugs such as l-ascorbic acid (vitamin C), which is known to exhibit cytotoxicity towards various cancer cells at high concentrations. In this study, we evaluated a combinatorial strategy utilizing sulindac and vitamin C. The death of HCT116 cells upon combination therapy occurred via a p53-mediated mechanism. The combination therapeutic resistance developed in isogenic p53 null HCT116 cells and siRNA-mediated p53 knockdown HCT116 cells, but the exogenous expression of p53 in p53 null isogenic cells resulted in the induction of cell death. In addition, we investigated an increased level of intracellular ROS (reactive oxygen species), which was preceded by p53 activation. The expression level of PUMA (p53-upregulated modulator of apoptosis), but not Bim, was significantly increased in HCT116 cells in response to the combination treatment. Taken together, our results demonstrate that combination therapy with sulindac and vitamin C could be a novel anti-cancer therapeutic strategy for p53 wild type colon cancers. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Inhibition of breast cancer cell motility with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGFβ/miR-21 signaling.

    PubMed

    Yi, Bin; Chang, Hong; Ma, Ruixia; Feng, Xiangling; Li, Wei; Piazza, Gary A; Xi, Yaguang

    2016-02-16

    Compelling efficacy on intervention of tumorigenesis by nonsteroidal anti-inflammatory drugs (NSAIDs) has been documented intensively. However, the toxicities related to cyclooxygenase (COX) inhibition resulting in suppression of physiologically important prostaglandins limit their clinical use for human cancer chemoprevention. A novel derivative of the NSAID sulindac sulfide (SS), referred as sulindac sulfide amide (SSA), was recently developed, which lacks COX inhibitory activity, yet shows greater suppressive effect than SS on growth of various cancer cells. In this study, we focus on the inhibitory activity of SSA on breast tumor cell motility, which has not been studied previously. Our results show that SSA treatment at non-cytotoxic concentrations can specifically reduce breast tumor cell motility without influencing tumor cell growth, and the mechanism of action involves the suppression of TGFβ signaling by directly blocking Smad2/3 phosphorylation. Moreover, miR-21, a well-documented oncogenic miRNA for promoting tumor cell metastasis, was also found to be involved in inhibitory activity of SSA in breast tumor cell motility through the modulation of TGFβ pathway. In conclusion, we demonstrate that a non-COX inhibitory derivative of sulindac can inhibit breast tumor metastasis by a mechanism involving the TGFβ/miR-21 signaling axis.

  2. Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers

    PubMed Central

    Tang, Yong-Jun; Hu, Kai; Liu, Zhi; Chen, Yao; Ouyang, Dong-Sheng; Zhou, Hong-Hao

    2017-01-01

    Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 HHDD) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 hhdd) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium (D′ = 0.977, r2 = 0.944). The mean values of Cmax, AUC0–24, and AUC0–∞ of sulindac were significantly higher in FMO3 hhdd group than those of FMO3 HHDD group (P < 0.05), while the pharmacokinetic parameters except Tmax of sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers. PMID:28331852

  3. Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers.

    PubMed

    Tang, Yong-Jun; Hu, Kai; Huang, Wei-Hua; Wang, Chong-Zhi; Liu, Zhi; Chen, Yao; Ouyang, Dong-Sheng; Tan, Zhi-Rong; Zhou, Hong-Hao; Yuan, Chun-Su

    2017-01-01

    Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 HHDD) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 hhdd) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium (D' = 0.977, r(2) = 0.944). The mean values of Cmax, AUC0-24, and AUC0-∞ of sulindac were significantly higher in FMO3 hhdd group than those of FMO3 HHDD group (P < 0.05), while the pharmacokinetic parameters except Tmax of sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers.

  4. Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: results of a Children's Oncology Group (COG) phase II study.

    PubMed

    Skapek, Stephen X; Anderson, James R; Hill, D Ashley; Henry, David; Spunt, Sheri L; Meyer, William; Kao, Simon; Hoffer, Fredric A; Grier, Holcombe E; Hawkins, Douglas S; Raney, R Beverly

    2013-07-01

    Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children's Oncology Group. Eligible patients were <19 years of age who had measurable DT that was recurrent or not amenable to surgery or radiation. The primary objective was to estimate progression-free survival (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging. Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10-18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23-0.48) and 96%, respectively. All three deaths were due to progressive DT. Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates. Copyright © 2012 Wiley Periodicals, Inc.

  5. Studies on the metabolism and biological activity of the epimers of sulindac.

    PubMed

    Brunell, David; Sagher, Daphna; Kesaraju, Shailaja; Brot, Nathan; Weissbach, Herbert

    2011-06-01

    Sulindac is a nonsteroidal, anti-inflammatory drug (NSAID) that has also been studied for its anticancer activity. Recent studies suggest that sulindac and its metabolites act by sensitizing cancer cells to oxidizing agents and drugs that affect mitochondrial function, resulting in the production of reactive oxygen species and death by apoptosis. In contrast, normal cells are not killed under these conditions and, in some instances, are protected against oxidative stress. Sulindac has a methyl sulfoxide moiety with a chiral center and was used in all of the previous studies as a mixture of the R- and S-epimers. Because epimers of a compound can have very different chemical and biological properties, we have separated the R- and S-epimers of sulindac, studied their individual metabolism, and performed preliminary experiments on their effect on normal and lung cancer cells exposed to oxidative stress. Previous results had indicated that the reduction of (S)-sulindac to sulindac sulfide, the active NSAID, was catalyzed by methionine sulfoxide reductase (Msr) A. In the present study, we purified an enzyme that reduces (R)-sulindac and resembles MsrB in its substrate specificity. The oxidation of both epimers to sulindac sulfone is catalyzed primarily by the microsomal cytochrome P450 (P450) system, and the individual enzymes responsible have been identified. (S)-Sulindac increases the activity of the P450 system better than (R)-sulindac, but both epimers increase primarily the enzymes that oxidize (R)-sulindac. Both epimers can protect normal lung cells against oxidative damage and enhance the killing of lung cancer cells exposed to oxidative stress.

  6. Studies on the Metabolism and Biological Activity of the Epimers of Sulindac

    PubMed Central

    Brunell, David; Sagher, Daphna; Kesaraju, Shailaja; Brot, Nathan

    2011-01-01

    Sulindac is a nonsteroidal, anti-inflammatory drug (NSAID) that has also been studied for its anticancer activity. Recent studies suggest that sulindac and its metabolites act by sensitizing cancer cells to oxidizing agents and drugs that affect mitochondrial function, resulting in the production of reactive oxygen species and death by apoptosis. In contrast, normal cells are not killed under these conditions and, in some instances, are protected against oxidative stress. Sulindac has a methyl sulfoxide moiety with a chiral center and was used in all of the previous studies as a mixture of the R- and S-epimers. Because epimers of a compound can have very different chemical and biological properties, we have separated the R- and S-epimers of sulindac, studied their individual metabolism, and performed preliminary experiments on their effect on normal and lung cancer cells exposed to oxidative stress. Previous results had indicated that the reduction of (S)-sulindac to sulindac sulfide, the active NSAID, was catalyzed by methionine sulfoxide reductase (Msr) A. In the present study, we purified an enzyme that reduces (R)-sulindac and resembles MsrB in its substrate specificity. The oxidation of both epimers to sulindac sulfone is catalyzed primarily by the microsomal cytochrome P450 (P450) system, and the individual enzymes responsible have been identified. (S)-Sulindac increases the activity of the P450 system better than (R)-sulindac, but both epimers increase primarily the enzymes that oxidize (R)-sulindac. Both epimers can protect normal lung cells against oxidative damage and enhance the killing of lung cancer cells exposed to oxidative stress. PMID:21383205

  7. Sulindac metabolites induce proteosomal and lysosomal degradation of the epidermal growth factor receptor.

    PubMed

    Pangburn, Heather A; Ahnen, Dennis J; Rice, Pamela L

    2010-04-01

    The epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases. In response to ligand, EGFR is internalized and degraded by the ubiquitin-proteasome/lysosome pathway. We previously reported that metabolites of the nonsteroidal anti-inflammatory drug sulindac downregulate the expression of EGFR and inhibit basal and EGF-induced EGFR signaling through extracellular signal-regulated kinase 1/2. We now have evaluated the mechanisms of sulindac metabolite-induced downregulation of EGFR. EGF-induced downregulation of EGFR occurs within 10 minutes and lasts for 24 hours. By contrast, downregulation of EGFR by sulindac sulfide and sulindac sulfone was first evident at 4 and 24 hours, respectively, with maximal downregulation at 72 hours. Pretreatment with either the lysosomal inhibitor chloroquine or the proteosomal inhibitor MG132 blocked sulindac metabolite-induced downregulation of EGFR. Sulindac metabolites also increased the ubiquitination of EGFR. Whereas sulindac metabolites inhibited phosphorylation of EGFR pY1068, they increased phosphorylation of EGFR pY1045, the docking site where c-Cbl binds, thereby enabling receptor ubiquitination and degradation. Immunofluorescence analysis of EGF and EGFR distribution confirmed the biochemical observations that sulindac metabolites alter EGFR localization and EGFR internalization in a manner similar to that seen with EGF treatment. Expression of ErbB family members HER2 and HER3 was also downregulated by sulindac metabolites. We conclude that downregulation of EGFR expression by sulindac metabolites is mediated via lysosomal and proteosomal degradation that may be due to drug-induced phosphorylation at pY1045 with resultant ubiquitination of EGFR. Thus, sulindac metabolite-induced downregulation of EGFR seems to be mediated through mechanism(s) similar, at least in part, to those involved in EGF-induced downregulation of EGFR. (c) 2010 AACR.

  8. Docosahexaenoic acid sensitizes colon cancer cells to sulindac sulfide-induced apoptosis.

    PubMed

    Lim, Soo-Jeong; Lee, Eunmyong; Lee, Eun-Hye; Kim, Soo-Yeon; Cha, Jun Hyung; Choi, Hwanho; Park, Wanseo; Choi, Hyeon Kyeom; Ko, Seong-Hee; Kim, So Hee

    2012-06-01

    Sulindac analogs represent one of the most efficacious groups of NSAIDs reducing the risk of colon cancer. Recent studies have shown that sulindac sulfide, a sulindac analog effective at lower doses compared to its parent compound, triggers the death receptor (DR)5-dependent extrinsic apoptotic pathway. Induction of apoptosis via activation of the DR-mediated pathway would be an ideal therapeutic strategy to eliminate cancer cells. In this study, we investigated the possibility that colon cancer cells are sensitized to sulindac sulfide-induced apoptosis by docosahexaenoic acid (DHA), via activation of the DR/extrinsic apoptotic pathway. Our data demonstrated that DHA combination sensitized colon cancer cells to sulindac sulfide-induced apoptosis, leading to enhanced growth suppression of human colon cancer xenografts. The combination effect was primarily attributed to increased cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-8 activation. Moreover, pretreatment with z-IETD-FMK (caspase-8 inhibitor) or stable expression of dominant negative caspase-8 genes blocked DHA/sulindac sulfide cotreatment-induced apoptosis. In view of the finding that DR5 silencing abrogated the combination-stimulated apoptosis, we propose that apoptotic synergy induced by sulindac sulfide plus DHA is mediated via DR5. Our findings collectively support the utility of a combination of sulindac sulfide and DHA in the effective prevention and treatment of colon cancer.

  9. The inhibition of Wnt/β-catenin signaling pathway in human colon cancer cells by sulindac.

    PubMed

    Tai, Wei-Ping; Hu, Pin-Jin; Wu, Jing; Lin, Xiang-Chun

    2014-01-01

    The aberrant activation of Wnt/β-catenin signaling plays important roles in the initial development of colon cancer. Sulindac is a commonly used non-steroidal anti-inflammatory drug. We demonstrated the effects of sulindac on growth inhibition, apoptosis induction, and Wnt/β-catenin signaling suppression in human colon cancer cells. Sulindac significantly inhibited proliferation of HT-29 colon cancer cells in a dose- and time-dependent manner. Sulindac was found to induce the apoptosis of HT-29 cells and inhibit the Wnt/β-catenin pathway. The inhibition was further confirmed by the decreased protein levels of β-catenin. The results indicate that sulindac may play a beneficial role in the comprehensive treatment of colon cancer.

  10. Myeloid zinc finger 1 mediates sulindac sulfide-induced upregulation of death receptor 5 of human colon cancer cells

    PubMed Central

    Horinaka, Mano; Yoshida, Tatsushi; Tomosugi, Mitsuhiro; Yasuda, Shusuke; Sowa, Yoshihiro; Sakai, Toshiyuki

    2014-01-01

    A combined therapy of sulindac sulfide and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising strategy for the treatment of cancer. Sulindac sulfide had been shown to induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism underlying the upregulation of DR5 has not yet been elucidated. We demonstrate here that myeloid zinc finger 1 (MZF1) mediates the induction of DR5 by sulindac sulfide. Sulindac sulfide induced the expression of DR5 at the protein and mRNA levels in colon cancer SW480 cells. Furthermore, sulindac sulfide increased DR5 promoter activity. We showed that sulindac sulfide stimulated DR5 promoter activity via the −301 to −253 region. This region contained a putative MZF1-binding site. Site-directed mutations in the site abrogated the enhancement in DR5 promoter activity by sulindac sulfide. MZF1 directly bound to the putative MZF1-binding site of the DR5 promoter and the binding was increased by sulindac sulfide. The expression of MZF1 was also increased by sulindac sulfide, and MZF1 siRNA attenuated the upregulation of DR5 by sulindac sulfide. These results indicate that sulindac sulfide induces the expression of DR5 by up-regulating MZF1. PMID:25102912

  11. Myeloid zinc finger 1 mediates sulindac sulfide-induced upregulation of death receptor 5 of human colon cancer cells.

    PubMed

    Horinaka, Mano; Yoshida, Tatsushi; Tomosugi, Mitsuhiro; Yasuda, Shusuke; Sowa, Yoshihiro; Sakai, Toshiyuki

    2014-08-08

    A combined therapy of sulindac sulfide and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising strategy for the treatment of cancer. Sulindac sulfide had been shown to induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism underlying the upregulation of DR5 has not yet been elucidated. We demonstrate here that myeloid zinc finger 1 (MZF1) mediates the induction of DR5 by sulindac sulfide. Sulindac sulfide induced the expression of DR5 at the protein and mRNA levels in colon cancer SW480 cells. Furthermore, sulindac sulfide increased DR5 promoter activity. We showed that sulindac sulfide stimulated DR5 promoter activity via the -301 to -253 region. This region contained a putative MZF1-binding site. Site-directed mutations in the site abrogated the enhancement in DR5 promoter activity by sulindac sulfide. MZF1 directly bound to the putative MZF1-binding site of the DR5 promoter and the binding was increased by sulindac sulfide. The expression of MZF1 was also increased by sulindac sulfide, and MZF1 siRNA attenuated the upregulation of DR5 by sulindac sulfide. These results indicate that sulindac sulfide induces the expression of DR5 by up-regulating MZF1.

  12. Molecular alterations associated with sulindac-resistant colon tumors in ApcMin/+ mice.

    PubMed

    Greenspan, Emily J; Nichols, Frank C; Rosenberg, Daniel W

    2010-09-01

    Although nonsteroidal anti-inflammatory drugs (NSAID), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer, results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study, we evaluated the effect of sulindac on colon tumorigenesis in the Apc(Min/+) mouse model. Sulindac (180 ppm) given in drinking water for 9 weeks to Apc(Min/+) mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 versus 1.6 tumors per mouse, respectively; P < 0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. As expected, in the small intestine, sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 versus 42.0 tumors per mouse, respectively; P < 0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to exert its growth inhibitory effects through regulation of many noncyclooxygenase targets, including p21, beta-catenin, E-cadherin, mitochondrial apoptotic proteins, and peroxisome proliferator-activated receptor-gamma. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear beta-catenin accumulation. Importantly, p21(WAF1/cip1) and peroxisome proliferator-activated receptor-gamma expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. Together, these observations may be translatable to designing novel clinical therapies using combinations of agents that target multiple molecular pathways to overcome sulindac resistance.

  13. Molecular alterations associated with sulindac resistant colon tumors in ApcMin/+ mice

    PubMed Central

    Greenspan, Emily J.; Nichols, Frank C.; Rosenberg, Daniel W.

    2010-01-01

    Although non-steroidal anti-inflammatory drugs (NSAIDs), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer (CRC), results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study we evaluated the effect of sulindac on colon tumorigenesis in the ApcMin/+ mouse model. Sulindac (180 p.p.m.) given in drinking water for 9 weeks to ApcMin/+ mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 vs. 1.6 tumors/mouse, respectively; P<0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. As expected, in the small intestine sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 vs. 42.0 tumors/mouse, respectively; P<0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to exert its growth inhibitory effects through regulation of many non-COX targets, including p21, β-catenin, E-cadherin, mitochondrial apoptotic proteins and PPARγ. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear β-catenin accumulation. Importantly, p21WAF1/cip1 and PPARγ expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. Together, these observations may be translatable to designing novel clinical therapies utilizing combinations of agents that target multiple molecular pathways to overcome sulindac resistance. PMID:20716632

  14. Dietary anthocyanin-rich tart cherry extract inhibits intestinal tumorigenesis in APC(Min) mice fed suboptimal levels of sulindac.

    PubMed

    Bobe, Gerd; Wang, Bing; Seeram, Navindra P; Nair, Muraleedharan G; Bourquin, Leslie D

    2006-12-13

    A promising approach for cancer chemoprevention might be a combination therapy utilizing dietary phytochemicals and anticarcinogenic pharmaceuticals at a suboptimal dosage to minimize any potential adverse side effects. To test this hypothesis, various dosages of anthocyanin-rich tart cherry extract were fed in combination with suboptimal levels of the nonsteroidal anti-inflammatory drug sulindac to APCMin mice for 19 weeks. By the end of the feeding period, fewer mice that were fed the anthocyanin-rich extract in combination with sulindac lost more than 10% of body weight than mice fed sulindac alone. Mice that were fed anthocyanin-rich extract (at any dose) in combination with sulindac had fewer tumors and a smaller total tumor burden (total tumor area per mouse) in the small intestine when compared to mice fed sulindac alone. These results suggest that a dietary combination of tart cherry anthocyanins and sulindac is more protective against colon cancer than sulindac alone.

  15. Renal hemodynamic effects of nabumetone, sulindac, and placebo in patients with osteoarthritis.

    PubMed

    Cangiano, J L; Figueroa, J; Palmer, R

    1999-03-01

    We assessed the effects of nabumetone, sulindac, and placebo on renal function and renal excretion of vasodilatory prostaglandins in older female patients (age >50 years) with osteoarthritis and normal renal function. Using a prospective, crossover design, we compared the effects of nabumetone 2000 mg/d and sulindac 400 mg/d with placebo on glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary excretion of prostaglandin E2 and 6-keto-prostaglandin F1alpha in 12 patients. Urinary excretion of vasodilatory prostaglandins was not decreased after 14 days of treatment with either nabumetone or sulindac. Likewise, treatment with nabumetone or sulindac did not significantly alter renal function compared with placebo. There were no differences in mean changes in GFR or RPF from baseline after treatment with nabumetone or sulindac compared with placebo. The mean (+/- SD) changes in GFR from baseline were 0%+/-8% in patients receiving nabumetone, -8%+/-15% in patients receiving sulindac, and -7%+/-15% in patients receiving placebo. The results of this study demonstrate that treatment with nabumetone or sulindac caused no deterioration in renal function in older female patients with osteoarthritis and normal renal function.

  16. Selenium and sulindac are synergistic to inhibit intestinal tumorigenesis in Apc/p21 mice.

    PubMed

    Bi, Xiuli; Pohl, Nicole; Dong, Huali; Yang, Wancai

    2013-01-17

    Both selenium and non-steroidal anti-inflammatory drug (NSAID) sulindac are effective in cancer prevention, but their effects are affected by several factors including epigenetic alterations and gene expression. The current study was designed to determine the effects of the combination of selenium and sulindac on tumor inhibition and the underlying mechanisms. We fed the intestinal tumor model Apc/p21 mice with selenium- and sulindac-supplemented diet for 24 weeks, and found that the combination of selenium and sulindac significantly inhibited intestinal tumorigenesis, in terms of reducing tumor incidence by 52% and tumor multiplicities by 80% (p<0.01). Mechanistic studies revealed that the combination of selenium and sulindac led to the significant induction of the expression of p27 and p53 and JNK1 phosphorylation, and led to the suppression of β-catenin and its downstream targets. Impressively, the data also showed that demythelation on p21 promoter was associated with tumor inhibition by the combination of selenium and sulindac. The selenium is synergistic with sulindac to exert maximal effects on tumor inhibition. This finding provides an important chemopreventive strategy using combination of anti-cancer agents, which has a great impact on cancer prevention and has a promising translational potential.

  17. Combination of sulindac and dichloroacetate kills cancer cells via oxidative damage.

    PubMed

    Ayyanathan, Kasirajan; Kesaraju, Shailaja; Dawson-Scully, Ken; Weissbach, Herbert

    2012-01-01

    Sulindac is an FDA-approved non-steroidal anti-inflammatory drug with documented anticancer activities. Our recent studies showed that sulindac selectively enhanced the killing of cancer cells exposed to oxidizing agents via production of reactive oxygen species (ROS) resulting in mitochondrial dysfunction. This effect of sulindac and oxidative stress on cancer cells could be related to the defect in respiration in cancer cells, first described by Warburg 50 years ago, known as the Warburg effect. We postulated that sulindac might enhance the selective killing of cancer cells when combined with any compound that alters mitochondrial respiration. To test this hypothesis we have used dichloroacetate (DCA), which is known to shift pyruvate metabolism away from lactic acid formation to respiration. One might expect that DCA, since it stimulates aerobic metabolism, could stress mitochondrial respiration in cancer cells, which would result in enhanced killing in the presence of sulindac. In this study, we have shown that the combination of sulindac and DCA enhances the selective killing of A549 and SCC25 cancer cells under the conditions used. As predicted, the mechanism of killing involves ROS production, mitochondrial dysfunction, JNK signaling and death by apoptosis. Our results suggest that the sulindac-DCA drug combination may provide an effective cancer therapy.

  18. Combination of Sulindac and Dichloroacetate Kills Cancer Cells via Oxidative Damage

    PubMed Central

    Dawson-Scully, Ken; Weissbach, Herbert

    2012-01-01

    Sulindac is an FDA-approved non-steroidal anti-inflammatory drug with documented anticancer activities. Our recent studies showed that sulindac selectively enhanced the killing of cancer cells exposed to oxidizing agents via production of reactive oxygen species (ROS) resulting in mitochondrial dysfunction. This effect of sulindac and oxidative stress on cancer cells could be related to the defect in respiration in cancer cells, first described by Warburg 50 years ago, known as the Warburg effect. We postulated that sulindac might enhance the selective killing of cancer cells when combined with any compound that alters mitochondrial respiration. To test this hypothesis we have used dichloroacetate (DCA), which is known to shift pyruvate metabolism away from lactic acid formation to respiration. One might expect that DCA, since it stimulates aerobic metabolism, could stress mitochondrial respiration in cancer cells, which would result in enhanced killing in the presence of sulindac. In this study, we have shown that the combination of sulindac and DCA enhances the selective killing of A549 and SCC25 cancer cells under the conditions used. As predicted, the mechanism of killing involves ROS production, mitochondrial dysfunction, JNK signaling and death by apoptosis. Our results suggest that the sulindac-DCA drug combination may provide an effective cancer therapy. PMID:22866174

  19. Selenium and sulindac are synergistic to inhibit intestinal tumorigenesis in Apc/p21 mice

    PubMed Central

    2013-01-01

    Background Both selenium and non-steroidal anti-inflammatory drug (NSAID) sulindac are effective in cancer prevention, but their effects are affected by several factors including epigenetic alterations and gene expression. The current study was designed to determine the effects of the combination of selenium and sulindac on tumor inhibition and the underlying mechanisms. Results We fed the intestinal tumor model Apc/p21 mice with selenium- and sulindac-supplemented diet for 24 weeks, and found that the combination of selenium and sulindac significantly inhibited intestinal tumorigenesis, in terms of reducing tumor incidence by 52% and tumor multiplicities by 80% (p<0.01). Mechanistic studies revealed that the combination of selenium and sulindac led to the significant induction of the expression of p27 and p53 and JNK1 phosphorylation, and led to the suppression of β-catenin and its downstream targets. Impressively, the data also showed that demythelation on p21 promoter was associated with tumor inhibition by the combination of selenium and sulindac. Conclusions The selenium is synergistic with sulindac to exert maximal effects on tumor inhibition. This finding provides an important chemopreventive strategy using combination of anti-cancer agents, which has a great impact on cancer prevention and has a promising translational potential. PMID:23327547

  20. The NSAID sulindac is chemopreventive in the mouse distal colon but carcinogenic in the proximal colon.

    PubMed

    Mladenova, Dessislava; Daniel, Joseph J; Dahlstrom, Jane E; Bean, Elaine; Gupta, Ruta; Pickford, Russell; Currey, Nicola; Musgrove, Elizabeth A; Kohonen-Corish, Maija R J

    2011-03-01

    The non-steroidal anti-inflammatory drug sulindac is an effective chemopreventive agent in sporadic colorectal cancer but its potential benefit in mismatch repair deficient cancers remains to be defined. We wanted to determine whether genetic defects that are relevant for colorectal cancer, such as Msh2 or p53 deficiency, would influence the efficiency of sulindac chemoprevention or increase the side effects. Msh2 or p53 deficient and wild-type mice received feed containing 160-320 ppm sulindac for up to 25 weeks with or without a concurrent treatment with the carcinogen azoxymethane. Colon tissue was analysed by histopathology and molecular biology methods. We show that sulindac prevented azoxymethane-induced distal colon tumours in all mice. In the proximal colon, however, sulindac induced new inflammatory lesions on the mucosal folds, which further developed into adenocarcinoma in up to 18-25% of the p53 or Msh2 deficient mice but rarely in wild-type mice. This region in the proximal colon was characterised by a distinct profile of pro- and anti-inflammatory factors, which were modulated by the sulindac diet, including upregulation of hypoxia inducible factor 1α and macrophage inflammatory protein 2. These data show that the sulindac diet promotes carcinogenesis in the mouse proximal colon possibly through chronic inflammation. Sulindac has both beneficial and harmful effects in vivo, which are associated with different microenvironments within the colon of experimental mice. Deficiency for the Msh2 or p53 tumour suppressor genes increases the harmful side effects of long-term sulindac treatment in the mouse colon.

  1. In Vivo Antineoplastic Effects of the NSAID Sulindac in an Oral Carcinogenesis Model.

    PubMed

    Katoumas, Konstantinos; Nikitakis, Nikolaos; Perrea, Despina; Dontas, Ismene; Sklavounou, Alexandra

    2015-07-01

    The antineoplastic properties of the NSAID sulindac have long been studied. The purpose of this study was to explore sulindac's in vivo effects on oral squamous cell carcinoma (SCC) oncogenesis using the hamster cheek pouch oral carcinogenesis model (HOCM). Thirty Syrian golden hamsters were divided into three experimental and two control groups (n = 6 each). The animals' right buccal pouches were treated with carcinogen for 9 weeks in one experimental and one control group and for 14 weeks in all other three groups. The animals of two experimental groups received sulindac from the 1st week and those of the third experimental group from the 10th week. After the end of carcinogenesis, treated buccal pouches were removed and examined. In animals treated with carcinogen for 14 weeks, development of oral SCC and tumor volume were significantly lower in animals that received sulindac from the first week of the experiment. Oral SCC developing in animals that received sulindac were more frequently well differentiated compared with the control group. In animals treated with carcinogen for 9 weeks, the animals that received sulindac developed lower grade of epithelial dysplasia. Proliferation index Ki-67 and positivity for the antiapoptotic molecule survivin were lower in the animals that received sulindac. Treatment with sulindac appears to delays the progression of oral premalignant lesions to oral SCC in the HOCM, also resulting in smaller and better differentiated tumors. These in vivo antineoplastic effects may be related to sulindac's ability to decrease cell proliferation and to prevent survivin expression. ©2015 American Association for Cancer Research.

  2. Acute kidney injury, hyperbilirubinemia, and ischemic skin necrosis due to massive sulindac overdose.

    PubMed

    Vaughn, John L; Shah, Kejal V; Ghossein, Maroun M; Meyer, William L; Kirkpatrick, Robert B

    2015-01-01

    Sulindac is a long-acting nonsteroidal anti-inflammatory drug (NSAID) widely used for the management of osteoarthritis, rheumatoid arthritis, ankylosing sponydlitis, and acute gouty arthritis. Reports of sulindac toxicity in the literature are rare. We report the case of a 22-year old male with a history of bipolar disorder who was brought to the emergency department after ingesting approximately 15 g of sulindac in a suicide attempt. He was found to have acute kidney injury and hyperbilirubinemia. Despite aggressive fluid resuscitation, his renal function progressively worsened requiring the initiation of hemodialysis. Ten days following ingestion of sulindac, he began to develop ischemic skin changes with a gangrenous appearance in his hands and feet. He continued to receive supportive treatment, and his acute kidney injury, hyperbillirubinemia, and ischemic skin necrosis eventually resolved. Clinicians should be aware of this long-acting NSAID and its ability to cause prolonged multisystem organ dysfunction.

  3. Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice.

    PubMed

    Bravi, Luca; Rudini, Noemi; Cuttano, Roberto; Giampietro, Costanza; Maddaluno, Luigi; Ferrarini, Luca; Adams, Ralf H; Corada, Monica; Boulday, Gwenola; Tournier-Lasserve, Elizabeth; Dejana, Elisabetta; Lampugnani, Maria Grazia

    2015-07-07

    Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of β-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin-driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-β/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.

  4. Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice

    PubMed Central

    Bravi, Luca; Rudini, Noemi; Cuttano, Roberto; Giampietro, Costanza; Maddaluno, Luigi; Ferrarini, Luca; Adams, Ralf H.; Corada, Monica; Boulday, Gwenola; Tournier-Lasserve, Elizabeth; Dejana, Elisabetta; Lampugnani, Maria Grazia

    2015-01-01

    Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell–selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor–independent stimulation of β-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin–driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-β/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas. PMID:26109568

  5. Sulindac activates NF-κB signaling in colon cancer cells

    PubMed Central

    2013-01-01

    Background The non-steroidal anti-inflammatory drug (NSAID) sulindac has shown efficacy in preventing colorectal cancer. This potent anti-tumorigenic effect is mediated through multiple cellular pathways but is also accompanied by gastrointestinal side effects, such as colon inflammation. We have recently shown that sulindac can cause up-regulation of pro-inflammatory factors in the mouse colon mucosa. The aim of this study was to determine the signaling pathways that mediate the transcriptional activation of pro-inflammatory cytokines in colon cancer epithelial cells treated with sulindac sulfide. Results We found that sulindac sulfide increased NF-κB signaling in HCT-15, HCT116, SW480 and SW620 cells, although the level of induction varied between cell lines. The drug caused a decrease in IκBα levels and an increase of p65(RelA) binding to the NF-κB DNA response element. It induced expression of IL-8, ICAM1 and A20, which was inhibited by the NF-κB inhibitor PDTC. Sulindac sulfide also induced activation of the AP-1 transcription factor, which co-operated with NF-κB in up-regulating IL-8. Up-regulation of NF-κB genes was most prominent in conditions where only a subset of cells was undergoing apoptosis. In TNFα stimulated conditions the drug treatment inhibited phosphorylation on IκBα (Ser 32) which is consistent with previous studies and indicates that sulindac sulfide can inhibit TNFα-induced NF-κB activation. Sulindac-induced upregulation of NF-κB target genes occurred early in the proximal colon of mice given a diet containing sulindac for one week. Conclusions This study shows for the first time that sulindac sulfide can induce pro-inflammatory NF-κB and AP-1 signaling as well as apoptosis in the same experimental conditions. Therefore, these results provide insights into the effect of sulindac on pro-inflammatory signaling pathways, as well as contribute to a better understanding of the mechanism of sulindac-induced gastrointestinal side

  6. Sulindac and Its Metabolites Inhibit Multiple Transport Proteins in Rat and Human Hepatocytes

    PubMed Central

    Lee, Jin Kyung; Paine, Mary F.

    2010-01-01

    Sulindac is a commonly used nonsteroidal anti-inflammatory drug. This study tested the hypothesis that sulindac-mediated drug–drug interactions and/or hepatotoxicity may be caused, in part, by inhibition of proteins responsible for the hepatic transport of drugs and/or bile acids by sulindac and/or sulindac metabolites [sulindac sulfone (S-sulfone) and sulindac sulfide (S-sulfide)]. The uptake and excretion of model substrates, [3H]taurocholate (TC), [3H]estradiol 17-β-glucuronide (E217G), and nitrofurantoin (NF), were investigated in rat and human suspended and sandwich-cultured hepatocytes (SCH). In suspended rat hepatocytes, S-sulfone and S-sulfide inhibited Na+-dependent TC initial uptake (IC50 of 24.9 ± 6.4 and 12.5 ± 1.8 μM, respectively) and Na+-independent E217G initial uptake (IC50 of 12.1 ± 1.6 and 6.3 ± 0.3 μM, respectively). In rat SCH, sulindac metabolites (100 μM) decreased the in vitro biliary clearance (Clbiliary) of TC, E217G, and NF by 38 to 83%, 81 to 97%, and 33 to 57%, respectively; S-sulfone and S-sulfide also decreased the TC and NF biliary excretion index by 39 to 55%. In suspended human hepatocytes, S-sulfone and S-sulfide inhibited Na+-dependent TC initial uptake (IC50 of 42.2 and 3.1 μM, respectively); S-sulfide also inhibited the TC Clbiliary in human SCH. Sulindac/metabolites markedly inhibited hepatic uptake and biliary excretion of E217G by 51 to 100% in human SCH. In conclusion, sulindac and metabolites are potent inhibitors of the uptake and biliary clearance of bile acids in rat and human hepatocytes and also inhibit substrates of rat breast cancer resistance protein, rat and human organic anion-transporting polypeptides, and human multidrug resistance-associated protein 2. Inhibition of multiple hepatic transport proteins by sulindac/metabolites may play an important role in clinically significant sulindac-mediated drug–drug interactions and/or liver injury. PMID:20430841

  7. Sulindac and its metabolites inhibit multiple transport proteins in rat and human hepatocytes.

    PubMed

    Lee, Jin Kyung; Paine, Mary F; Brouwer, Kim L R

    2010-08-01

    Sulindac is a commonly used nonsteroidal anti-inflammatory drug. This study tested the hypothesis that sulindac-mediated drug-drug interactions and/or hepatotoxicity may be caused, in part, by inhibition of proteins responsible for the hepatic transport of drugs and/or bile acids by sulindac and/or sulindac metabolites [sulindac sulfone (S-sulfone) and sulindac sulfide (S-sulfide)]. The uptake and excretion of model substrates, [(3)H]taurocholate (TC), [(3)H]estradiol 17-beta-glucuronide (E217G), and nitrofurantoin (NF), were investigated in rat and human suspended and sandwich-cultured hepatocytes (SCH). In suspended rat hepatocytes, S-sulfone and S-sulfide inhibited Na(+)-dependent TC initial uptake (IC(50) of 24.9 +/- 6.4 and 12.5 +/- 1.8 microM, respectively) and Na(+)-independent E217G initial uptake (IC(50) of 12.1 +/- 1.6 and 6.3 +/- 0.3 microM, respectively). In rat SCH, sulindac metabolites (100 microM) decreased the in vitro biliary clearance (Cl(biliary)) of TC, E217G, and NF by 38 to 83%, 81 to 97%, and 33 to 57%, respectively; S-sulfone and S-sulfide also decreased the TC and NF biliary excretion index by 39 to 55%. In suspended human hepatocytes, S-sulfone and S-sulfide inhibited Na(+)-dependent TC initial uptake (IC(50) of 42.2 and 3.1 microM, respectively); S-sulfide also inhibited the TC Cl(biliary) in human SCH. Sulindac/metabolites markedly inhibited hepatic uptake and biliary excretion of E217G by 51 to 100% in human SCH. In conclusion, sulindac and metabolites are potent inhibitors of the uptake and biliary clearance of bile acids in rat and human hepatocytes and also inhibit substrates of rat breast cancer resistance protein, rat and human organic anion-transporting polypeptides, and human multidrug resistance-associated protein 2. Inhibition of multiple hepatic transport proteins by sulindac/metabolites may play an important role in clinically significant sulindac-mediated drug-drug interactions and/or liver injury.

  8. Sulindac activates NF-κB signaling in colon cancer cells.

    PubMed

    Mladenova, Dessislava; Pangon, Laurent; Currey, Nicola; Ng, Irvin; Musgrove, Elizabeth A; Grey, Shane T; Kohonen-Corish, Maija R J

    2013-10-01

    The non-steroidal anti-inflammatory drug (NSAID) sulindac has shown efficacy in preventing colorectal cancer. This potent anti-tumorigenic effect is mediated through multiple cellular pathways but is also accompanied by gastrointestinal side effects, such as colon inflammation. We have recently shown that sulindac can cause up-regulation of pro-inflammatory factors in the mouse colon mucosa. The aim of this study was to determine the signaling pathways that mediate the transcriptional activation of pro-inflammatory cytokines in colon cancer epithelial cells treated with sulindac sulfide. We found that sulindac sulfide increased NF-κB signaling in HCT-15, HCT116, SW480 and SW620 cells, although the level of induction varied between cell lines. The drug caused a decrease in IκBα levels and an increase of p65(RelA) binding to the NF-κB DNA response element. It induced expression of IL-8, ICAM1 and A20, which was inhibited by the NF-κB inhibitor PDTC. Sulindac sulfide also induced activation of the AP-1 transcription factor, which co-operated with NF-κB in up-regulating IL-8. Up-regulation of NF-κB genes was most prominent in conditions where only a subset of cells was undergoing apoptosis. In TNFα stimulated conditions the drug treatment inhibited phosphorylation on IκBα (Ser 32) which is consistent with previous studies and indicates that sulindac sulfide can inhibit TNFα-induced NF-κB activation. Sulindac-induced upregulation of NF-κB target genes occurred early in the proximal colon of mice given a diet containing sulindac for one week. This study shows for the first time that sulindac sulfide can induce pro-inflammatory NF-κB and AP-1 signaling as well as apoptosis in the same experimental conditions. Therefore, these results provide insights into the effect of sulindac on pro-inflammatory signaling pathways, as well as contribute to a better understanding of the mechanism of sulindac-induced gastrointestinal side effects.

  9. The metabolism and pharmacokinetics of phospho-sulindac (OXT-328) and the effect of difluoromethylornithine

    PubMed Central

    Xie, G; Nie, T; Mackenzie, GG; Sun, Y; Huang, L; Ouyang, N; Alston, N; Zhu, C; Murray, OT; Constantinides, PP; Kopelovich, L; Rigas, B

    2012-01-01

    BACKGROUND AND PURPOSE Phospho-sulindac (PS; OXT-328) prevents colon cancer in mice, especially when combined with difluoromethylornithine (DFMO). Here, we explored its metabolism and pharmacokinetics. EXPERIMENTAL APPROACH PS metabolism was studied in cultured cells, liver microsomes and cytosol, intestinal microsomes and in mice. Pharmacokinetics and biodistribution of PS were studied in mice. KEY RESULTS PS undergoes reduction and oxidation yielding PS sulphide and PS sulphone; is hydrolysed releasing sulindac, which generates sulindac sulphide (SSide) and sulindac sulphone (SSone), all of which are glucuronidated. Liver and intestinal microsomes metabolized PS extensively but cultured cells converted only 10% of it to PS sulphide and PS sulphone. In mice, oral PS is rapidly absorbed, metabolized and distributed to the blood and other tissues. PS survives only partially intact in blood; of its three major metabolites (sulindac, SSide and SSone), sulindac has the highest Cmax and SSone the highest t1/2; their AUC0–24h are similar. Compared with conventional sulindac, PS generated more SSone but less SSide, which may contribute to the safety of PS. In the gastroduodenal wall of mice, 71% of PS was intact; sulindac, SSide and SSone together accounted for <30% of the total. This finding may explain the lack of gastrointestinal toxicity by PS. DFMO had no effect on PS metabolism but significantly reduced drug level in mouse plasma and other tissues. CONCLUSIONS AND IMPLICATIONS Our findings establish the metabolism of PS define its pharmacokinetics and biodistribution, describe its interactions with DFMO and largely explain its gastrointestinal safety. PMID:21955327

  10. The metabolism and pharmacokinetics of phospho-sulindac (OXT-328) and the effect of difluoromethylornithine.

    PubMed

    Xie, G; Nie, T; Mackenzie, G G; Sun, Y; Huang, L; Ouyang, N; Alston, N; Zhu, C; Murray, O T; Constantinides, P P; Kopelovich, L; Rigas, B

    2012-04-01

    Phospho-sulindac (PS; OXT-328) prevents colon cancer in mice, especially when combined with difluoromethylornithine (DFMO). Here, we explored its metabolism and pharmacokinetics. PS metabolism was studied in cultured cells, liver microsomes and cytosol, intestinal microsomes and in mice. Pharmacokinetics and biodistribution of PS were studied in mice. PS undergoes reduction and oxidation yielding PS sulphide and PS sulphone; is hydrolysed releasing sulindac, which generates sulindac sulphide (SSide) and sulindac sulphone (SSone), all of which are glucuronidated. Liver and intestinal microsomes metabolized PS extensively but cultured cells converted only 10% of it to PS sulphide and PS sulphone. In mice, oral PS is rapidly absorbed, metabolized and distributed to the blood and other tissues. PS survives only partially intact in blood; of its three major metabolites (sulindac, SSide and SSone), sulindac has the highest C(max) and SSone the highest t(1/2) ; their AUC(0-24h) are similar. Compared with conventional sulindac, PS generated more SSone but less SSide, which may contribute to the safety of PS. In the gastroduodenal wall of mice, 71% of PS was intact; sulindac, SSide and SSone together accounted for <30% of the total. This finding may explain the lack of gastrointestinal toxicity by PS. DFMO had no effect on PS metabolism but significantly reduced drug level in mouse plasma and other tissues. Our findings establish the metabolism of PS define its pharmacokinetics and biodistribution, describe its interactions with DFMO and largely explain its gastrointestinal safety. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  11. Target delivery and controlled release of the chemopreventive drug sulindac by using an advanced layered double hydroxide nanomatrix formulation system.

    PubMed

    Minagawa, Keiji; Berber, Mohamed R; Hafez, Inas H; Mori, Takeshi; Tanaka, Masami

    2012-04-01

    Target delivery and controlled release of the chemopreventive drug sulindac that possesses low water solubility present a great challenge for its pharmaceutical industry. Here, we offered an advanced nanomatrix formulation system of sulindac based on layered double hydroxide materials. The X-ray analysis and infrared spectroscopy confirmed the incorporation of sulindac into the gallery of the layered double hydroxides. The incorporation ratios of sulindac were recorded to be 45, 31 and 20 for coprecipitation, anion-exchange and reconstruction techniques, respectively. The scanning electron microscopy showed a nanomatrix-structure of ~50 nm. The release studies of sulindac-nanomatrix showed a 96% controlled release at the small intestine solution during 3 h(s), indicating an enhancement in the dissolution profile of sulindac after the matrix formation. The layered structure of the matrix supplied sulindac with a well-ordered structure and a relatively hydrophobic microenvironment that controlled the guest hydrolysis and reactivity during the release process. The laminar structure of layered double hydroxides offered a safe preservation for sulindac against photodecarboxylation, and enhanced the drug thermal stability from 190 to 230° C. The ionic electrostatic interaction of sulindac through its acidic group with layered double hydroxides demolished the gastrointestinal ulceration.

  12. Sulindac has strong antifibrotic effects by suppressing STAT3-related miR-21

    PubMed Central

    Zhou, Xue; Li, You-Jie; Gao, Shu-Yan; Wang, Xiao-Zhi; Wang, Ping-Yu; Yan, Yun-Fei; Xie, Shu-Yang; Lv, Chang-Jun

    2015-01-01

    Pulmonary fibrosis (PF) is a disease with an unknown cause and a poor prognosis. In this study, we aimed to explore the pathogenesis of PF and the mechanism of sulindac in attenuating bleomycin (BLM)-induced PF. The rat PF model was induced by BLM and verified through histological studies and hydroxyproline assay. The severity of BLM-induced PF in rats and other effects, such as the extent of the wet lung to bw ratios, thickening of alveolar interval or collagen deposition, was obviously ameliorated in sulindac-treated rat lungs compared with BLM-induced lungs. Sulindac also reversed the epithelial mesenchymal transition (EMT) and inhibited the PF process by restoring the levels of E-cadherin and α-smooth muscle actin (SMA) in A549 cells. Our results further demonstrated that the above effects of sulindac might be related to regulating of interferon gamma (IFN-γ) expression, which further affects signal transducers and activators of transcription 3 (STAT3) and phosphorylated STAT3 (p-STAT3) levels. Moreover, higher miR-21 levels with the decreased E-cadherin and increased α-SMA expressions were found in transforming growth factor-β1-treated A549 cells, which can be reversed by sulindac. Collectively, our results demonstrate that by decreasing IFN-γ-induced STAT3/p-STAT3 expression to down-regulate miR-21, sulindac could significantly reverse EMT in A549 cells and prevent BLM-induced PF. PMID:25704671

  13. Evaluating the inhibitory potential of sulindac against the bleomycin-induced pulmonary fibrosis in wistar rats.

    PubMed

    Verma, Ramesh; Brahmankar, Mahesh; Kushwah, Lokendra; Suresh, Balakrishnan

    2013-11-01

    The present study examined the protective effect of sulindac on bleomycin-induced lung fibrosis in rats. Animals were divided into saline group, bleomycin group (single intra-tracheal instillation of bleomycin) and bleomycin+sulindac (orally from day 1 to day 20). Bleomycin administration reduced the body weight, altered antioxidant status (such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione) while it increased the lung weight, hydroxyproline content, collagen deposition and lipid peroxidation. However, simultaneous administration of sulindac improved the body weight, antioxidant status and decreased the collagen deposition in lungs. Moreover, the levels of inflammatory cytokine tumour necrosis factor-α increased in bleomycin-induced group, whereas, on treatment with sulindac the levels of tumour necrosis factor-α were found reduced. Finally, histological evidence also supported the ability of sulindac to inhibit bleomycin-induced lung fibrosis. The results of the present study indicate that sulindac can be used as an agent against bleomycin-induced pulmonary fibrosis. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Protective mechanism of sulindac in an animal model of ischemic stroke.

    PubMed

    Modi, Jigar Pravinchandra; Gharibani, Payam M; Ma, Zhiyuan; Tao, Rui; Menzie, Janet; Prentice, Howard; Wu, Jang-Yen

    2014-08-12

    The present study analyzed whether administration of sulindac, a non-steroidal anti-inflammatory drug (NSAID) would prevent, attenuate or repair ischemia induced brain injury and reverse functional impairment in a focal ischemia model of stroke. Male Sprague-Dawley rats (weight 250-300 g) were subjected to middle cerebral artery occlusion (MCAO). Sulindac was given 2 days before and 24 h after ischemia at 0.2 mg/day with daily injections until sacrifice on day 3 or day 11. Infarct size was measured by TTC staining and western immunoblot was employed. TTC analysis of brain slices indicated a decrease in infarct size in sulindac treated animals. Western blot results indicated that sulindac induced expression of Hsp 27, a marker of cell stress, in the ischemic penumbra and core on days 3 and 11. Hsp 27 is important as a protective molecular chaperone. Increases were also found in the protective molecules Akt and Bcl-2 in the ischemic penumbra and core following sulindac administration. Our data indicate that administration of sulindac results in decreased infarct size and that there is a central role for the molecular chaperone Hsp 27, the pro-survival kinase Akt and the anti-apoptotic component Bcl-2 in mediating these protective effects. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Randomized, Double-blind, Placebo Controlled Trial of Sulindac in Individuals at Risk for Melanoma: Evaluation of Potential Chemopreventive Activity

    PubMed Central

    Curiel-Lewandrowski, Clara; Swetter, Susan M.; Einsphar, Janine G.; Hsu, Chiu-Hsieh; Nagle, Ray; Sagerman, Paul; Tangrea, Joseph; Parnes, Howard; Alberts, David S.; Chow, Hsiao-Hui

    2012-01-01

    Background Reduced melanoma risk has been reported with regular use of non-steroidal anti-inflammatory drugs (NSAIDs). However, NSAIDs ability to reach melanocytes in vivo and modulate key biomarkers in pre-neoplastic lesions such as atypical nevi has not been evaluated. Methods Randomized, double-blind, placebo controlled trial of sulindac conducted in individuals with atypical nevi (AN) to determine bioavailability of sulindac and metabolites in nevi and effect on apoptosis and vascular endothelial growth factor A (VEGFA) expression in AN. Fifty subjects with ≥ 4mm AN and one benign nevus (BN) were randomized to sulindac (150 mg BID) or placebo for 8 weeks. Two AN were randomized for baseline excision, and 2 AN and BN were excised post-intervention. Results Post-intervention sulindac, sulindac sulfone, and sulindac sulfide concentrations were 0.31 ± 0.36, 1.56 ± 1.35, 2.25 ± 2.24 μg/ml in plasma, and 0.51 ± 1.05, 1.38 ± 2.86, 0.12 ± 0.12 μg/g in BN, respectively. Sulindac intervention did not significantly change VEGFA expression but did increase expression of the apoptotic marker cleaved caspase 3 in AN (increase of 3 ± 33 in sulindac vs. decrease of 25 ± 45 in placebo arm, p=0.0056), although significance was attenuated (p =0.1103) after adjusting for baseline expression. Conclusion Eight weeks of sulindac intervention resulted in high concentrations of sulindac sulfone, a pro-apoptotic metabolite, in BN but did not effectively modulate VEGFA and cleaved caspase-3 expression. Study limitations included limited exposure time to sulindac and the need to optimize a panel of biomarkers for NSAIDs intervention studies. PMID:22605570

  16. Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α.

    PubMed

    Sur, Arunodoy; Kesaraju, Shailaja; Prentice, Howard; Ayyanathan, Kasirajan; Baronas-Lowell, Diane; Zhu, Danhong; Hinton, David R; Blanks, Janet; Weissbach, Herbert

    2014-11-25

    The retinal pigmented epithelial (RPE) layer is one of the major ocular tissues affected by oxidative stress and is known to play an important role in the etiology of age-related macular degeneration (AMD), the major cause of blinding in the elderly. In the present study, sulindac, a nonsteroidal antiinflammatory drug (NSAID), was tested for protection against oxidative stress-induced damage in an established RPE cell line (ARPE-19). Besides its established antiinflammatory activity, sulindac has previously been shown to protect cardiac tissue against ischemia/reperfusion damage, although the exact mechanism was not elucidated. As shown here, sulindac can also protect RPE cells from chemical oxidative damage or UV light by initiating a protective mechanism similar to what is observed in ischemic preconditioning (IPC) response. The mechanism of protection appears to be triggered by reactive oxygen species (ROS) and involves known IPC signaling components such as PKG and PKC epsilon in addition to the mitochondrial ATP-sensitive K(+) channel. Sulindac induced iNOS and Hsp70, late-phase IPC markers in the RPE cells. A unique feature of the sulindac protective response is that it involves activation of the peroxisome proliferator-activated receptor alpha (PPAR-α). We have also used low-passage human fetal RPE and polarized primary fetal RPE cells to validate the basic observation that sulindac can protect retinal cells against oxidative stress. These findings indicate a mechanism for preventing oxidative stress in RPE cells and suggest that sulindac could be used therapeutically for slowing the progression of AMD.

  17. Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

    PubMed Central

    Sur, Arunodoy; Kesaraju, Shailaja; Prentice, Howard; Ayyanathan, Kasirajan; Baronas-Lowell, Diane; Zhu, Danhong; Hinton, David R.; Blanks, Janet; Weissbach, Herbert

    2014-01-01

    The retinal pigmented epithelial (RPE) layer is one of the major ocular tissues affected by oxidative stress and is known to play an important role in the etiology of age-related macular degeneration (AMD), the major cause of blinding in the elderly. In the present study, sulindac, a nonsteroidal antiinflammatory drug (NSAID), was tested for protection against oxidative stress-induced damage in an established RPE cell line (ARPE-19). Besides its established antiinflammatory activity, sulindac has previously been shown to protect cardiac tissue against ischemia/reperfusion damage, although the exact mechanism was not elucidated. As shown here, sulindac can also protect RPE cells from chemical oxidative damage or UV light by initiating a protective mechanism similar to what is observed in ischemic preconditioning (IPC) response. The mechanism of protection appears to be triggered by reactive oxygen species (ROS) and involves known IPC signaling components such as PKG and PKC epsilon in addition to the mitochondrial ATP-sensitive K+ channel. Sulindac induced iNOS and Hsp70, late-phase IPC markers in the RPE cells. A unique feature of the sulindac protective response is that it involves activation of the peroxisome proliferator-activated receptor alpha (PPAR-α). We have also used low-passage human fetal RPE and polarized primary fetal RPE cells to validate the basic observation that sulindac can protect retinal cells against oxidative stress. These findings indicate a mechanism for preventing oxidative stress in RPE cells and suggest that sulindac could be used therapeutically for slowing the progression of AMD. PMID:25385631

  18. Facilitation of human osteoblast apoptosis by sulindac and indomethacin under hypoxic injury.

    PubMed

    Liu, Cheng; Tsai, An-Ly; Chen, Yen-Chu; Fan, Shih-Chen; Huang, Chun-Hsien; Wu, Chia-Ching; Chang, Chih-Han

    2012-01-01

    Hypoxic-ischemia injury occurs after trauma causes consequential bone necrosis. Non-steroid anti-inflammatory drugs (NSAIDs) are frequently used in orthopedic clinics for pain relief. However, the underlying mechanism and outcome for usage of NSAIDs is poorly understood. To investigate the damage and loss of osteoblast function in hypoxia, two hypoxia mimetics, cobalt chloride (CoCl(2)) and desferrioxamine (DFO), were used to create an in vitro hypoxic microenvironment. The cell damage was observed by decreases of cell viability and increases in cyclooxygenase-2 and cleaved poly(ADP-ribose) polymerase (PARP). Cell apoptosis was confirmed by WST-1 cytotoxic assays and flow cytometry. The functional expression of osteoblast in alkaline phosphatase (ALP) activity was significantly decreased by CoCl(2) and inhibited when treated with DFO. To simulate the use of NSAID after hypoxic injury, four types of anti-inflammatory drugs, sulindac sulfide (SUL), indomethacin (IND), aspirin (Asp), and sodium salicylate (NaS), were applied to osteoblasts after 1 h of hypoxia mimetic treatment. SUL and IND further enhanced cell death after hypoxia. ALP activity was totally abolished in hypoxic osteoblasts under IND treatment. Facilitation of osteoblast apoptosis occurred regardless of IND dosage under hypoxic conditions. To investigate osteoblast in vivo, local hypoxia was created by fracture of tibia and then treated the injured mice with IND by oral feeding. IND-induced osteoblast apoptosis was confirmed by positive staining of TUNEL assay in fractured mice. Significant delay of fracture healing in bone tissue was also observed with the treatment of IND. These results provide information pertaining to choosing appropriate anti-inflammatory drugs for orthopedic patients.

  19. Sulindac, a non-steroidal anti-inflammatory drug, mediates breast cancer inhibition as an immune modulator.

    PubMed

    Yin, Tao; Wang, Guoping; Ye, Tinghong; Wang, Yongsheng

    2016-01-18

    The cooperation of adaptive immunity with pharmacologic therapy influences cancer progression. Though non-steroidal anti-inflammatory drugs (NSAIDs) have a long history of cancer prevention, it is unclear whether adaptive immune system affects the action of those drugs. In present study, we revealed a novel immunological mechanism of sulindac. Our data showed that sulindac had substantial efficacy as a single agent against 4T1 murine breast cancer and prolonged the survival of tumor-bearing mice. However, in the athymic nude mice, sulindac treatment was ineffective. Further in vivo T cell subsets depletion experiments showed that CD8+ T lymphocytes deficiency reversed the anti-tumor effect of sulindac. In addition, sulindac significantly reduced M2 macrophages recruitment, cancer-related inflammation and tumor angiogenesis. Our results advance our understanding of the mechanisms of NSAIDs, and more importantly, this will provide insight into rational drug design or antitumor immunotherapy.

  20. Sulindac, a non-steroidal anti-inflammatory drug, mediates breast cancer inhibition as an immune modulator

    PubMed Central

    Yin, Tao; Wang, Guoping; Ye, Tinghong; Wang, Yongsheng

    2016-01-01

    The cooperation of adaptive immunity with pharmacologic therapy influences cancer progression. Though non-steroidal anti-inflammatory drugs (NSAIDs) have a long history of cancer prevention, it is unclear whether adaptive immune system affects the action of those drugs. In present study, we revealed a novel immunological mechanism of sulindac. Our data showed that sulindac had substantial efficacy as a single agent against 4T1 murine breast cancer and prolonged the survival of tumor-bearing mice. However, in the athymic nude mice, sulindac treatment was ineffective. Further in vivo T cell subsets depletion experiments showed that CD8+ T lymphocytes deficiency reversed the anti-tumor effect of sulindac. In addition, sulindac significantly reduced M2 macrophages recruitment, cancer-related inflammation and tumor angiogenesis. Our results advance our understanding of the mechanisms of NSAIDs, and more importantly, this will provide insight into rational drug design or antitumor immunotherapy. PMID:26777116

  1. Inhibition of islet amyloid polypeptide aggregation and associated cytotoxicity by nonsteroidal anti-inflammatory drugs.

    PubMed

    Fortin, Jessica S; Benoit-Biancamano, Marie-Odile

    2016-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) constitute an important pharmacotherapeutic class that, over the past decade, have expanded in application to a panoply of medical conditions. They have been tested for neurodegenerative diseases such as Alzheimer's to reduce inflammation and also in the attempt to abrogate amyloid deposition. However, the use of NSAIDs as aggregation inhibitors has not been extensively studied in pancreatic amyloid deposition. Pancreatic amyloidosis involves the misfolding of islet amyloid polypeptide (IAPP) and contributes to the progression of type-2 diabetes in humans and felines. To ascertain their antiamyloidogenic activity, several NSAIDs were tested using fluorometric thioflavin-T assays, circular dichroism, photo-induced cross-linking assays, and cell culture. Celecoxib, diclofenac, indomethacin, meloxicam, niflumic acid, nimesulide, phenylbutazone, piroxicam, sulindac, and tenoxicam reduced fibrillization at a molar ratio of 1:10. The circular dichroism spectra of diclofenac, piroxicam, and sulindac showed characteristic spectral signatures found in predominantly α-helical structures. The oligomerization of human IAPP was abrogated with diclofenac and sulindac at a molar ratio of 1:5. The cytotoxic effects of pre-incubated human IAPP on cultured INS-1 cells were noticeably reduced in the presence of diclofenac, meloxicam, phenylbutazone, sulindac, and tenoxicam at a molar ratio of 1:10. Our results demonstrate that NSAIDs can provide chemical scaffolds to generate new and promising antiamyloidogenic agents that can be used alone or as a coadjuvant therapy.

  2. Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits

    PubMed Central

    Verheul, H M W; Panigrahy, D; Yuan, J; D'Amato, R J

    1999-01-01

    Neovascularization facilitates tumour growth and metastasis formation. In our laboratory, we attempt to identify clinically available oral efficacious drugs for antiangiogenic activity. Here, we report which non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit corneal neovascularization, induced by basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF). This antiangiogenic activity may contribute to the known effects of NSAIDs on gastric ulcers, polyps and tumours. We found that sulindac was one of the most potent antiangiogenic NSAIDs, inhibiting bFGF-induced neovascularization by 50% and VEGF-induced neovascularization by 55%. Previously, we reported that thalidomide inhibited growth factor-induced corneal neovascularization. When we combined sulindac with thalidomide, we found a significantly increased inhibition of bFGF- or VEGF-induced corneal neovascularization (by 63% or 74% respectively) compared with either agent alone (P< 0.01). Because of this strong antiangiogenic effect, we tested the oral combination of thalidomide and sulindac for its ability to inhibit the growth of V2 carcinoma in rabbits. Oral treatment of thalidomide or sulindac alone inhibited tumour growth by 55% and 35% respectively. When given together, the growth of the V2 carcinoma was inhibited by 75%. Our results indicated that oral antiangiogenic combination therapy with thalidomide and sulindac may be a useful non-toxic treatment for cancer. © 1999 Cancer Research Campaign PMID:10408702

  3. The Cox inhibitor, sulindac sulfide inhibits EP4 expression and suppresses the growth of glioblastoma cells

    PubMed Central

    Kambe, Atsushi; Yoshioka, Hiroki; Kamitani, Hideki; Watanabe, Takashi; Baek, Seung Joon; Eling, Thomas E.

    2009-01-01

    EP4 expression in human glioblastoma cells correlates with growth on soft agar. The cyclooxygenase (COX) inhibitor, sulindac sulfide, first altered specificity protein-1 (Sp-1) and, early growth response gene-1 (Egr1) expression, then increased the expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) and activating transcription factor-3 (ATF3), and then decreased EP4 expression. EP4 suppression was dependent on blocking the Sp-1 binding sites in the human EP4 promoter. Mutation in the Sp-1 sites in EP4 altered the promoter activity and abolished sulindac sulfide effects. The inhibitory effect of sulindac sulfide on EP4 expression was reversed by PD98059, an MEK-1/Erk inhibitor. Sp-1 phosphorylation was dependent on sulindac sulfide-induced Erk activation. ChIP assay confirmed that Sp-1 phosphorylation decreases Sp-1 binding to DNA and leads to the suppression of EP4. Inhibition of cell growth on soft agar assay was found to be a highly complex process and appears to require not only the inhibition of COX activity but also increased expression of NAG-1 and ATF3 and suppression of EP4 expression. Our data suggest that the suppression of EP4 expression by sulindac sulfide represents a new mechanism for understanding the tumor suppressor activity. PMID:19934343

  4. Crystallization of micro particles of sulindac using rapid expansion of supercritical solution

    NASA Astrophysics Data System (ADS)

    Zeinolabedini Hezave, Ali; Esmaeilzadeh, Feridun

    2010-11-01

    In pharmaceutical industry, many drugs exhibit poor solubility in biological fluid. Solubility of drugs affects on the rate of dissolution and bioavailability in biological fluids. The bioavailability of drugs can be enhanced by decreasing the drug particle size. In this study, sulindac was micronized via rapid expansion of supercritical solution (RESS) where CO2 was used as a solvent. The experiments were conducted to investigate the effect of the extraction pressure and temperature (140-230 bar and 40-60 °C), collection distance (1-10 cm), effective nozzle diameter (450-1700 μm) and nozzle length (2-15 mm) on the size and morphology of the sulindac particles. The size and morphology of the precipitated particles were monitored by scanning electron microscopy (SEM). The particle size of intact sulindac particles was about 33.03 μm, while the average particle size of the micronized sulindac particles was between 0.76 and 8.02 μm based on different experimental conditions. Additionally, the different morphology of the micronized particles was observed like needle, rectangular, quasi spherical and irregular form while the morphology of the intact particles of sulindac was rectangular and irregular.

  5. Sulindac Enhances the Killing of Cancer Cells Exposed to Oxidative Stress

    PubMed Central

    Marchetti, Maria; Resnick, Lionel; Gamliel, Edna; Kesaraju, Shailaja; Weissbach, Herbert; Binninger, David

    2009-01-01

    Background Sulindac is an FDA-approved non-steroidal anti-inflammatory drug (NSAID) that affects prostaglandin production by inhibiting cyclooxygenases (COX) 1 and 2. Sulindac has also been of interest for more than decade as a chemopreventive for adenomatous colorectal polyps and colon cancer. Principal Findings Pretreatment of human colon and lung cancer cells with sulindac enhances killing by an oxidizing agent such as tert-butyl hydroperoxide (TBHP) or hydrogen peroxide. This effect does not involve cyclooxygenase (COX) inhibition. However, under the conditions used, there is a significant increase in reactive oxygen species (ROS) within the cancer cells and a loss of mitochondrial membrane potential, suggesting that cell death is due to apoptosis, which was confirmed by Tunel assay. In contrast, this enhanced killing was not observed with normal lung or colon cells. Significance These results indicate that normal and cancer cells handle oxidative stress in different ways and sulindac can enhance this difference. The combination of sulindac and an oxidizing agent could have therapeutic value. PMID:19503837

  6. Sulindac reversal of 15-PGDH-mediated resistance to colon tumor chemoprevention with NSAIDs

    PubMed Central

    Fink, Stephen P.; Dawson, Dawn M.; Zhang, Yongyou; Kresak, Adam; Lawrence, Earl G.; Yang, Peiying; Chen, Yanwen; Barnholtz-Sloan, Jill S.; Willis, Joseph E.; Kopelovich, Levy; Markowitz, Sanford D.

    2015-01-01

    Non-steroidal anti-inflammatory drugs prevent colorectal cancer by inhibiting cyclooxygenase (COX) enzymes that synthesize tumor-promoting prostaglandins. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a tumor suppressor that degrades tumor-promoting prostaglandins. Murine knockout of 15-PGDH increases susceptibility to azoxymethane-induced colon tumors. It also renders these mice resistant to celecoxib, a selective inhibitor of inducible COX-2 during colon neoplasia. Similarly, humans with low colonic 15-PGDH are also resistant to colon adenoma prevention with celecoxib. Here, we used aspirin and sulindac, which inhibit both COX-1 and COX-2, in order to determine if these broader COX inhibitors can prevent colon tumors in 15-PGDH knockout (KO) mice. Unlike celecoxib, sulindac proved highly effective in colon tumor prevention of 15-PGDH KO mice. Significantly, however, aspirin demonstrated no effect on colon tumor incidence in either 15-PGDH wild-type or KO mice, despite a comparable reduction in colonic mucosal Prostaglandin E2 (PGE2) levels by both sulindac and aspirin. Notably, colon tumor prevention activity by sulindac was accompanied by a marked induction of lymphoid aggregates and proximal colonic inflammatory mass lesions, a side effect seen to a lesser degree with celecoxib, but not with aspirin. These findings suggest that sulindac may be the most effective agent for colon cancer prevention in humans with low 15-PGDH, but its use may also be associated with inflammatory lesions in the colon. PMID:25503930

  7. Preparation and characterization of a sulindac sensor based on PVC/TOA-SUL membrane.

    PubMed

    Lenik, Joanna

    2014-04-01

    A potentiometric sulindac sensitive sensor based on tetraoctylammonium (Z)-5-fluoro-2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetate (TOA-SUL) was described. The electrode responded with sensitivity of 57.5±1.6mV decade(-1) over the linear range 5×10(-5)-1×10(-2)mol L(-1) at pH6.0-9.0. It had the limit of detection 1.4×10(-5)mol L(-1), a fast response time of 13s and showed clear discrimination of sulindac ions from several inorganic and organic compounds and also amino acids. This electrode did not contain any inner solutions, so it was easy and comfortable to use. The proposed sensor was used to determine sulindac in clear solution and in urine sample solution. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Sulindac has strong antifibrotic effects by suppressing STAT3-related miR-21.

    PubMed

    Zhou, Xue; Li, You-Jie; Gao, Shu-Yan; Wang, Xiao-Zhi; Wang, Ping-Yu; Yan, Yun-Fei; Xie, Shu-Yang; Lv, Chang-Jun

    2015-05-01

    Pulmonary fibrosis (PF) is a disease with an unknown cause and a poor prognosis. In this study, we aimed to explore the pathogenesis of PF and the mechanism of sulindac in attenuating bleomycin (BLM)-induced PF. The rat PF model was induced by BLM and verified through histological studies and hydroxyproline assay. The severity of BLM-induced PF in rats and other effects, such as the extent of the wet lung to bw ratios, thickening of alveolar interval or collagen deposition, was obviously ameliorated in sulindac-treated rat lungs compared with BLM-induced lungs. Sulindac also reversed the epithelial mesenchymal transition (EMT) and inhibited the PF process by restoring the levels of E-cadherin and α-smooth muscle actin (SMA) in A549 cells. Our results further demonstrated that the above effects of sulindac might be related to regulating of interferon gamma (IFN-γ) expression, which further affects signal transducers and activators of transcription 3 (STAT3) and phosphorylated STAT3 (p-STAT3) levels. Moreover, higher miR-21 levels with the decreased E-cadherin and increased α-SMA expressions were found in transforming growth factor-β1-treated A549 cells, which can be reversed by sulindac. Collectively, our results demonstrate that by decreasing IFN-γ-induced STAT3/p-STAT3 expression to down-regulate miR-21, sulindac could significantly reverse EMT in A549 cells and prevent BLM-induced PF. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  9. Efficacy of dimethylaminoparthenolide and sulindac in combination with gemcitabine in a genetically engineered mouse model of pancreatic cancer.

    PubMed

    Yip-Schneider, Michele T; Wu, Huangbing; Hruban, Ralph H; Lowy, Andrew M; Crooks, Peter A; Schmidt, Christian Max

    2013-01-01

    Pancreatic cancer remains one of the deadliest diseases, with limited surgical and treatment options. Two targets of interest include the transcription factor nuclear factor-κB and cyclooxygenase-2, which are constitutively activated and overexpressed, respectively, in human pancreatic adenocarcinoma. We have previously shown that dimethylaminoparthenolide (DMAPT), a bioavailable nuclear factor-κB inhibitor, and the cyclooxygenase inhibitors sulindac and celecoxib have potential chemotherapeutic efficacy. The current study evaluates the efficacy of intervention with DMAPT and sulindac in the LSL-Kras(G12D);Pdx-1-Cre genetically engineered mouse model. Gemcitabine, traditionally a chemotherapeutic agent, has relatively low toxicity; thus, combinations with low-dose gemcitabine were also explored. LSL-Kras(G12D);Pdx-1-Cre mice at 7 months of age were randomized into placebo, DMAPT (40 mg/kg per day), sulindac (20 mg/kg per day), gemcitabine (50 mg/kg twice weekly), and combination treatment groups. After 3 months of treatment, the mice were killed. The percentage of normal pancreatic ducts was significantly increased by the combinations of DMAPT/sulindac, DMAPT/gemcitabine, sulindac/gemcitabine, and DMAPT/sulindac/gemcitabine compared to placebo. Additionally, the percentage of mouse pancreatic intraepithelial neoplasia-2 lesions was significantly decreased by DMAPT/gemcitabine. Intervention with DMAPT and sulindac in combination with gemcitabine may delay or prevent progression of premalignant pancreatic lesions in the LSL-Kras(G12D);Pdx-1-Cre mouse model of pancreatic cancer.

  10. Photoprotective effects of sulindac against ultraviolet B-induced phototoxicity in the skin of SKH-1 hairless mice.

    PubMed

    Athar, Mohammad; An, Kathy P; Tang, Xiuwei; Morel, Kimberly D; Kim, Arianna L; Kopelovich, Levy; Bickers, David R

    2004-03-15

    Sulindac is a nonsteroidal anti-inflammatory drug with demonstrated potency as a chemopreventive agent in animal models of carcinogenesis and in patients with familial adenomatous polyposis. Because tumor promotion is generally associated with exposure to pro-inflammatory stimuli, it is likely that anti-inflammatory agents may have potent antitumor effects. In human skin, sulindac reduces bradykinin-induced edema. In this study, we tested the hypothesis that the cyclooxygenase inhibitor sulindac can protect against ultraviolet (UVB)-induced injury that is crucial for the induction of cancer. Exposure of SKH-1 hairless mice to two consecutive doses of UVB (230 mJ/cm2) induces various inflammatory responses including erythema, edema, epidermal hyperplasia, infiltration of polymorphonuclear leukocytes, etc. Topical application of sulindac (1.25-5.0 mg/0.2 ml acetone) to the dorsal skin of SKH-1 hairless mice either 1 h before or immediately after UVB exposure substantially inhibited these inflammatory responses in a dose-dependent manner. Oral administration of sulindac in drinking water (160 ppm) for 15 days before and during UVB irradiation similarly reduced these inflammatory responses. These potent anti-inflammatory effects of sulindac suggested the possibility that the drug could inhibit signaling processes that relate to carcinogenic insult by UVB. Accordingly, studies were conducted to assess the efficacy of sulindac in attenuating the expression of UVB-induced early surrogate molecular markers of photodamage and carcinogenesis. UVB exposure enhanced the expression of p53, c-fos, cyclins D1 and A, and PCNA 24 h after irradiation. Treatment of animals with either topical or oral administration of sulindac largely abrogated the expression of these UVB-induced surrogate markers. These results indicate that the cyclooxygenase inhibitor sulindac is effective in reducing UVB-induced events relevant to carcinogenesis and that this category of topically applied or

  11. CXCR2 inhibition enhances sulindac-mediated suppression of colon cancer development.

    PubMed

    Lee, Yong Suk; Choi, Dongwon; Kim, Nam Yoon; Yang, Sara; Jung, Eunson; Hong, Mingu; Yang, Dongyun; Lenz, Heinz-Josef; Hong, Young-Kwon

    2014-07-01

    Small chemical compound sulindac has been approved as a preventive approach against colon cancer for its effectiveness in treatment of precancerous adenoma. Due to its severe toxicities in the cardiovascular, gastrointestinal and renal systems, however, a combination of low-dose sulindac with other chemopreventive agents has been sought after as an alternative therapeutic strategy that could increase its effectiveness, while minimizing its adverse effects. To identify the promising alternative approach, we investigated the therapeutic potential of targeting the interleukin (IL)-8/CXCR2 pathway in colon cancer treatment using both loss-of-function (CXCR2 knockout) and gain-of-function (IL-8 overexpression) mouse models, as the IL-8/CXCR2 pathway has been shown to be activated in intestinal tumors of both human and experimental animals. We found that deletion of CXCR2 gene and ectopic expression of IL-8 suppresses and enhances, respectively, intestinal tumor development caused by a mutation in the APC gene. Moreover, a single copy deletion of CXCR2 gene resulted in abrogation of COX-2 and Gro-α upregulation in intestinal tumors caused by the APC mutation. Moreover, a single copy (heterozygote) deletion of CXCR2 gene was sufficient to synergize with a low-dose sulindac treatment in suppressing APCmin-induced intestinal polyposis. Together, our study provides a therapeutic justification of combined inhibition of CXCR2 and sulindac treatment in colon cancer prevention. © 2013 UICC.

  12. Sulindac modulates secreted protein expression from LIM1215 colon carcinoma cells prior to apoptosis.

    PubMed

    Greening, David W; Ji, Hong; Kapp, Eugene A; Simpson, Richard J

    2013-11-01

    Colorectal cancer (CRC) is a major cause of mortality in Western populations. Growing evidence from human and rodent studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) cause regression of existing colon tumors and act as effective chemopreventive agents in sporadic colon tumor formation. Although much is known about the action of the NSAID sulindac, especially its role in inducing apoptosis, mechanisms underlying these effects is poorly understood. In previous secretome-based proteomic studies using 2D-DIGE/MS and cytokine arrays we identified over 150 proteins released from the CRC cell line LIM1215 whose expression levels were dysregulated by treatment with 1mM sulindac over 16h; many of these proteins are implicated in molecular and cellular functions such as cell proliferation, differentiation, adhesion, angiogenesis and apoptosis (Ji et al., Proteomics Clin. Appl. 2009, 3, 433-451). We have extended these studies and describe here an improved protein/peptide separation strategy that facilitated the identification of 987 proteins and peptides released from LIM1215 cells following 1mM sulindac treatment for 8h preceding the onset of apoptosis. This peptidome separation strategy involved fractional centrifugal ultrafiltration of concentrated cell culture media (CM) using nominal molecular weight membrane filters (NMWL 30K, 3K and 1K). Proteins isolated in the >30K and 3-30K fractions were electrophoretically separated by SDS-PAGE and endogenous peptides in the 1-3K membrane filter were fractioned by RP-HPLC; isolated proteins and peptides were identified by nanoLC-MS-MS. Collectively, our data show that LIM1215 cells treated with 1mM sulindac for 8h secrete decreased levels of proteins associated with extracellular matrix remodeling (e.g., collagens, perlecan, syndecans, filamins, dyneins, metalloproteinases and endopeptidases), cell adhesion (e.g., cadherins, integrins, laminins) and mucosal maintenance (e.g., glycoprotein 340 and mucins 5AC, 6

  13. Therapeutic potential of sulindac against ischemia-reperfusion-induced myocardial infarction in diabetic and nondiabetic rats

    PubMed Central

    Annapurna, Akula; Challa, Siva Reddy; Prakash, Gomedhikam J; Viswanath, Routhu Kasi

    2008-01-01

    BACKGROUND Diabetes mellitus is an independent risk factor for cardiovascular disease and is also associated with increased susceptibility to cardiovascular complications. It has been suggested that alterations in glucose metabolism and glucose flux via the aldose reductase pathway make the diabetic heart more sensitive to ischemic-reperfusion injury. Previous studies have found sulindac to have inhibitory and anti-inflammatory effects on aldose reductase. The use of aldose reductase inhibitors for the protection of ischemic myocardium is still in an exploratory state. OBJECTIVES To evaluate the therapeutic potential of sulindac in an in vivo rat model of acute ischemia (30 min) and reperfusion (4 h) in diabetic and nondiabetic rats. METHODS Diabetes was induced in rats by administering streptozotocin (45 mg/kg, intravenously). Myocardial infarction was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 4 h of reperfusion. Infarct size was measured using the staining agent 2,3,5-triphenyltetrazolium chloride. A lead II electrocardiogram was monitored at various intervals throughout the experiment. Sorbitol dehydrogenase levels in heart tissue, as well as lipid peroxide levels in serum and heart tissue, were estimated spectrophotometrically. RESULTS Infarct size was increased in diabetic rats in comparison with normal rats. Pretreatment with sulindac significantly reduced infarct size, lipid peroxidation and sorbitol dehydrogenase levels in both diabetic and nondiabetic rats. The degree of cardioprotection was greater in diabetic rats than in nondiabetic rats. CONCLUSIONS The present study indicates that the observed cardioprotection provided by sulindac in terms of reducing infarct size in normal rats may be due to its combined antioxidant and anti-inflammatory activities. The inhibition of aldose reductase may be responsible for the enhanced cardioprotection observed in diabetic rats treated with sulindac. PMID:19343118

  14. Therapeutic potential of sulindac against ischemia-reperfusion-induced myocardial infarction in diabetic and nondiabetic rats.

    PubMed

    Annapurna, Akula; Challa, Siva Reddy; Prakash, Gomedhikam J; Viswanath, Routhu Kasi

    2008-01-01

    Diabetes mellitus is an independent risk factor for cardiovascular disease and is also associated with increased susceptibility to cardiovascular complications. It has been suggested that alterations in glucose metabolism and glucose flux via the aldose reductase pathway make the diabetic heart more sensitive to ischemic-reperfusion injury. Previous studies have found sulindac to have inhibitory and anti-inflammatory effects on aldose reductase. The use of aldose reductase inhibitors for the protection of ischemic myocardium is still in an exploratory state. To evaluate the therapeutic potential of sulindac in an in vivo rat model of acute ischemia (30 min) and reperfusion (4 h) in diabetic and nondiabetic rats. Diabetes was induced in rats by administering streptozotocin (45 mg/kg, intravenously). Myocardial infarction was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 4 h of reperfusion. Infarct size was measured using the staining agent 2,3,5-triphenyltetrazolium chloride. A lead II electrocardiogram was monitored at various intervals throughout the experiment. Sorbitol dehydrogenase levels in heart tissue, as well as lipid peroxide levels in serum and heart tissue, were estimated spectrophotometrically. Infarct size was increased in diabetic rats in comparison with normal rats. Pretreatment with sulindac significantly reduced infarct size, lipid peroxidation and sorbitol dehydrogenase levels in both diabetic and nondiabetic rats. The degree of cardioprotection was greater in diabetic rats than in nondiabetic rats. The present study indicates that the observed cardioprotection provided by sulindac in terms of reducing infarct size in normal rats may be due to its combined antioxidant and anti-inflammatory activities. The inhibition of aldose reductase may be responsible for the enhanced cardioprotection observed in diabetic rats treated with sulindac.

  15. Phospho-sulindac (OXT-328) combined with difluoromethylornithine prevents colon cancer in mice.

    PubMed

    Mackenzie, Gerardo G; Ouyang, Nengtai; Xie, Gang; Vrankova, Kvetoslava; Huang, Liqun; Sun, Yu; Komninou, Despina; Kopelovich, Levy; Rigas, Basil

    2011-07-01

    The nonsteroidal anti-inflammatory drug (NSAID) sulindac and the ornithine decarboxylase (ODC) antagonist difluoromethylornithine (DFMO), individually and together, are effective inhibitors of colon carcinogenesis. However, chronic use of sulindac is associated with significant side effects. We evaluated the chemopreventive efficacy of phospho-sulindac (P-S, OXT-328), an apparently safe derivative of sulindac, together with DFMO, in HT-29 human colon cancer xenografts. Nude mice were divided into four groups as follows: group 1 received vehicle (corn oil); group 2 received P-S (100 mg/kg/d) by oral gavage; group 3 received DFMO (2% in drinking water); and group 4 received P-S (100 mg/kg/d) by gavage plus DFMO (2% in drinking water; P-S/DFMO). Eighteen days after implantation, compared with controls, tumor volume was inhibited 65.9% by P-S, 52.9% by DFMO, and 70.9% by P-S/DFMO (P < 0.01 for all). P-S/DFMO reduced cell proliferation 27.1% and increased apoptosis 38.9% compared with controls (P < 0.05 for both). Compared with controls, P-S reduced the levels of thioredoxin-1 (Trx-1) and thioredoxin reductase (TrxR), whereas DFMO reduced polyamine content (putrescine and spermidine) and TrxR levels. Importantly, P-S/DFMO decreased putrescine and spermidine levels and the expression of Trx-1, TrxR, and cyclooxygenase (COX) 2. Of these molecular targets, TrxR most consistently correlated with tumor growth. Study results show that P-S/DFMO is an efficacious drug combination for colon cancer prevention and also show the safety of P-S, which may overcome the limiting side effects of conventional sulindac. P-S/DFMO has an intricate mechanism of action extending beyond polyamines and including the thioredoxin system, an emerging regulator of chemoprevention. P-S/DFMO merits further evaluation.

  16. Sulindac reversal of 15-PGDH-mediated resistance to colon tumor chemoprevention with NSAIDs.

    PubMed

    Fink, Stephen P; Dawson, Dawn M; Zhang, Yongyou; Kresak, Adam; Lawrence, Earl G; Yang, Peiying; Chen, Yanwen; Barnholtz-Sloan, Jill S; Willis, Joseph E; Kopelovich, Levy; Markowitz, Sanford D

    2015-02-01

    Non-steroidal anti-inflammatory drugs prevent colorectal cancer by inhibiting cyclooxygenase (COX) enzymes that synthesize tumor-promoting prostaglandins. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a tumor suppressor that degrades tumor-promoting prostaglandins. Murine knockout of 15-PGDH increases susceptibility to azoxymethane-induced colon tumors. It also renders these mice resistant to celecoxib, a selective inhibitor of inducible COX-2 during colon neoplasia. Similarly, humans with low colonic 15-PGDH are also resistant to colon adenoma prevention with celecoxib. Here, we used aspirin and sulindac, which inhibit both COX-1 and COX-2, in order to determine if these broader COX inhibitors can prevent colon tumors in 15-PGDH knockout (KO) mice. Unlike celecoxib, sulindac proved highly effective in colon tumor prevention of 15-PGDH KO mice. Significantly, however, aspirin demonstrated no effect on colon tumor incidence in either 15-PGDH wild-type or KO mice, despite a comparable reduction in colonic mucosal Prostaglandin E₂ (PGE₂) levels by both sulindac and aspirin. Notably, colon tumor prevention activity by sulindac was accompanied by a marked induction of lymphoid aggregates and proximal colonic inflammatory mass lesions, a side effect seen to a lesser degree with celecoxib, but not with aspirin. These findings suggest that sulindac may be the most effective agent for colon cancer prevention in humans with low 15-PGDH, but its use may also be associated with inflammatory lesions in the colon. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Therapeutic potential of sulindac hydroxamic acid against human pancreatic and colonic cancer cells.

    PubMed

    Fogli, Stefano; Banti, Irene; Stefanelli, Fabio; Picchianti, Luca; Digiacomo, Maria; Macchia, Marco; Breschi, Maria Cristina; Lapucci, Annalina

    2010-11-01

    The non-steroidal anti-inflammatory drug (NSAID) sulindac exhibits cyclooxygenase (COX)-dependent and COX-independent chemopreventive properties in human cancer. The present study was aimed at investigating whether the hydroxamic acid substitution for the carboxylic acid group could enhance the in vitro antitumor and antiangiogenic activities of sulindac. Characterization tools used on this study included analyses of cell viability, caspase 3/7 induction, DNA fragmentation, and gene expression. Our findings demonstrate that the newly synthesized hydroxamic acid derivative of sulindac and its sulfone and sulfide metabolites were characterized by a good anticancer activity on human pancreatic and colon cancer cells, both in terms of potency (IC(50) mean values from 6 ± 1.1 μM to 64 ± 1.1 μM) and efficacy (E(max) of ∼100%). Hydroxamic acid derivatives trigger a higher degree of apoptosis than carboxylic acid counterparts, increase bax/bcl-2 expression ratio and induce caspase 3/7 activation. Most notably, these compounds significantly inhibit proangiogenic growth factor-stimulated proliferation of vascular endothelial cell (HUVEC) at sub-micromolar concentrations. Our data also provide evidence that the COX-active metabolite of sulindac hydroxamic acid were the most active of the series and selective inhibition of COX-1 but not COX-2 can mimic its effects, suggesting that COX inhibition could only play a partial role in the mechanism of compound action. In conclusion, these data demonstrate that substitution of the carboxylic acid group with the hydroxamic acid moiety enhances in vitro antiproliferative, proapoptotic and antiangiogenic properties of sulindac, therefore increasing the therapeutic potential of this drug. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  18. Nitric oxide-releasing sulindac is a novel skin cancer chemopreventive agent for UVB-induced photocarcinogenesis

    SciTech Connect

    Chaudhary, Sandeep C.; Singh, Tripti; Kapur, Puneet; Weng, Zhiping; Arumugam, Aadithya; Elmets, Craig A.; Kopelovich, Levy; Athar, Mohammad

    2013-05-01

    Nitric oxide (NO)-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) which have been synthesized to reduce gastro-intestinal and cardiovascular toxicities of NSAIDs, possess anti-proliferative, pro-apoptotic and anti-cancer activities. Here, we show that NO-sulindac inhibited UVB-induced skin tumorigenesis in SKH-1 hairless mice. Topical application of NO-sulindac reduced tumor incidence, number (p < 0.05) and volume (p < 0.005) as compared to UVB (alone)-irradiated vehicle-treated mice. An increase in TUNEL-positive cells in skin lesions was accompanied by the enhanced Bax:Bcl-2 ratio. The expression of pro-apoptotic Bax was increased whereas anti-apoptotic Bcl-2 reduced. However, proliferation was identified as the major target of NO-sulindac in this study. A reduced expression of PCNA and cyclin D1 associated with the dampening of cell cycle progression was observed. The mechanism of this inhibition was related to the reduction in UVB-induced Notch signaling pathway. UVB-induced inflammatory responses were diminished by NO-sulindac as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases Erk1/2, p38 and JNK1/2. In this regard, NO-sulindac also inhibited NFκB by enhancing IκBα as evidenced by the reduced expression of iNOS and COX-2, the direct NFκB transcription target proteins. NO-sulindac significantly diminished the progression of benign lesions to invasive carcinomas by suppressing the tumor aggressiveness and retarding epithelial–mesenchymal transition. A marked decrease in the expression of mesenchymal markers such as Fibronectin, N-cadherin, SNAI, Slug and Twist and an increase in epithelial cell polarity marker E-cadherin were noted in NO-sulindac-treated tumors. Our data suggest that NO-sulindac is a potent inhibitor of UVB-induced skin carcinogenesis and acts by targeting proliferation-regulatory pathways. - Highlights: ► NO-sulindac is a potent chemopreventive agent for UVB-induced skin cancer. ► NO-sulindac

  19. Intervening in β-Catenin Signaling by Sulindac Inhibits S100A4-Dependent Colon Cancer Metastasis12

    PubMed Central

    Stein, Ulrike; Arlt, Franziska; Smith, Janice; Sack, Ulrike; Herrmann, Pia; Walther, Wolfgang; Lemm, Margit; Fichtner, Iduna; Shoemaker, Robert H; Schlag, Peter M

    2011-01-01

    Colon cancer metastasis is often associated with activation of the Wnt/β-catenin signaling pathway and high expression of the metastasis mediator S100A4. We previously demonstrated the transcriptional regulation of S100A4 by β-catenin and the importance of the interconnection of these cellular programs for metastasis. Here we probe the hypothesis that the nonsteroidal anti-inflammatory drug sulindac sulfide can inhibit colon cancer metastasis by intervening in β-catenin signaling and thereby interdicting S100A4. We treated colon cancer cell lines heterozygous for gain-of-function and wild-type β-catenin with sulindac. We analyzed sulindac's effects on β-catenin expression and subcellular localization, β-catenin binding to the T-cell factor (TCF)/S100A4 promoter complex, S100A4 promoter activity, S100A4 expression, cell motility, and proliferation. Mice intrasplenically transplanted with S100A4-overexpressing colon cancer cells were treated with sulindac. Tumor growth and metastasis, and their β-catenin and S100A4 expressions, were determined. We report the expression knockdown of β-catenin by sulindac, leading to its reduced nuclear accumulation. The binding of β-catenin to TCF was clearly lowered, resulting in reduced S100A4 promoter activity and expression. This correlated well with the inhibition of cell migration and invasion, which could be rescued by ectopic S100A4 expression. In mice, sulindac treatment resulted in reduced tumor growth in the spleen (P = .014) and decreased liver metastasis in a human colon cancer xenograft model (P = .025). Splenic tumors and liver metastases of sulindac-treated mice showed lowered β-catenin and S100A4 levels. These results suggest that modulators of β-catenin signaling such as sulindac offer potential as antimetastatic agents by interdicting S100A4 expression. PMID:21403839

  20. Intervening in β-catenin signaling by sulindac inhibits S100A4-dependent colon cancer metastasis.

    PubMed

    Stein, Ulrike; Arlt, Franziska; Smith, Janice; Sack, Ulrike; Herrmann, Pia; Walther, Wolfgang; Lemm, Margit; Fichtner, Iduna; Shoemaker, Robert H; Schlag, Peter M

    2011-02-01

    Colon cancer metastasis is often associated with activation of the Wnt/β-catenin signaling pathway and high expression of the metastasis mediator S100A4. We previously demonstrated the transcriptional regulation of S100A4 by β-catenin and the importance of the interconnection of these cellular programs for metastasis. Here we probe the hypothesis that the nonsteroidal anti-inflammatory drug sulindac sulfide can inhibit colon cancer metastasis by intervening in β-catenin signaling and thereby interdicting S100A4. We treated colon cancer cell lines heterozygous for gain-of-function and wild-type β-catenin with sulindac. We analyzed sulindac's effects on β-catenin expression and subcellular localization, β-catenin binding to the T-cell factor (TCF)/S100A4 promoter complex, S100A4 promoter activity, S100A4 expression, cell motility, and proliferation. Mice intrasplenically transplanted with S100A4-overexpressing colon cancer cells were treated with sulindac. Tumor growth and metastasis, and their β-catenin and S100A4 expressions, were determined. We report the expression knockdown of β-catenin by sulindac, leading to its reduced nuclear accumulation. The binding of β-catenin to TCF was clearly lowered, resulting in reduced S100A4 promoter activity and expression. This correlated well with the inhibition of cell migration and invasion, which could be rescued by ectopic S100A4 expression. In mice, sulindac treatment resulted in reduced tumor growth in the spleen (P = .014) and decreased liver metastasis in a human colon cancer xenograft model (P = .025). Splenic tumors and liver metastases of sulindac-treated mice showed lowered β-catenin and S100A4 levels. These results suggest that modulators of β-catenin signaling such as sulindac offer potential as antimetastatic agents by interdicting S100A4 expression.

  1. The effects of naproxen and sulindac on renal function and their interaction with hydrochlorothiazide and piretanide in man.

    PubMed

    Dixey, J J; Noormohamed, F H; Lant, A F; Brewerton, D A

    1987-01-01

    We have studied the effect of a single dose challenge of naproxen (500 mg) and sulindac (200 mg) on renal function in five volunteers, and the effect of a single dose challenge of the thiazide, hydrochlorothiazide (100 mg), and loop diuretic, piretanide (6 mg) on renal function when the diuretics were given alone or when superimposed on chronic therapy of either naproxen or sulindac. None of the nonsteroidal anti-inflammatory drug (NSAID) or diuretic exposures significantly influenced glomerular filtration rate, as measured by creatinine clearance. Over the first 4 h of the study, both naproxen and sulindac reduced fractional excretion of sodium by approximately 50%. Sulindac also caused a significant uricosuria whilst naproxen promoted urate retention. Similar changes were observed over 8 h. Superimposition of either hydrochlorothiazide or piretanide on top of chronic sulindac therapy resulted in a blunting of the natriuresis by approximately 30% compared to when these diuretics were given alone: the action of the diuretics was unchanged by naproxen. Sulindac pretreatment did not alter the urinary excretion of either hydrochlorothiazide or piretanide; naproxen did not alter hydrochlorothiazide excretion. On the basis of these findings, it is concluded that NSAIDs exert direct tubular effects that do not necessarily interfere with the delivery of diuretics to their sites of action within the nephron.

  2. Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis

    PubMed Central

    Samadder, N. Jewel; Neklason, Deborah W.; Boucher, Kenneth M.; Byrne, Kathryn R.; Kanth, Priyanka; Samowitz, Wade; Jones, David; Tavtigian, Sean V.; Done, Michelle W.; Berry, Therese; Jasperson, Kory; Pappas, Lisa; Smith, Laurel; Sample, Danielle; Davis, Rian; Topham, Matthew K.; Lynch, Patrick; Strait, Elena; McKinnon, Wendy; Burt, Randall W.; Kuwada, Scott K.

    2016-01-01

    IMPORTANCE Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal polyps and cancer. Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful. OBJECTIVE To evaluate the effect of a combination of sulindac and erlotinib on duodenal adenoma regression in patients with FAP. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, placebo-controlled trial, enrolling 92 participants with FAP, conducted from July 2010 through June 2014 at Huntsman Cancer Institute in Salt Lake City, Utah. INTERVENTIONS Participants with FAP were randomized to sulindac (150 mg) twice daily and erlotinib (75 mg) daily (n = 46) vs placebo (n = 46) for 6 months. MAIN OUTCOMES AND MEASURES The total number and diameter of polyps in the proximal duodenum were mapped at baseline and 6 months. The primary outcome was change in total polyp burden at 6 months. Polyp burden was calculated as the sum of the diameters of polyps. The secondary outcomes were change in total duodenal polyp count, change in duodenal polyp burden or count stratified by genotype and initial polyp burden, and percentage of change from baseline in duodenal polyp burden. RESULTS Ninety-two participants (mean age, 41 years [range, 24–55]; women, 56 [61%]) were randomized when the trial was stopped by the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87% of participants receiving treatment and 20% of participants receiving placebo (P < .001). Only 2 participants experienced grade 3 adverse events. OutcomeBaseline6-moFollow-upMedianChangeBetween-GroupDifference (95% CI)PValueMedian Duodenal Polyp Burden, mmSulindac-erlotinib29.019.5−8.5−19.0 (−32.0 to −10.9)<.001Placebo23.031.08.0Median Duodenal Polyp Count, No.Sulindac

  3. Randomized, double-blind, placebo-controlled trial of sulindac in individuals at risk for melanoma: evaluation of potential chemopreventive activity.

    PubMed

    Curiel-Lewandrowski, Clara; Swetter, Susan M; Einspahr, Janine G; Hsu, Chiu-Hsieh; Nagle, Ray; Sagerman, Paul; Tangrea, Joseph; Parnes, Howard; Alberts, David S; Chow, Hsiao-Hui

    2012-12-01

    Reduced melanoma risk has been reported with regular use of nonsteroidal anti-inflammatory drugs (NSAIDs). However, the ability of NSAIDs to reach melanocytes in vivo and modulate key biomarkers in preneoplastic lesions such as atypical nevi has not been evaluated. This randomized, double-blind, placebo-controlled trial of sulindac was conducted in individuals with atypical nevi (AN) to determine bioavailability of sulindac and metabolites in nevi and effect on apoptosis and vascular endothelial growth factor A (VEGFA) expression in AN. Fifty subjects with AN ≥ 4 mm in size and 1 benign nevus (BN) were randomized to sulindac (150 mg twice a day) or placebo for 8 weeks. Two AN were randomized for baseline excision, and 2 AN and BN were excised after intervention. Postintervention sulindac, sulindac sulfone, and sulindac sulfide concentrations were 0.31 ± 0.36, 1.56 ± 1.35, and 2.25 ± 2.24 μg/mL in plasma, and 0.51 ± 1.05, 1.38 ± 2.86, and 0.12 ± 0.12 μg/g in BN, respectively. Sulindac intervention did not significantly change VEGFA expression but did increase expression of the apoptotic marker cleaved caspase-3 in AN (increase of 3 ± 33 in sulindac vs decrease of 25 ± 45 in the placebo arm, P = .0056), although significance was attenuated (P = .1103) after adjusting for baseline expression. Eight weeks of sulindac intervention resulted in high concentrations of sulindac sulfone, a proapoptotic metabolite, in BN but did not effectively modulate VEGFA and cleaved caspase-3 expression. Study limitations included limited exposure time to sulindac and the need to optimize a panel of biomarkers for NSAID intervention studies. Copyright © 2012 American Cancer Society.

  4. Beneficial effects of sulindac in focal cerebral ischemia: a positive role in Wnt/β-catenin pathway.

    PubMed

    Xing, Yinxue; Zhang, Xiangjian; Zhao, Kang; Cui, Lili; Wang, Lina; Dong, Lipeng; Li, Yanhua; Liu, Zongjie; Wang, Chaohui; Zhang, Xiaolin; Zhu, Chunhua; Qiao, Huimin; Ji, Ye; Cao, Xiaoyun

    2012-10-30

    Accumulated evidences have established that inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Sulindac is well known as a nonsteroidal anti-inflammatory drug. However, little is known regarding the effect of sulindac in acute cerebral ischemia. Here, we designed this study to investigate the potential protective effects of sulindac in focal cerebral ischemia and the mechanisms underlying in vivo. Focal cerebral ischemia was induced in male Sprague-Dawley rats by permanent middle cerebral artery occlusion (pMCAO). Sulindac was administrated at dose of 4, 10, or 20mg/kg at 30 min before the operation. Neurological deficit scores, brain water content and infarct volumes were measured at 24h after pMCAO. Immunohistochemistry, western blot and reverse transcription-polymerase chain reaction were used for examining the mediators involved in Wnt/β-catenin signaling pathway, including the positive regulators dishevelled (Dvl) and β-catenin, the negative regulators adenomatous polyposis coli (APC), and P-β-catenin, as well as the downstream targets Bcl-2, Bax and claudin-5. Compared with Vehicle group, 20mg/kg sulindac reduced neurological deficits, brain water content and infarct volumes. The same dose of sulindac upregulated the expression of Dvl, β-catenin, Bcl2 and claudin-5, and downregulated APC, P-β-catenin and Bax compared with Vehicle group. These results showed that sulindac had a significant beneficial effect in cerebral ischemia; this effect may be correlated with the activation of the Wnt/β-catenin signaling. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Anti-inflammatory properties of new bioisosteres of indomethacin synthesized from safrole which are sulindac analogues.

    PubMed

    Pereira, E F; Pereira, N A; Lima, M E; Coelho, F A; Barreiro, E J

    1989-01-01

    The anti-inflammatory activities of new compounds (I, II, III and IV) synthesized in 30% overall yield from the abundant natural product safrole, the principal chemical constituent of the oil of sassafras (Ocotea pretiosa, Lauraceae), were determined in mice. The synthesis of these new indenyl-acetic acids (I and II) and indenyl-propionic acids (III and IV) was based on the minimal structural features of non-steroid anti-inflammatory agents of the aryl- or heteroarylcarboxylic acid group. The compounds exhibited potencies 4- to 10-fold less than that of indomethacin in inhibiting carrageenan-induced hindpaw edema. In contrast, like sulindac, all the new compounds were more potent than indomethacin in antagonizing writhing pain and increased vascular permeability caused by acetic acid. The results confirm the anticipated bioisosteric relationship between these synthetic derivatives, designed as sulindac analogues, and the classical non-steroidal anti-inflammatory agent, indomethacin.

  6. The neuroprotective effect of Sulindac after ischemia-reperfusion injury in rats.

    PubMed

    Cosar, Murat; Kaner, Tuncay; Sahin, Onder; Topaloglu, Naci; Guven, Mustafa; Aras, Adem Bozkurt; Akman, Tarık; Ozkan, Adile; Sen, Halil Murat; Memi, Gulsum; Deniz, Mustafa

    2014-04-01

    To investigate the neuroprotective effects of Sulindac on the hippocampal complex after global cerebral ischemia/reperfusion (I/R) injury in rats. Thirty one Sprague-Dawley rats were used, distributed into group I (sham) n:7 were used as control. For group II (n:8), III (n:8) and IV (n:8) rats, cerebral ischemia was performed via the occlusion of bilateral internal carotid artery for 45 minutes and continued with reperfusion process. 0.3 mL/kg/h 0.9 % sodium chloride was infused intraperitoneally to the Group II rats before ischemia, 5μg/kg/h/0.3 ml sulindac was infused intraperitoneally to the Group III rats before ischemia and 5μg/kg/h/0.3 ml sulindac was infused intraperitoneally to the Group IV rats after ischemia and before reperfusion process. The levels of MDA, GSH and MPO activity were measured in the left hippocampus tissue. The hippocampal tissue of all group members were taken for histopathological study. The MDA and MPO levels increased from group I (control) to group II (I/R) (P<0.05) and decreased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05). Beside these, the GSH levels decreased from group I (control) to group II (I/R) (P<0.05) and increased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05).The number of apoptotic neurons increased from group I (control) to group II (I/R) (P<0.05) and decreased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05). The Sulindac may have neuroprotective effects on ischemic neural tissue to prevent the reperfusion injury after ischemia.

  7. Advanced Nanohybrid Formulation of the Sparingly Soluble Drug Sulindac for Controlled Release Studies

    NASA Astrophysics Data System (ADS)

    Minagawa, Keiji; Berber, Mohamed R.; Hafez, Inas H.; Mori, Takeshi; Tanaka, Masami

    We offered an advanced nanohybrid formulation system of Sulindac (SUL) based on layered double hydroxide (LDH) nanoparticles. The formulated materials were characterized by X-rays, Infrared and SEM techniques to confirm the nanohybrid structure. The drug incorporation ratio was determined to be 45%. The drug solubility was improved after the LDH nanohybrid formation. The anion-exchange mechanism of LDH supported the dissolution process for the intercalated SUL.

  8. Effects of single-nucleotide polymorphisms of FMO3 and FMO6 genes on pharmacokinetic characteristics of sulindac sulfide in premature labor.

    PubMed

    Park, Sunny; Lee, Na Ra; Lee, Kyung Eun; Park, Jin Young; Kim, Young Ju; Gwak, Hye Sun

    2014-01-01

    This study aimed to investigate the effects of polymorphisms of the flavin-containing mono-oxygenase 3 (FMO3) and flavin-containing mono-oxygenase 6 (FMO6) genes on the pharmacokinetics of sulindac sulfide, the active metabolite of sulindac, in patients with preterm labor. Ten single-nucleotide polymorphisms (SNPs) were genotyped, and plasma sulindac sulfide concentrations were measured at 0, 1.5, 4, and 10 hours after drug administration. The area under the curve from time 0 to the last sampling time point (AUC(last)) for sulindac sulfide was obtained. The AUC(last) of sulindac sulfide was significantly higher in patients with variant-type homozygotes of FMO3 (rs909530) than those with ancestral alleles or heterozygotes. FMO3 (rs2266780) was in complete linkage disequilibrium with FMO6 (rs7885012), and there was marginal significance between the genotypes (P = 0.049). From multiple linear regression models, FMO3 (rs909530) was found to have significant influence on the AUClast of sulindac sulfide after adjusting for gestational age, weight, and all studied SNPs. The predictive contribution of rs909530 to the variability of sulindac sulfide AUC(last) was 27.0%. In conclusion, the results of this study could help clinicians predict the efficacies and side effects of sulindac in the development of individualized treatment of patients with preterm labor.

  9. COX inhibitors Indomethacin and Sulindac derivatives as antiproliferative agents: synthesis, biological evaluation, and mechanism investigation.

    PubMed

    Chennamaneni, Snigdha; Zhong, Bo; Lama, Rati; Su, Bin

    2012-10-01

    Cyclooxygenase (COX) inhibitors Indomethacin and its structural analogs Sulindac exhibit cell growth inhibition and apoptosis inducing activities in various cancer cell lines via COX independent mechanisms. In this study, the molecular structures of Indomethacin and Sulindac were used as starting scaffolds to design novel analogs and their effects on the proliferation of human cancer cells were evaluated. Compared to Indomethacin and Sulindac inhibiting cancer cell proliferation with IC(50)s of more than 1 mM, the derivatives displayed significantly increased activities. Especially, one of the Indomethacin analogs inhibited the growth of a series of cancer cell lines with IC(50)s around 0.5 μM-3 μM. Mechanistic investigation revealed that the new analog was in fact a tubulin inhibitor, although the parental compound Indomethacin did not show any tubulin inhibitory activity. Tubulin polymerization assay indicated this compound inhibited tubulin assembly at high concentrations, but promoted this process at low concentrations which is a very unique mechanism. The binding mode of this compound in tubulin was predicted using the molecular docking simulation. Published by Elsevier Masson SAS.

  10. NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling.

    PubMed

    Zhou, Hu; Liu, Wen; Su, Ying; Wei, Zhen; Liu, Jie; Kolluri, Siva Kumar; Wu, Hua; Cao, Yu; Chen, Jiebo; Wu, Yin; Yan, Tingdong; Cao, Xihua; Gao, Weiwei; Molotkov, Andrei; Jiang, Fuquan; Li, Wen-Gang; Lin, Bingzhen; Zhang, Hai-Ping; Yu, Jinghua; Luo, Shi-Peng; Zeng, Jin-Zhang; Duester, Gregg; Huang, Pei-Qiang; Zhang, Xiao-Kun

    2010-06-15

    Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their anticancer effects through cyclooxygenase-2 (COX-2)-dependent and independent mechanisms. Here, we report that Sulindac, an NSAID, induces apoptosis by binding to retinoid X receptor-alpha (RXRalpha). We identified an N-terminally truncated RXRalpha (tRXRalpha) in several cancer cell lines and primary tumors, which interacted with the p85alpha subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-alpha (TNFalpha) promoted tRXRalpha interaction with the p85alpha, activating PI3K/AKT signaling. When combined with TNFalpha, Sulindac inhibited TNFalpha-induced tRXRalpha/p85alpha interaction, leading to activation of the death receptor-mediated apoptotic pathway. We designed and synthesized a Sulindac analog K-80003, which has increased affinity to RXRalpha but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRalpha-dependent AKT activation and tRXRalpha tumor growth in animals. Copyright 2010 Elsevier Inc. All rights reserved.

  11. Sulindac-derived RXRα modulators inhibit cancer cell growth by binding to a novel site.

    PubMed

    Chen, Liqun; Wang, Zhi-Gang; Aleshin, Alexander E; Chen, Fan; Chen, Jiebo; Jiang, Fuquan; Alitongbieke, Gulimiran; Zeng, Zhiping; Ma, Yue; Huang, Mingfeng; Zhou, Hu; Cadwell, Gregory; Zheng, Jian-Feng; Huang, Pei-Qiang; Liddington, Robert C; Zhang, Xiao-kun; Su, Ying

    2014-05-22

    Retinoid X receptor-alpha (RXRα), an intriguing and unique drug target, can serve as an intracellular target mediating the anticancer effects of certain nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac. We report the synthesis and characterization of two sulindac analogs, K-8008 and K-8012, which exert improved anticancer activities over sulindac in a RXRα-dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXRα (tRXRα) with the p85α subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRα ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRα LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXRα modulators and define a binding mechanism for regulating the nongenomic action of tRXRα. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling

    PubMed Central

    Zhou, Hu; Liu, Wen; Su, Ying; Wei, Zhen; Liu, Jie; Kolluri, Siva Kumar; Wu, Hua; Cao, Yu; Chen, Jiebo; Wu, Yin; Yan, Tingdong; Cao, Xihua; Gao, Weiwei; Molotkov, Andrei; Jiang, Fuquan; Li, Wen-Gang; Lin, Bingzhen; Zhang, Hai-Ping; Yu, Jinghua; Luo, Shi-Peng; Zeng, Jin-zhang; Duester, Gregg; Huang, Pei-Qiang; Zhang, Xiao-kun

    2010-01-01

    SUMMARY Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-cancer effects through cyclooxygenase-2 (COX-2)-dependent and -independent mechanisms. Here we report that Sulindac, an NSAID, induces apoptosis by binding to retinoid X receptor-α (RXRα). We identified an N-terminally-truncated RXRα (tRXRα) in several cancer cell lines and primary tumors, which interacted with the p85α subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-α (TNFα) promoted tRXRα interaction with the p85α, activating PI3K/AKT signaling. When combined with TNFα, Sulindac inhibited TNFα-induced tRXRα/p85α interaction, leading to activation of the death receptor-mediated apoptotic pathway. We designed and synthesized a Sulindac analog K-80003, which has increased affinity to RXRα but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRα-dependent AKT activation and tRXRα tumor growth in animals. PMID:20541701

  13. A novel sulindac derivative lacking COX-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model

    PubMed Central

    Zhang, Yong; Zhang, Jinhui; Wang, Lei; Quealy, Emily; Gary, Bernard D.; Reynolds, Robert C.; Piazza, Gary A.; Lü, Junxuan

    2016-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac are well-documented to be highly effective for cancer chemoprevention. However, their cyclooxygenase (COX) inhibitory activities cause severe gastrointestinal and cardiovascular toxicities, limiting their chronic use. Recent studies suggest that COX-independent mechanisms may be responsible for the chemopreventive benefits of the NSAIDs, and support the potential for development of a novel generation of sulindac derivatives lacking COX inhibition for cancer chemoprevention. A prototypic sulindac derivative with a N,N-dimethylammonium substitution, referred to as sulindac sulfide amide (SSA) was recently identified to be devoid of COX inhibitory activity yet displays much more potent tumor cell growth inhibitory activity in vitro compared to sulindac sulfide. In this study, we investigated the androgen receptor (AR) signaling pathway as a potential target for its COX-independent antineoplastic mechanism and evaluated its chemopreventive efficacy against prostate carcinogenesis using the TRAMP mouse model. The results showed that SSA significantly suppressed the growth of human and mouse prostate cancer cells expressing AR in strong association with G1 arrest, and decreased AR level and AR-dependent transactivation. Dietary SSA consumption from 6 to 24 weeks of age dramatically attenuated prostatic growth and suppressed AR-dependent glandular epithelial lesion progression via repressing cell proliferation in the TRAMP mice, whereas it did not significantly impact neuroendocrine carcinoma growth. Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial carcinogenesis. PMID:20587701

  14. A novel sulindac derivative lacking cyclooxygenase-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model.

    PubMed

    Zhang, Yong; Zhang, Jinhui; Wang, Lei; Quealy, Emily; Gary, Bernard D; Reynolds, Robert C; Piazza, Gary A; Lü, Junxuan

    2010-07-01

    Nonsteroidal anti-inflammatory drugs including sulindac are well documented to be highly effective for cancer chemoprevention. However, their cyclooxygenase (COX)-inhibitory activities cause severe gastrointestinal, renal, and cardiovascular toxicities, limiting their chronic use. Recent studies suggest that COX-independent mechanisms may be responsible for the chemopreventive benefits of nonsteroidal anti-inflammatory drugs and support the potential for the development of a novel generation of sulindac derivatives lacking COX inhibition for cancer chemoprevention. A prototypic sulindac derivative with a N,N-dimethylammonium substitution called sulindac sulfide amide (SSA) was recently identified to be devoid of COX-inhibitory activity yet displays much more potent tumor cell growth-inhibitory activity in vitro compared with sulindac sulfide. In this study, we investigated the androgen receptor (AR) signaling pathway as a potential target for its COX-independent antineoplastic mechanism and evaluated its chemopreventive efficacy against prostate carcinogenesis using the transgenic adenocarcinoma of mouse prostate model. The results showed that SSA significantly suppressed the growth of human and mouse prostate cancer cells expressing AR in strong association with G(1) arrest, and decreased AR level and AR-dependent transactivation. Dietary SSA consumption dramatically attenuated prostatic growth and suppressed AR-dependent glandular epithelial lesion progression through repressing cell proliferation in the transgenic adenocarcinoma of mouse prostate mice, whereas it did not significantly affect neuroendocrine carcinoma growth. Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial carcinogenesis. 2010 AACR.

  15. Randomized double-blind trial of sulindac and etodolac to eradicate aberrant crypt foci and to prevent sporadic colorectal polyps.

    PubMed

    Takayama, Tetsuji; Nagashima, Hiroyuki; Maeda, Masahiro; Nojiri, Shuichi; Hirayama, Michiaki; Nakano, Yoichiro; Takahashi, Yasuo; Sato, Yasushi; Sekikawa, Hitoshi; Mori, Mitsuru; Sonoda, Tomoko; Kimura, Tetsuo; Kato, Junji; Niitsu, Yoshiro

    2011-06-01

    On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer. Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted. ACF number at 2 months was significantly suppressed in the sulindac group (P = 0.0075), but not in the etodolac group (P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly (P = 0.02) and marginally (P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed. ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer. ©2011 AACR.

  16. Nitric Oxide-releasing Sulindac is a Novel Skin Cancer Chemopreventive Agent for UVB-induced Photocarcinogenesis

    PubMed Central

    Chaudhary, Sandeep C.; Singh, Tripti; Kapur, Puneet; Weng, Zhiping; Arumugam, Aadithya; Elmets, Craig A.; Kopelovich, Levy; Athar, Mohammad

    2013-01-01

    Nitric oxide (NO)-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) which have been synthesized to reduce gastro-intestinal and cardiovascular toxicities of NSAIDs, possess anti-proliferative, pro-apoptotic and anti-cancer activities. Here, we show that NO-sulindac inhibited UVB-induced skin tumorigenesis in SKH-1 hairless mice. Topical application of NO-sulindac reduced tumor incidence, number (p<0.05) and volume (p<0.005) as compared to UVB (alone)-irradiated vehicle-treated mice. An increase in TUNEL-positive cells in skin lesions was accompanied by the enhanced Bax:Bcl-2 ratio. The expression of pro-apoptotic Bax was increased whereas anti-apoptotic Bcl-2 reduced. However, proliferation was identified as the major target of NO-sulindac in this study. A reduced expression of PCNA and cyclin D1 associated with the dampening of cell cycle progression was observed. The mechanism of this inhibition was related to the reduction in UVB-induced Notch signaling pathway. UVB-induced inflammatory responses were diminished by NO-sulindac as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases Erk1/2, p38 and JNK1/2. In this regard, NO-sulindac also inhibited NFκB by enhancing IκBα as evidenced by the reduced expression of iNOS and COX-2, the direct NFκB transcription target proteins. NO-sulindac significantly diminished the progression of benign lesions to invasive carcinomas by suppressing the tumor aggressiveness and retarding epithelial-mesenchymal transition. A marked decrease in the expression of mesenchymal markers such as Fibronectin, N-cadherin, SNAI, Slug and Twist and an increase in epithelial cell polarity marker E-cadherin were noted in NO-sulindac-treated tumors. Our data suggest that NO-sulindac is a potent inhibitor of UVB-induced skin carcinogenesis and acts by targeting proliferation-regulatory pathways. PMID:23274568

  17. Nitric oxide-releasing sulindac is a novel skin cancer chemopreventive agent for UVB-induced photocarcinogenesis.

    PubMed

    Chaudhary, Sandeep C; Singh, Tripti; Kapur, Puneet; Weng, Zhiping; Arumugam, Aadithya; Elmets, Craig A; Kopelovich, Levy; Athar, Mohammad

    2013-05-01

    Nitric oxide (NO)-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) which have been synthesized to reduce gastro-intestinal and cardiovascular toxicities of NSAIDs, possess anti-proliferative, pro-apoptotic and anti-cancer activities. Here, we show that NO-sulindac inhibited UVB-induced skin tumorigenesis in SKH-1 hairless mice. Topical application of NO-sulindac reduced tumor incidence, number (p<0.05) and volume (p<0.005) as compared to UVB (alone)-irradiated vehicle-treated mice. An increase in TUNEL-positive cells in skin lesions was accompanied by the enhanced Bax:Bcl-2 ratio. The expression of pro-apoptotic Bax was increased whereas anti-apoptotic Bcl-2 reduced. However, proliferation was identified as the major target of NO-sulindac in this study. A reduced expression of PCNA and cyclin D1 associated with the dampening of cell cycle progression was observed. The mechanism of this inhibition was related to the reduction in UVB-induced Notch signaling pathway. UVB-induced inflammatory responses were diminished by NO-sulindac as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases Erk1/2, p38 and JNK1/2. In this regard, NO-sulindac also inhibited NFκB by enhancing IκBα as evidenced by the reduced expression of iNOS and COX-2, the direct NFκB transcription target proteins. NO-sulindac significantly diminished the progression of benign lesions to invasive carcinomas by suppressing the tumor aggressiveness and retarding epithelial-mesenchymal transition. A marked decrease in the expression of mesenchymal markers such as Fibronectin, N-cadherin, SNAI, Slug and Twist and an increase in epithelial cell polarity marker E-cadherin were noted in NO-sulindac-treated tumors. Our data suggest that NO-sulindac is a potent inhibitor of UVB-induced skin carcinogenesis and acts by targeting proliferation-regulatory pathways. Copyright © 2012. Published by Elsevier Inc.

  18. Sulindac, a nonsteroidal anti-inflammatory drug, selectively inhibits interferon-{gamma}-induced expression of the chemokine CXCL9 gene in mouse macrophages

    SciTech Connect

    Sakaeda, Yoshiichi; Hiroi, Miki; Shimojima, Takahiro; Iguchi, Mayumi; Kanegae, Haruhide; Ohmori, Yoshihiro . E-mail: ohmori@dent.meikai.ac.jp

    2006-11-17

    Sulindac, a non-steroidal anti-inflammatory drug, has been shown to exert an anti-tumor effect on several types of cancer. To determine the effect of sulindac on intracellular signaling pathways in host immune cells such as macrophages, we investigated the effect of the drug on interferon gamma (IFN{gamma})-induced expression of signal transducer and activator of transcription 1 (STAT1) and other genes in mouse macrophage-like cell line RAW264.7 cells. Sulindac, but not aspirin or sodium salicylate, inhibited IFN{gamma}-induced expression of the CXC ligand 9 (CXCL9) mRNA, a chemokine for activated T cells, whereas the interferon-induced expression of CXCL10 or IFN regulatory factor-1 was not affected by sulindac. Luciferase reporter assay demonstrated that sulindac inhibited IFN{gamma}-induced promoter activity of the CXCL9 gene. Surprisingly, sulindac had no inhibitory effect on IFN{gamma}-induced STAT1 activation; however, constitutive nuclear factor {kappa}B activity was suppressed by the drug. These results indicate that sulindac selectively inhibited IFN{gamma}-inducible gene expression without inhibiting STAT1 activation.

  19. The effect of sulindac, a non-steroidal anti-inflammatory drug, attenuates inflammation and fibrosis in a mouse model of chronic pancreatitis

    PubMed Central

    2012-01-01

    Background Chronic pancreatitis is characterized by progressive fibrosis, pain and loss of exocrine and endocrine functions. The long-standing chronic pancreatitis and its associated pancreatic fibrosis are the most common pathogenic events involved in human pancreatic carcinogenesis, but the therapeutic strategies to chronic pancreatitis and the chemoprevention of pancreatic carcinogenesis are very limited. Methods We investigated the effect of sulindac, a non-steroidal anti-inflammatory drug (NSAID), on inhibition of chronic pancreatitis in a caerulein induced chronic pancreatitis mouse model. Results Sulindac significantly reduced the severity of chronic pancreatitis including the extent of acini loss, inflammatory cell infiltration and stromal fibrosis. The protein expression of phosphorylation of MEK/ERK was inhibited in the chronic pancreatic tissues by sulindac treatment as measured by Western blot assay. The levels of inflammatory cytokines including TNF-α and MCP-1 were also significantly decreased with sulindac treatment, as well as the expression of TGF-β, PDGF-β, SHH and Gli in the chronic pancreatic tissue detected by qPCR assay and confirmed by western blot assay. The activation of pancreatic satellet cells was also inhibited by sulindac as measured by the activity of α-smooth muscle actin (α-SMA) in the pancreatic tissue of chronic pancreatitis. Conclusions Sulindac is a promising reagent for the treatment of chronic pancreatitis via inhibition of inflammatory cell infiltration and stromal fibrosis, the inhibitory effect of sulindac on chronic pancreatitis may through targeting the activation ERK/MAPK signaling pathway. PMID:22920325

  20. The effect of sulindac, a non-steroidal anti-inflammatory drug, attenuates inflammation and fibrosis in a mouse model of chronic pancreatitis.

    PubMed

    Bai, Han; Chen, Xiaokai; Zhang, Lin; Dou, Xiaoguang

    2012-08-24

    Chronic pancreatitis is characterized by progressive fibrosis, pain and loss of exocrine and endocrine functions. The long-standing chronic pancreatitis and its associated pancreatic fibrosis are the most common pathogenic events involved in human pancreatic carcinogenesis, but the therapeutic strategies to chronic pancreatitis and the chemoprevention of pancreatic carcinogenesis are very limited. We investigated the effect of sulindac, a non-steroidal anti-inflammatory drug (NSAID), on inhibition of chronic pancreatitis in a caerulein induced chronic pancreatitis mouse model. Sulindac significantly reduced the severity of chronic pancreatitis including the extent of acini loss, inflammatory cell infiltration and stromal fibrosis. The protein expression of phosphorylation of MEK/ERK was inhibited in the chronic pancreatic tissues by sulindac treatment as measured by Western blot assay. The levels of inflammatory cytokines including TNF-α and MCP-1 were also significantly decreased with sulindac treatment, as well as the expression of TGF-β, PDGF-β, SHH and Gli in the chronic pancreatic tissue detected by qPCR assay and confirmed by western blot assay. The activation of pancreatic satellet cells was also inhibited by sulindac as measured by the activity of α-smooth muscle actin (α-SMA) in the pancreatic tissue of chronic pancreatitis. Sulindac is a promising reagent for the treatment of chronic pancreatitis via inhibition of inflammatory cell infiltration and stromal fibrosis, the inhibitory effect of sulindac on chronic pancreatitis may through targeting the activation ERK/MAPK signaling pathway.

  1. A Combination of Sulindac and Antimicrobial Eradication of H. pylori Prevents Progression of Gastric Cancer in Hypergastrinemic INS-GAS Mice

    PubMed Central

    Lee, Chung-Wei; Rickman, Barry; Rogers, Arlin B.; Muthupalani, Sureshkumar; Takaishi, Shigeo; Yang, Peiying; Wang, Timothy C.; Fox, James G.

    2009-01-01

    Helicobacter pylori infection causes severe dysplasia manifested as gastrointestinal intraepithelial neoplasia (GIN) after 28 weeks post H. pylori infection (WPI) in cancer-prone, hypergastrinemic male INS-GAS mice. We examined the efficacy of the NSAID sulindac (400 ppm in drinking water) alone, the CCK2/gastrin receptor antagonist YM022 (45 mg/kg/week) alone, and sulindac or YM022 combined with H. pylori eradication therapy to prevent H. pylori-associated gastric cancer in male INS-GAS mice. Treatments started at 22 WPI, and mice were euthanized at 28 WPI. In uninfected mice, all treatments significantly delayed development of spontaneous GIN (p<0.05). In H. pylori-infected mice, sulindac alone or YM022 alone had no protective effect on H. pylori-associated GIN. Importantly, sulindac exacerbated the severity of H. pylori-associated gastritis despite decreased gastric PEG2 levels. However, sulindac combined with H. pylori antimicrobial eradication reduced the incidence of GIN (p<0.05), whereas YM022 combined with antimicrobial eradication did not reduce GIN. In infected mice, sulindac or YM022 treatment did not alter gastric expression of the proinflammatory cytokines Ifn-γ and Tnf-α and mucosal cell proliferation. Sulindac or YM022 combined with antimicrobial eradication down-regulated mRNA levels of Ifnγ and Tnfα, and mucosal cell proliferation (p<0.05). We conclude that sulindac enhances H. pylori gastritis and may promote inflammation-mediated gastric carcinogenesis. The combination of sulindac and antimicrobial H. pylori eradication was beneficial for reducing proinflammatory cytokine mRNA in the stomach and preventing progression from severe dysplasia to gastric cancer in H. pylori-infected INS-GAS mice. PMID:19826057

  2. Sulindac sulfide induces autophagic death in gastric epithelial cells via survivin down-regulation: a mechanism of NSAIDs-induced gastric injury.

    PubMed

    Chiou, Shiun-Kwei; Hoa, Neil; Hodges, Amy

    2011-06-01

    Sulindac sulfide, a nonsteroidal anti-inflammatory drug (NSAID), has anti-tumorigenic and anti-inflammatory activities, but causes gastric mucosal damage. NSAIDs cause gastric injury in part by down-regulation of Survivin, an apoptosis inhibitor, resulting in apoptosis induction. Autophagy is a process that promotes cellular health by destroying unwanted cellular materials. Excessive autophagy induction could lead to a non-apoptotic cell death (autophagic cell death). The present study showed that sulindac sulfide at a physiological concentration also induces autophagic death in human gastric epithelial AGS and rat gastric epithelial RGM-1 cells, and that Survivin down-regulation is a mechanism involved: Sulindac sulfide treatment increased LC3b-II and APG7 levels and cytosolic vacuole formation, indications of autophagy induction, in AGS and RGM-1 cells. Sulindac sulfide treatment induced AGS and RGM-1 cell death, which was significantly reduced by pretreatment with the autophagy inhibitors 3-methyladenine and chloroquine, indicating that sulindac sulfide induced autophagic cell death. Stable overexpression of Survivin in RGM-1 cells did not inhibit the induction of LC3b-II levels or vacuole formation by sulindac sulfide, but significantly reduced the resulting cell death, suggesting that Survivin may inhibit autophagic cell death downstream of LC3b-II induction and vacuole formation. Indeed, siRNA depletion of LC3b in AGS cells inhibited the down-regulation of Survivin levels and the induction of cell death by sulindac sulfide, confirming that down-regulation of Survivin occurs in the autophagy pathway downstream of LC3b-II induction by sulindac sulfide. Induction of Survivin-dependent autophagic cell death is a novel mechanism by which sulindac sulfide induces gastric mucosal injury. Published by Elsevier Inc.

  3. The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent.

    PubMed

    Xie, Gang; Cheng, Ka-Wing; Huang, Liqun; Rigas, Basil

    2014-09-15

    Phospho-sulindac amide (PSA) is a novel potential anti-cancer and anti-inflammatory agent. Here we report the metabolism of PSA in vitro. PSA was rapidly hydroxylated at its butane-phosphate moiety to form two di-hydroxyl-PSA and four mono-hydroxyl-PSA metabolites in mouse and human liver microsomes. PSA also can be oxidized or reduced at its sulindac moiety to form PSA sulfone and PSA sulfide, respectively. PSA was mono-hydroxylated and cleared more rapidly in mouse liver microsomes than in human liver microsomes. Of eight major human cytochrome P450s (CYPs), CYP3A4 and CYP2D6 exclusively catalyzed the hydroxylation and sulfoxidation reactions of PSA, respectively. We also examined the metabolism of PSA by three major human flavin monooxygenases (FMOs). FMO1, FMO3 and FMO5 were all capable of catalyzing the sulfoxidation (but not hydroxylation) of PSA, with FMO1 being by far the most active isoform. PSA was predominantly sulfoxidized in human kidney microsomes because FMO1 is the dominant isoform in human kidney. PSA (versus sulindac) is a preferred substrate of both CYPs and FMOs, likely because of its greater lipophilicity and masked-COOH group. Ketoconazole (a CYP3A4 inhibitor) and alkaline pH strongly inhibited the hydroxylation of PSA, but moderately suppressed its sulfoxidation in liver microsomes. Together, our results establish the metabolic pathways of PSA, identify the major enzymes mediating its biotransformations and reveal significant inter-species and inter-tissue differences in its metabolism. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent

    PubMed Central

    Xie, Gang; Cheng, Ka-Wing; Huang, Liqun; Rigas, Basil

    2014-01-01

    Phospho-sulindac amide (PSA) is a novel potential anti-cancer and anti-inflammatory agent. Here we report the metabolism of PSA in vitro. PSA was rapidly hydroxylated at its butane-phosphate moiety to form two di-hydroxyl-PSA and four mono-hydroxyl-PSA metabolites in mouse and human liver microsomes. PSA also can be oxidized or reduced at its sulindac moiety to form PSA sulfone and PSA sulfide, respectively. PSA was mono-hydroxylated and cleared more rapidly in mouse liver microsomes than in human liver microsomes. Of eight major human cytochrome P450s (CYPs), CYP3A4 and CYP2D6 exclusively catalyzed the hydroxylation and sulfoxidation reactions of PSA, respectively. We also examined the metabolism of PSA by three major human flavin monooxygenases (FMOs). FMO1, FMO3 and FMO5 were all capable of catalyzing the sulfoxidation (but not hydroxylation) of PSA, with FMO1 being by far the most active isoform. PSA was predominantly sulfoxidized in human kidney microsomes because FMO1 is the dominant isoform in human kidney. PSA (versus sulindac) is a preferred substrate of both CYPs and FMOs, likely because of its greater lipophilicity and masked –COOH group. Ketoconazole (a CYP3A4 inhibitor) and alkaline pH strongly inhibited the hydroxylation of PSA, but moderately suppressed its sulfoxidation in liver microsomes. Together, our results establish the metabolic pathways of PSA, identify the major enzymes mediating its biotransformations and reveal significant inter-species and inter-tissue differences in its metabolism. PMID:25044307

  5. NOSH-sulindac (AVT-18A) is a novel nitric oxide- and hydrogen sulfide-releasing hybrid that is gastrointestinal safe and has potent anti-inflammatory, analgesic, antipyretic, anti-platelet, and anti-cancer properties

    PubMed Central

    Kashfi, Khosrow; Chattopadhyay, Mitali; Kodela, Ravinder

    2015-01-01

    Sulindac is chemopreventive and has utility in patients with familial adenomatous polyposis; however, side effects preclude its long-term use. NOSH-sulindac (AVT-18A) releases nitric oxide and hydrogen sulfide, was designed to be a safer alternative. Here we compare the gastrointestinal safety, anti-inflammatory, analgesic, anti-pyretic, anti-platelet, and anti-cancer properties of sulindac and NOSH-sulindac administered orally to rats at equimolar doses. Gastrointestinal safety: 6 h post-administration, number/size of hemorrhagic lesions in stomachs were counted. Tissue samples were frozen for PGE2, SOD, and MDA determination. Anti-inflammatory: 1 h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 5 h. Anti-pyretic: fever was induced by LPS (ip) an hour before administration of the test drugs, core body temperature was measured hourly for 5 h. Analgesic: time-dependent analgesic effects were evaluated by carrageenan-induced hyperalgesia. Antiplatelet: anti-aggregatory effects were studied on collagen-induced platelet aggregation of human platelet-rich plasma. Anti-cancer: We examined the effects of NOSH-sulindac on the growth properties of 12 human cancer cell lines of six different tissue origins. Both agents reduced PGE2 levels in stomach tissue; however, NOSH-sulindac did not cause any stomach ulcers, whereas sulindac caused significant bleeding. Lipid peroxidation induced by sulindac was higher than that from NOSH-sulindac. SOD activity was significantly lowered by sulindac but increased by NOSH-sulindac. Both agents showed similar anti-inflammatory, analgesic, anti-pyretic, and anti-platelet activities. Sulindac increased plasma TNFα whereas this rise was lower in the NOSH-sulindac-treated animals. NOSH-sulindac inhibited the growth of all cancer cell lines studied, with potencies of 1000- to 9000-fold greater than that of sulindac. NOSH-sulindac inhibited cell proliferation, induced apoptosis, and caused G2/M

  6. NOSH-sulindac (AVT-18A) is a novel nitric oxide- and hydrogen sulfide-releasing hybrid that is gastrointestinal safe and has potent anti-inflammatory, analgesic, antipyretic, anti-platelet, and anti-cancer properties.

    PubMed

    Kashfi, Khosrow; Chattopadhyay, Mitali; Kodela, Ravinder

    2015-12-01

    Sulindac is chemopreventive and has utility in patients with familial adenomatous polyposis; however, side effects preclude its long-term use. NOSH-sulindac (AVT-18A) releases nitric oxide and hydrogen sulfide, was designed to be a safer alternative. Here we compare the gastrointestinal safety, anti-inflammatory, analgesic, anti-pyretic, anti-platelet, and anti-cancer properties of sulindac and NOSH-sulindac administered orally to rats at equimolar doses. Gastrointestinal safety: 6h post-administration, number/size of hemorrhagic lesions in stomachs were counted. Tissue samples were frozen for PGE2, SOD, and MDA determination. Anti-inflammatory: 1h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 5h. Anti-pyretic: fever was induced by LPS (ip) an hour before administration of the test drugs, core body temperature was measured hourly for 5h. Analgesic: time-dependent analgesic effects were evaluated by carrageenan-induced hyperalgesia. Antiplatelet: anti-aggregatory effects were studied on collagen-induced platelet aggregation of human platelet-rich plasma. Anti-cancer: We examined the effects of NOSH-sulindac on the growth properties of 12 human cancer cell lines of six different tissue origins. Both agents reduced PGE2 levels in stomach tissue; however, NOSH-sulindac did not cause any stomach ulcers, whereas sulindac caused significant bleeding. Lipid peroxidation induced by sulindac was higher than that from NOSH-sulindac. SOD activity was significantly lowered by sulindac but increased by NOSH-sulindac. Both agents showed similar anti-inflammatory, analgesic, anti-pyretic, and anti-platelet activities. Sulindac increased plasma TNFα whereas this rise was lower in the NOSH-sulindac-treated animals. NOSH-sulindac inhibited the growth of all cancer cell lines studied, with potencies of 1000- to 9000-fold greater than that of sulindac. NOSH-sulindac inhibited cell proliferation, induced apoptosis, and caused G2/M cell

  7. The influence of polymorphism on the manufacturability and in vitro dissolution of sulindac-containing hard gelatin capsules.

    PubMed

    Guadalupe Sánchez-González, Elizabeth; Yépez-Mulia, Lilian; Jesús Hernández-Abad, Vicente; Jung Cook, Helgi

    2015-05-01

    Drug polymorphism could affect drug product dissolution, manufacturability, stability and bioavailability/bioequivalence. The impact of polymorphism on the manufacturability and in vitro dissolution profiles of sulindac capsules has not been studied yet. To evaluate the impact of polymorphism on the manufacturability and in vitro dissolution of sulindac hard gelatin capsules. Sulindac crystal forms I and II (SLDI and SLDII, respectively) were prepared and characterized. Powder formulations containing one of the polymorphs, lactose and magnesium stearate (at three different levels) were prepared and their flow properties determined. Hard gelatin capsules were filled with the formulations and tested for fill-weight variations. Drug dissolution for SLDI- and SLDII-containing hard gelatin capsules was determined. Differences in flow properties for each polymorph were observed, as well as for their formulations, which in turn affected capsule weight homogeneity. Statistically significant differences in the rate and extent of drug release were observed between SLDI- and SLDII-containing capsules. Formulations containing SLDI showed a better manufacturability and a better dissolution profile than those with SLDII. Sulindac crystalline form I was the best candidate for hard gelatin capsule formulation because of its technological and in vitro dissolution properties.

  8. New use for an old drug: COX‐independent anti‐inflammatory effects of sulindac in models of cystic fibrosis

    PubMed Central

    Rocca, Jérémy; Manin, Sylvie; Hulin, Anne; Aissat, Abdel; Verbecq‐Morlot, Wilfried; Prulière‐Escabasse, Virginie; Wohlhuter‐Haddad, Adeline; Epaud, Ralph; Tarze, Agathe

    2016-01-01

    Background and Purpose Pulmonary disease is the main cause of morbidity and mortality in cystic fibrosis (CF) patients due to exacerbated inflammation. To date, the only anti‐inflammatory drug available to CF patients is high‐dose ibuprofen, which can slow pulmonary disease progression, but whose cyclooxygenase‐dependent digestive adverse effects limit its clinical use. Here we have tested sulindac, another non‐steroidal anti‐inflammatory drug with an undefined anti‐inflammatory effect in CF airway epithelial cells. Experimental Approach Using in vitro and in vivo models, we NF‐κB activity and IL‐8 secretion. In HeLa‐F508del cells, we performed luciferase reporter gene assays in order to measure i) IL‐8 promoter activity, and ii) the activity of synthetic promoter containing NF‐κB responsive elements. We quantified IL‐8 secretion in airway epithelial CFBE cells cultured at an air‐liquid interface and in a mouse model of CF. Key Results Sulindac inhibited the transcriptional activity of NF‐κB and decreased IL‐8 transcription and secretion in TNF‐α stimulated CF cells via a cyclooxygenase‐independent mechanism. This effect was confirmed in vivo in a mouse model of CF induced by intra‐tracheal instillation of LPS, with a significant decrease of the induction of mRNA for MIP‐2, following treatment with sulindac. Conclusion and Implications Overall, sulindac decrease lung inflammation by a mechanism independent of cycolooxygenase. This drug could be beneficially employed in CF. PMID:26894321

  9. Multistage vector delivery of sulindac and silymarin for prevention of colon cancer.

    PubMed

    Scavo, Maria Principia; Gentile, Emanuela; Wolfram, Joy; Gu, Jianhua; Barone, Michele; Evangelopoulos, Michael; Martinez, Jonathan O; Liu, Xuewu; Celia, Christian; Tasciotti, Ennio; Vilar, Eduardo; Shen, Haifa

    2015-12-01

    Familial adenomatous polyposis (FAP) is an inherited condition secondary to germline mutations in the APC gene, thus resulting in the formation of hundreds of colonic adenomas that eventually progress into colon cancer. Surgical removal of the colon remains the only treatment option to avoid malignancy, as long-term exposure to chemopreventive agents such as sulindac (a non-steroidal anti-inflammatory drug) and silymarin (phytoestrogen) is not feasible. Here, we have developed a multistage silicon-based drug delivery platform for sulindac and silymarin that preferentially interacts with colon cancer cells as opposed to normal intestinal mucosa. Preferential binding and internalization of these drugs into colon cancer cells was obtained using a targeting strategy against the protein meprin A, which we demonstrate is overexpressed in human colon cancer cells and in the small intestine of Apc(Min/+) mice. We propose that this delivery system could potentially be used to reduce drug-induced side effects in FAP patients, thus enabling long-term prevention of adenoma formation. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Phospho-sulindac (OXT-922) inhibits the growth of human colon cancer cell lines: a redox/polyamine-dependent effect.

    PubMed

    Huang, Liqun; Zhu, Caihua; Sun, Yu; Xie, Gang; Mackenzie, Gerardo G; Qiao, George; Komninou, Despina; Rigas, Basil

    2010-11-01

    Non-steroidal anti-inflammatory drugs such as sulindac are promising chemoprevention agents against colon cancer, but their weak potency and side effects limit their use for both chemoprevention and chemotherapy. Here, we evaluated the effect of a new sulindac derivative, phospho-sulindac or OXT-922, on the growth of human cancer cell lines and its mechanism of action. OXT-922 inhibited the growth of human cancer cell lines originating from colon, pancreas and breast ~11- to 30-fold more potently than sulindac. This effect was mediated by a strong cytokinetic effect. Compared with control, OXT-922 inhibited cell proliferation by up to 67%, induced apoptosis 4.1-fold over control and blocked the G(1) to S cell cycle phase transition. OXT-922 suppressed the levels of cell cycle regulating proteins, including cyclins D(1) and D(3) and Cyclin-dependent kinases (CDK) 4 and 6. The levels of intracellular reactive oxygen species (ROS), especially those of mitochondrial O₂ⁱ⁻, were markedly elevated (5.5-fold) in response to OXT-922. ROS collapsed the mitochondrial membrane potential and triggered apoptosis, which was largely abrogated by antioxidants. OXT-922 suppressed nuclear factor-kappaB activation and downregulated thioredoxin-1 expression. It also suppressed the production of prostaglandin E(2) and decreased cyclooxygenase-1 expression. Similar to sulindac, OXT-922 enhanced spermidine/spermine N(1)-acetyltransferase activity, reduced the cellular polyamine content and synergized with difluoromethylornithine to inhibit cancer cell proliferation and induce apoptosis. Our results suggest that OXT-922 possesses promising anticancer properties and deserves further evaluation.

  11. Sulindac sulfide inhibits epidermal growth factor-induced phosphorylation of extracellular-regulated kinase 1/2 and Bad in human colon cancer cells.

    PubMed

    Rice, Pamela L; Washington, Michele; Schleman, Shea; Beard, K Scott; Driggers, Linda J; Ahnen, Dennis J

    2003-02-01

    Colorectal cancer is the second leading cause of cancer death in the United States. Nonsteroidal anti-inflammatory drugs including sulindac are promising chemopreventive agents for colorectal cancer. Sulindac and selective cyclooxygenase (COX)-2 inhibitors cause regression of colonic polyps in familial polyposis patients. Sulindac induces apoptotic cell death in cancer cells in vitro and in vivo. In tumor cells, activation of extracellular-regulated kinase (ERK) 1/2 results in phosphorylation of several ERK1/2 effectors, including the proapoptotic protein Bad. Phosphorylation of Ser112 by ERK1/2 inactivates Bad and protects the tumor cell from apoptosis. Sulindac metabolites and other nonsteroidal anti-inflammatory drugs selectively inhibit ERK1/2 phosphorylation in human colon cancer cells. In this study we show that epidermal growth factor (EGF) strongly induces phosphorylation of ERK1/2 and Bad in HT29 colon cancer cells. EGF-stimulated phosphorylation of ERK and Bad is blocked by pretreatment with U0126, a selective MAP kinase kinase (MKK)1/2 inhibitor. Similarly, pretreatment with sulindac sulfide blocks the ability of EGF to induce ERK1/2 and Bad phosphorylation, but also down-regulates total Bad but not ERK1/2 protein levels. The ability of sulindac to block ERK1/2 signaling by the EGF receptor may account for at least part of its potent growth-inhibitory effects against cancer cells.

  12. Celecoxib and sulindac inhibit TGF-β1-induced epithelial-mesenchymal transition and suppress lung cancer migration and invasion via downregulation of sirtuin 1

    PubMed Central

    Hwang, Ki-Eun; Cho, Kyung-Hwa; Oh, Seon-Hee; Kim, Byoung-Ryun; Jun, Hong-Young; Yoon, Kwon-Ha; Jeong, Eun-Taik; Kim, Hak-Ryul

    2016-01-01

    The non-steroidal anti-inflammatory drugs (NSAIDs) celecoxib and sulindac have been reported to suppress lung cancer migration and invasion. The class III deacetylase sirtuin 1 (SIRT1) possesses both pro- and anticarcinogenic properties. However, its role in inhibition of lung cancer cell epithelial-mesenchymal transition (EMT) by NSAIDs is not clearly known. We attempted to investigate the potential use of NSAIDs as inhibitors of TGF-β1-induced EMT in A549 cells, and the underlying mechanisms of suppression of lung cancer migration and invasion by celecoxib and sulindac. We demonstrated that celecoxib and sulindac were effective in preventing TGF-β1-induced EMT, as indicated by upregulation of the epithelial marker, E-cadherin, and downregulation of mesenchymal markers and transcription factors. Moreover, celecoxib and sulindac could inhibit TGF-β1-enhanced migration and invasion of A549 cells. SIRT1 downregulation enhanced the reversal of TGF-β1-induced EMT by celecoxib or sulindac. In contrast, SIRT1 upregulation promoted TGF-β1-induced EMT. Taken together, these results indicate that celecoxib and sulindac can inhibit TGF-β1-induced EMT and suppress lung cancer cell migration and invasion via downregulation of SIRT1. Our findings implicate overexpressed SIRT1 as a potential therapeutic target to reverse TGF-β1-induced EMT and to prevent lung cancer cell migration and invasion. PMID:27528025

  13. Sulindac Sulfide Induces the Formation of Large Oligomeric Aggregates of the Alzheimer's Disease Amyloid-β Peptide Which Exhibit Reduced Neurotoxicity.

    PubMed

    Prade, Elke; Barucker, Christian; Sarkar, Riddhiman; Althoff-Ospelt, Gerhard; Lopez del Amo, Juan Miguel; Hossain, Shireen; Zhong, Yifei; Multhaup, Gerd; Reif, Bernd

    2016-03-29

    Alzheimer's disease is characterized by deposition of the amyloid β-peptide (Aβ) in brain tissue of affected individuals. In recent years, many potential lead structures have been suggested that can potentially be used for diagnosis and therapy. However, the mode of action of these compounds is so far not understood. Among these small molecules, the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide received a lot of attention. In this manuscript, we characterize the interaction between the monomeric Aβ peptide and the NSAID sulindac sulfide. We find that sulindac sulfide efficiently depletes the pool of toxic oligomers by enhancing the rate of fibril formation. In vitro, sulindac sulfide forms colloidal particles which catalyze the formation of fibrils. Aggregation is immediate, presumably by perturbing the supersaturated Aβ solution. We find that sulindac sulfide induced Aβ aggregates are structurally homogeneous. The C-terminal part of the peptide adopts a β-sheet structure, whereas the N-terminus is disordered. The salt bridge between D23 and K28 is present, similar as in wild type fibril structures. (13)C-(19)F transferred echo double resonance experiments suggest that sulindac sulfide colocalizes with the Aβ peptide in the aggregate.

  14. The molecular basis for inhibition of sulindac and its metabolites towards human aldose reductase.

    PubMed

    Zheng, Xuehua; Zhang, Liping; Zhai, Jing; Chen, Yunyun; Luo, Haibin; Hu, Xiaopeng

    2012-01-02

    Sulindac (SLD) exhibits both the highest inhibitory activity towards human aldose reductase (AR) among popular non-steroidal anti-inflammatory drugs and clear beneficial clinical effects on Type 2 diabetes. However, the molecular basis for these properties is unclear. Here, we report that SLD and its pharmacologically active/inactive metabolites, SLD sulfide and SLD sulfone, are equally effective as un-competitive inhibitors of AR in vitro. Crystallographic analysis reveals that π-π stacking favored by the distinct scaffold of SLDs is pivotal to their high AR inhibitory activities. These results also suggest that SLD sulfone could be a potent lead compound for AR inhibition in vivo. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  15. Curcumin enhances the lung cancer chemopreventive efficacy of phospho-sulindac by improving its pharmacokinetics

    PubMed Central

    CHENG, KA-WING; WONG, CHI C.; MATTHEOLABAKIS, GEORGE; XIE, GANG; HUANG, LIQUN; RIGAS, BASIL

    2013-01-01

    Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tween-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse subcutaneous xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p<0.05) was significantly more efficacious than PS plus micelle curcumin (30%) or PS (25%) or curcumin alone (no effect). Consistent with the improved pharmacokinetics, the combination treatment group had higher levels of PS and its metabolites in the xenografts compared to PS alone. Our results show that curcumin substantially improves the pharmacokinetics of PS leading to synergistic inhibition of the growth of human lung cancer xenografts, representing a promising drug combination. PMID:23807084

  16. Curcumin enhances the lung cancer chemopreventive efficacy of phospho-sulindac by improving its pharmacokinetics.

    PubMed

    Cheng, Ka-Wing; Wong, Chi C; Mattheolabakis, George; Xie, Gang; Huang, Liqun; Rigas, Basil

    2013-09-01

    Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tween-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse subcutaneous xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p<0.05) was significantly more efficacious than PS plus micelle curcumin (30%) or PS (25%) or curcumin alone (no effect). Consistent with the improved pharmacokinetics, the combination treatment group had higher levels of PS and its metabolites in the xenografts compared to PS alone. Our results show that curcumin substantially improves the pharmacokinetics of PS leading to synergistic inhibition of the growth of human lung cancer xenografts, representing a promising drug combination.

  17. Erlotinib, erlotinib-sulindac versus placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer.

    PubMed

    Gross, Neil D; Bauman, Julie E; Gooding, William E; Denq, William; Thomas, Sufi M; Wang, Lin; Chiosea, Simion; Hood, Brian L; Flint, Melanie S; Sun, Mai; Conrads, Thomas P; Ferris, Robert L; Johnson, Jonas T; Kim, Seungwon; Argiris, Athanassios; Wirth, Lori; Nikiforova, Marina N; Siegfried, Jill M; Grandis, Jennifer R

    2014-06-15

    The EGF receptor (EGFR) and COX2 pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic antitumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a nonselective COX inhibitor; versus placebo. Patients with untreated, operable stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after seven to 14 days of treatment. The primary endpoint was change in Ki67 proliferation index. We hypothesized an ordering effect in Ki67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX2 signaling intermediates. From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, P = 0.04). Wilcoxon pairwise contrasts confirmed greater Ki67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo, P = 0.043; erlotinib vs. placebo, P = 0.027). There was a significant trend in ordering of Ki67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, P = 0.0185). Low baseline pSrc correlated with greater Ki67 reduction (R(2) = 0.312, P = 0.024). Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target. ©2014 American Association for Cancer Research.

  18. Sulindac-derived RXRα modulators inhibit cancer cell growth by binding to a novel site of RXRα

    PubMed Central

    Chen, Liqun; Wang, Zhi-Gang; Aleshin, Alexander; Chen, Fan; Chen, Jiebo; Jiang, Fuquan; Alitongbieke, Gulimiran; Zeng, Zhiping; Ma, Yue; Huang, Mingfeng; Zhou, Hu; Cadwell, Gregory; Zheng, Jian-Feng; Huang, Pei-Qiang; Liddington, Robert; Zhang, Xiao-kun; Su, Ying

    2014-01-01

    Summary Retinoid X receptor-alpha (RXRα), an intriguing and unique drug target, can serve as an intracellular target mediating the anti-cancer effects of certain non-steroidal anti-inflammatory drugs (NSAIDs), including Sulindac. We report the synthesis and characterization of two new Sulindac analogs, K-8008 and K-8012, which exert improved anti-cancer activities over Sulindac in a RXRα- dependent manner. The new analogs inhibit the interaction of the N-terminally truncated RXRα (tRXRα) with the p85α subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRα ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRα LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as new tRXRα modulators and define a new binding mechanism for regulating the nongenomic action of tRXRα. PMID:24704507

  19. Marmoset Flavin-Containing Monooxygenase 3 in the Liver Is a Major Benzydamine and Sulindac Sulfide Oxygenase.

    PubMed

    Uehara, Shotaro; Shimizu, Makiko; Uno, Yasuhiro; Inoue, Takashi; Sasaki, Erika; Yamazaki, Hiroshi

    2017-05-01

    Common marmosets (Callithrix jacchus) are potentially primate models for preclinical drug metabolism studies because there are similarities in the molecular characteristics of cytochrome P450 enzymes between this species and humans. However, characterization of non-cytochrome P450 enzymes has not been clarified in marmosets. Here, we report characterization of flavin-containing monooxygenases FMO1-FMO5 identified in marmoset tissues. Marmoset FMO forms shared high amino acid sequence identities (93%-95%) and phylogenetic closeness with human homologous FMO forms. FMO1 and FMO3 mRNA were abundantly expressed in the liver and kidneys among five marmoset tissues examined, where FMO3 protein was detected by immunoblotting. FMO inhibition assays using preheated tissue microsomes indicated that benzydamine N-oxygenation and sulindac sulfide S-oxygenation in the marmoset liver was mainly catalyzed by FMO3, the major hepatic FMO. Marmoset FMO3 protein heterologously expressed in Escherichia coli effectively catalyzed benzydamine N-oxygenation and sulindac sulfide S-oxygenation comparable to marmoset liver microsomes. These results indicate that the FMO3 enzyme expressed in marmoset livers mainly metabolizes benzydamine and sulindac sulfide (typical human FMO substrates), suggesting its importance for FMO-dependent drug metabolism in marmosets. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  20. Topical phospho-sulindac (OXT-328) is effective in the treatment of non-melanoma skin cancer.

    PubMed

    Cheng, Ka Wing; Mattheolabakis, George; Wong, Chi C; Ouyang, Nengtai; Huang, Liqun; Constantinides, Panayiotis P; Rigas, Basil

    2012-10-01

    Phospho-sulindac (P-S, OXT-328), a novel sulindac derivative, has shown superior anticancer efficacy and safety compared to sulindac. In this study, we investigated the efficacy of topical P-S hydrogel in the treatment of non-melanoma skin cancer in preclinical models. P-S is a potent inhibitor of A431 epidermoid carcinoma in vitro and achieves this effect by inhibiting cell proliferation and inducing apoptosis. The anticancer efficacy of topical and oral P-S was further evaluated in mice bearing A431 intradermal xenografts. Compared to the controls, topical P-S hydrogel inhibited the A431 xenografts by 70.5% (p<0.01), while oral P-S inhibited it by 43.4% (p<0.05), being significantly less effective than topical P-S (p=0.017). Topical P-S hydrogel generated significant levels (>500 nmol/g tumor tissue) of intact P-S in the tumors, accounting for 92.5% of the total metabolites in the A431 xenografts. This local delivery of high levels of intact P-S to the A431 xenografts is an important contributor to the potent activity of topical P-S and no local or systemic side effects were noted in the treatment group. Thus, topical P-S is a promising treatment modality against non-melanoma skin cancer and merits further evaluation.

  1. Sulindac reverses aberrant expression and localization of beta-catenin in papillary thyroid cancer cells with the BRAFV600E mutation.

    PubMed

    Cho, Nancy L; Lin, Chi-Iou; Whang, Edward E; Carothers, Adelaide M; Moore, Francis D; Ruan, Daniel T

    2010-06-01

    Activation of the Wnt/beta-catenin signaling pathway is implicated in thyroid tumorigenesis, and up to 90% of papillary thyroid cancer (PTC) demonstrate aberrant expression of beta-catenin. Nonsteroidal antiinflammatory drugs reverse aberrant beta-catenin expression and localization in colon cancer. In this study, we tested the hypothesis that the nonsteroidal antiinflammatory drug sulindac would reverse aberrant beta-catenin activity in thyroid cancer cells. beta-catenin protein levels were determined in thyroidectomy specimens from six consecutive patients and in three different thyroid cancer cells lines (8505-C, KTC-1, and TPC-1) by immunoblotting. Cells of 8505-C and KTC-1 harbor the BRAF(V600E) mutation, and TPC-1 has the RET/PTC rearrangement. All cell lines were treated with sulindac (100 microM for up to 72 hours). Protein levels of c-myc and cyclin D1 were detected by immunoblotting, and beta-catenin localization was determined by immunocytochemistry in the PTC cell lines. PCCL3 rat thyroid cells that conditionally overexpress either BRAF(V600E) or RET/PTC were also treated with sulindac. All PTC specimens and cell lines expressed high levels of beta-catenin protein and displayed aberrant nuclear and cytoplasmic localization of beta-catenin. Exposure to sulindac for 48 hours reduced beta-catenin expression in 8505-C and KTC-1 cells, but not in TPC-1 cells. Further, sulindac treatment reduced c-myc and cyclin D1 levels in 8505-C and KTC-1 cells, but had no effect in TPC-1 cells. Immunocytochemistry demonstrated that sulindac treatment redistributed beta-catenin from the nucleus to the membrane in 8505-C and KTC-1 cells. However, sulindac did not affect beta-catenin localization in TPC-1 cells. Finally, sulindac was effective in decreasing beta-catenin expression and cellular proliferation in BRAF(V600E)-overexpressing cells, but not in RET/PTC3-overexpressing cells. Taken together, our findings demonstrate that sulindac treatment reverses beta

  2. Levels of rectal mucosal polyamines and prostaglandin E2 predict ability of DFMO and sulindac to prevent colorectal adenoma

    PubMed Central

    Thompson, Patricia A.; Wertheim, Betsy C.; Zell, Jason A.; Chen, Wen-Pin; McLaren, Christine E.; LaFleur, Bonnie J.; Meyskens, Frank L.; Gerner, Eugene W.

    2011-01-01

    Background and Aims The combination of polyamine and prostaglandin E2 (PGE2) synthesis inhibitors reduced the risk of colorectal adenoma (CRA) by 70% in patients that received polypectomies. We studied the effects of the combination of difluoromethylornithine (DFMO) and sulindac on biomarkers and investigated factors that might modify efficacy of these drugs. Methods We analyzed rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment regimens, and risk of CRA in 267 participants of a phase IIb/III trial of DFMO/sulindac for prevention of CRA recurrence. Results In the group that received DFMO/sulindac, the spermidine to spermine ratio (Spd:Spm) in rectal mucosa decreased between baseline and the 12- and 36-month follow-up examinations (0.30, 0.23, and 0.24, respectively; P < 0.001 for both comparisons to baseline). Putrescine levels decreased between baseline and 12 months (0.46 to 0.15 nmol/mg protein; P < 0.001) but rebounded between 12 and 36 months (0.15 to 0.36 nmol/mg protein; P = 0.001). PGE2 levels did not change, though aspirin use was significantly associated with lower baseline levels of PGE2. There were no significant associations between changes in biomarker levels and efficacy. However, drug efficacy was greatest in subjects with low Spd:Spm and high levels of PGE2 at baseline. None of these subjects developed CRA, whereas 39% of the patients that received placebo did develop CRA (P < 0.001). Efficacy was lowest in subjects with high Spd:Spm and low levels of PGE2 at baseline; 28% developed CRA, compared with 36% of the patients given placebo (P = 0.563). Conclusions A combination of DFMO and sulindac significantly suppressed production of rectal mucosal polyamines but not PGE2. There was no relationship between changes in biomarker levels and response. However, baseline biomarker levels modified the effect of DFMO/sulindac for CRA prevention. PMID:20538001

  3. Sulindac overdose

    MedlinePlus

    ... measure and monitor the person's vital signs, including temperature, pulse, breathing rate, and blood pressure. Symptoms will be treated as appropriate. The person may receive: Activated charcoal Airway support, including oxygen, breathing tube through the ...

  4. Inhibitory effect of herbal remedy PERVIVO and anti-inflammatory drug sulindac on L-1 sarcoma tumor growth and tumor angiogenesis in Balb/c mice.

    PubMed

    Skopiński, P; Bałan, B J; Kocik, J; Zdanowski, R; Lewicki, S; Niemcewicz, M; Gawrychowski, K; Skopińska-Różewska, E; Stankiewicz, W

    2013-01-01

    Anticancer activity of many herbs was observed for hundreds of years. They act as modifiers of biologic response, and their effectiveness may be increased by combining multiple herbal extracts . PERVIVO, traditional digestive herbal remedy, contains some of them, and we previously described its antiangiogenic activity. Numerous studies documented anticancer effects of nonsteroidal anti-inflammatory drugs. We were the first to show that sulindac and its metabolites inhibit angiogenesis. In the present paper the combined in vivo effect of multicomponent herbal remedy PERVIVO and nonsteroidal anti-inflammatory drug sulindac on tumor growth, tumor angiogenesis, and tumor volume in Balb/c mice was studied. These effects were checked after grafting cells collected from syngeneic sarcoma L-1 tumors into mice skin. The strongest inhibitory effect was observed in experimental groups treated with PERVIVO and sulindac together. The results of our investigation showed that combined effect of examined drugs may be the best way to get the strongest antiangiogenic and antitumor effect.

  5. Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/β-catenin/cyclin D1 signaling pathway in rats

    PubMed Central

    Suh, Nanjoo; Reddy, Bandaru S.; DeCastro, Andrew; Paul, Shiby; Lee, Hong Jin; Smolarek, Amanda K.; So, Jae Young; Simi, Barbara; Wang, Chung Xiou; Janakiram, Naveena B.; Steele, Vernon; Rao, Chinthalapally V.

    2011-01-01

    Evidence supports the protective role of non-steroidal anti-inflammatory drugs (NSAIDs) and statins against colon cancer. Experiments were designed to evaluate the efficacies atorvastatin and NSAIDs administered individually and in combination against colon tumor formation. F344 rats were fed AIN-76A diet and colon tumors were induced with azoxymethane (AOM). One week after the second AOM-treatment groups of rats were fed diets containing atorvastatin (200 ppm), sulindac (100 ppm) or naproxen (150 ppm), or their combinations with low-dose atorvastatin (100 ppm) for 45 weeks. Administration of atorvastatin at 200 ppm significantly suppressed both adenocarcinoma incidence (52% reduction, p=0.005) and multiplicity (58% reduction, p=0.008). Most importantly, colon tumor multiplicities were profoundly decreased (80–85% reduction, p<0.0001) when given low-dose atorvastatin with either sulindac or naproxen. Also, a significant inhibition of colon tumor incidence was observed when given a low-dose atorvastatin with either sulindac (p=0.001) or naproxen (p =0.0005). Proliferation markers, proliferating cell nuclear antigen, cyclin D1 and β-catenin in tumors of rats exposed to sulindac, naproxen, atorvastatin, and/or combinations showed a significant suppression. Importantly, colon adenocarcinomas from atorvastatin and NSAIDs fed animals showed reduced key inflammatory markers, inducible nitric oxide synthase and cyclooxygenase-2, phospho-p65, as well as inflammatory cytokines, TNF-α, IL-1β, and IL-4. Overall, this is the first report on the combination treatment using low-dose atorvastatin with either low dose sulindac or naproxen, which greatly suppress the colon adenocarcinoma incidence and multiplicity. Our results suggest that low-dose atorvastatin with sulindac or naproxen might potentially be useful combinations for colon cancer prevention in humans. PMID:21764859

  6. Suppression of growth arrest and DNA damage-inducible 45alpha expression confers resistance to sulindac and indomethacin-induced gastric mucosal injury.

    PubMed

    Chiou, Shiun-Kwei; Hodges, Amy; Hoa, Neil

    2010-09-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac and indomethacin are a major cause of gastric erosions and ulcers. Induction of apoptosis by NSAIDs is an important mechanism involved. Understanding how NSAIDs affect genes that regulate apoptosis is useful for designing therapeutic or preventive strategies and for evaluating the efficacy of safer drugs being developed. We investigated whether growth arrest and DNA damage-inducible 45alpha (GADD45alpha), a stress signal response gene involved in regulation of DNA repair and induction of apoptosis, plays a part in NSAID-induced gastric mucosal injury and apoptosis in vivo in mice and in vitro in cultured human AGS and rat RGM-1 gastric epithelial cells. Intraperitoneal administration of sulindac and indomethacin both resulted in up-regulation of GADD45alpha expression and induction of significant injury and apoptosis in gastric mucosa of wild-type mice. GADD45alpha(-/-) mice were markedly more resistant to both sulindac- and indomethacin-induced gastric mucosal injury and apoptosis than wild-type mice. Sulindac sulfide and indomethacin treatments also concentration-dependently increased GADD45alpha expression and apoptosis in AGS and RGM-1 cells. Antisense suppression of GADD45alpha expression significantly reduced sulindac and indomethacin-induced activation of caspase-9 and apoptosis in AGS cells. Pretreatments with exogenous prostaglandins and small interfering RNA suppression of cyclooxygenase (COX)-1 and -2 did not affect up-regulation of GADD45alpha by sulindac sulfide and indomethacin in AGS cells. These findings indicate that GADD45alpha up-regulation is a COX-independent mechanism that is required for induction of severe gastric mucosal apoptosis and injury by NSAIDs, probably via a capase-9-dependent pathway of programmed cell death.

  7. Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/β-catenin/cyclin D1 signaling pathway in rats.

    PubMed

    Suh, Nanjoo; Reddy, Bandaru S; DeCastro, Andrew; Paul, Shiby; Lee, Hong Jin; Smolarek, Amanda K; So, Jae Young; Simi, Barbara; Wang, Chung Xiou; Janakiram, Naveena B; Steele, Vernon; Rao, Chinthalapally V

    2011-11-01

    Evidence supports the protective role of nonsteroidal anti-inflammatory drugs (NSAID) and statins against colon cancer. Experiments were designed to evaluate the efficacies atorvastatin and NSAIDs administered individually and in combination against colon tumor formation. F344 rats were fed AIN-76A diet, and colon tumors were induced with azoxymethane. One week after the second azoxymethane treatment, groups of rats were fed diets containing atorvastatin (200 ppm), sulindac (100 ppm), naproxen (150 ppm), or their combinations with low-dose atorvastatin (100 ppm) for 45 weeks. Administration of atorvastatin at 200 ppm significantly suppressed both adenocarcinoma incidence (52% reduction, P = 0.005) and multiplicity (58% reduction, P = 0.008). Most importantly, colon tumor multiplicities were profoundly decreased (80%-85% reduction, P < 0.0001) when given low-dose atorvastatin with either sulindac or naproxen. Also, a significant inhibition of colon tumor incidence was observed when given a low-dose atorvastatin with either sulindac (P = 0.001) or naproxen (P = 0.0005). Proliferation markers, proliferating cell nuclear antigen, cyclin D1, and β-catenin in tumors of rats exposed to sulindac, naproxen, atorvastatin, and/or combinations showed a significant suppression. Importantly, colon adenocarcinomas from atorvastatin and NSAIDs fed animals showed reduced key inflammatory markers, inducible nitric oxide synthase and COX-2, phospho-p65, as well as inflammatory cytokines, TNF-α, interleukin (IL)-1β, and IL-4. Overall, this is the first report on the combination treatment using low-dose atorvastatin with either low-dose sulindac or naproxen, which greatly suppress the colon adenocarcinoma incidence and multiplicity. Our results suggest that low-dose atorvastatin with sulindac or naproxen might potentially be useful combinations for colon cancer prevention in humans.

  8. Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2′-Des-methyl-sulindac Sulfide Scaffold

    PubMed Central

    2012-01-01

    Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2′-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents. PMID:22263894

  9. Cyclooxygenase-1-selective inhibitors based on the (E)-2'-des-methyl-sulindac sulfide scaffold.

    PubMed

    Liedtke, Andy J; Crews, Brenda C; Daniel, Cristina M; Blobaum, Anna L; Kingsley, Philip J; Ghebreselasie, Kebreab; Marnett, Lawrence J

    2012-03-08

    Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2'-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.

  10. Immunochemical identification of mouse hepatic protein adducts derived from the nonsteroidal anti-inflammatory drugs diclofenac, sulindac, and ibuprofen.

    PubMed

    Wade, L T; Kenna, J G; Caldwell, J

    1997-05-01

    Reactive metabolite-modified hepatic protein adducts have been proposed to play important roles in the mechanism(s) of hepatotoxicity of nonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, immunochemical techniques have been used to compare the patterns of drug-protein adducts expressed in livers of mice given single doses of one or other of three different NSAIDs. These were diclofenac and sulindac, which are widely used but potentially hepatotoxic drugs, and ibuprofen, which is considered to be nonhepatotoxic. Specific polyclonal antisera were produced by immunization of rabbits with conjugates prepared by coupling each of the NSAIDs to the carrier protein keyhole limpet hemocyanin. Immunoblotting studies revealed dose-dependent formation of major 110 kDa polypeptide adducts in livers from mice sacrificed 6 h after administration of single doses of either diclofenac (0-300 mg/kg) or sulindac (0-100 mg/kg). Lower levels of several other adducts, of 140 and 200 kDa, were also expressed in livers from these animals. In contrast, livers from mice treated with ibuprofen (0-200 mg/kg) predominantly expressed a 60 kDa adduct and only relatively low levels of a 110 kDa adduct. The various adducts were shown by differential centrifugation to be concentrated in the nuclear fraction of liver homogenates. Those derived from diclofenac and sulindac were further localized, by Percoll density gradient centrifugation, to a subfraction which contained a high activity of the bile canalicular marker enzyme alkaline phosphatase. This suggests that they are concentrated in the bile canalicular domain of hepatocytes. The different patterns of adduct formation raise the possibility that formation of certain NSAID protein adducts, particularly 110 kDa adducts, has toxicological significance.

  11. Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial.

    PubMed

    Samadder, N Jewel; Neklason, Deborah W; Boucher, Kenneth M; Byrne, Kathryn R; Kanth, Priyanka; Samowitz, Wade; Jones, David; Tavtigian, Sean V; Done, Michelle W; Berry, Therese; Jasperson, Kory; Pappas, Lisa; Smith, Laurel; Sample, Danielle; Davis, Rian; Topham, Matthew K; Lynch, Patrick; Strait, Elena; McKinnon, Wendy; Burt, Randall W; Kuwada, Scott K

    Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal polyps and cancer. Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful. To evaluate the effect of a combination of sulindac and erlotinib on duodenal adenoma regression in patients with FAP. Double-blind, randomized, placebo-controlled trial, enrolling 92 participants with FAP, conducted from July 2010 through June 2014 at Huntsman Cancer Institute in Salt Lake City, Utah. Participants with FAP were randomized to sulindac (150 mg) twice daily and erlotinib (75 mg) daily (n = 46) vs placebo (n = 46) for 6 months. The total number and diameter of polyps in the proximal duodenum were mapped at baseline and 6 months. The primary outcome was change in total polyp burden at 6 months. Polyp burden was calculated as the sum of the diameters of polyps. The secondary outcomes were change in total duodenal polyp count, change in duodenal polyp burden or count stratified by genotype and initial polyp burden, and percentage of change from baseline in duodenal polyp burden. Ninety-two participants (mean age, 41 years [range, 24-55]; women, 56 [61%]) were randomized when the trial was stopped by the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87% of participants receiving treatment and 20% of participants receiving placebo (P < .001). Only 2 participants experienced grade 3 adverse events. [table: see text]. Among participants with FAP, the use of sulindac and erlotinib compared with placebo resulted in a lower duodenal polyp burden after 6 months. Adverse events may limit the use of these medications at the doses used in this study. Further research is necessary to evaluate these preliminary findings in a larger study

  12. Synthesis and biological activity of NOSH-naproxen (AVT-219) and NOSH-sulindac (AVT-18A) as potent anti-inflammatory agents with chemotherapeutic potential

    PubMed Central

    Kodela, Ravinder; Chattopadhyay, Mitali; Kashfi, Khosrow

    2013-01-01

    Nitric oxide- (NO) and hydrogen sulfide- (H2S) releasing naproxen (NOSH-naproxen) and NO and H2S-releasing sulindac (NOSH-sulindac) were synthesized and their cell growth inhibitory properties were evaluated in four different human cancer cell lines. These cell lines are of adenomatous (colon, pancreas), epithelial (breast), and lymphocytic (leukemia) origin. Using HT-29 human colon cancer cells, NOSH-naproxen and NOSH-sulindac increased apoptosis, and inhibited proliferation. NOSH-naproxen caused a G0/G1 whereas NOSH-sulindac caused a G2/M block in the cell cycle. Both compounds exhibited significant anti-inflammatory properties, using the carrageenan rat paw edema model. Reconstitution and structure-activity studies representing a fairly close approximation to the intact molecule showed that NOSH-naproxen was approximately 8000-fold more potent than the sum of its parts in inhibiting cell growth. Our data suggest that these compounds merit further investigation as potential anti-cancer agents. PMID:24273639

  13. Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/β-catenin signaling.

    PubMed

    Li, Nan; Xi, Yaguang; Tinsley, Heather N; Gurpinar, Evrim; Gary, Bernard D; Zhu, Bing; Li, Yonghe; Chen, Xi; Keeton, Adam B; Abadi, Ashraf H; Moyer, Mary P; Grizzle, William E; Chang, Wen-Chi; Clapper, Margie L; Piazza, Gary A

    2013-09-01

    Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity for colorectal and other cancers, but toxicity from COX inhibition limits their long-term use for chemoprevention. Previous studies have concluded that the basis for their tumor cell growth inhibitory activity does not require COX inhibition, although the underlying mechanism is poorly understood. Here, we report that the NSAID sulindac sulfide inhibits cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE) activity to increase intracellular cGMP levels and activate cGMP-dependent protein kinase (PKG) at concentrations that inhibit proliferation and induce apoptosis of colon tumor cells. Sulindac sulfide did not activate the cGMP/PKG pathway, nor affect proliferation or apoptosis in normal colonocytes. Knockdown of the cGMP-specific PDE5 isozyme by siRNA and PDE5-specific inhibitors tadalafil and sildenafil also selectively inhibited the growth of colon tumor cells that expressed high levels of PDE5 compared with colonocytes. The mechanism by which sulindac sulfide and the cGMP/PKG pathway inhibits colon tumor cell growth involves the transcriptional suppression of β-catenin to inhibit Wnt/β-catenin T-cell factor transcriptional activity, leading to downregulation of cyclin D1 and survivin. These observations suggest that safer and more efficacious sulindac derivatives can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP-degrading isozymes.

  14. The influence of sulindac on diabetic cardiomyopathy: a non-invasive evaluation by Doppler echocardiography in streptozotocin-induced diabetic rats.

    PubMed

    Krishna, Kota M; Gopal, Gopisetty S; Chalam, Chitrapu R V; Madan, Kalagara; Kumar, Veeravalli K; Prakash, Gomedhikam J; Annapurna, Akula

    2005-08-01

    The aim of the present study was to investigate the cardioprotective activity of sulindac as an aldose reductase inhibitor in the development of cardiomyopathy by non-invasive techniques; M-mode and Doppler echocardiography. Diabetes was induced by streptozotocin (45 mg/kg, iv) in the Sprague-Dawley rats. Echocardiography, biochemical and histological studies were carried out in normal control, diabetic untreated, diabetic vehicle (sodium carboxy methyl cellulose, 1%, po) and sulindac (6 mg/kg and 20 mg/kg, po) treated animals at varying time intervals. In the diabetic untreated and vehicle treated rats at 12 weeks after induction of diabetes, there was a significant decrease in the E-wave, an increase in the A-wave and corresponding decrease in the E/A ratio was observed. Significant decrease in the Eat was found after 12 weeks (P < 0.05). Whereas systolic function variables; ejection fraction and fractional shortening were significantly decreased (P < 0.05) after 12 weeks compared to their baseline data. In the sulindac treated animals, there were no significant alterations in the systolic and diastolic parameters were found throughout the study period. Myocardial fructose levels were significantly increased in the diabetic untreated animals compared to normal control rats (P < 0.05), whereas these were significantly decreased in the sulindac (6 mg/kg and 20 mg/kg) treated animals (301.11+/-37.98, 214.11+/-25.31, vs. 914.88+/-56.01 nmol/g) compared to diabetic vehicle treated group (P < 0.05). Extensive focal ischemic myocyte degeneration was observed in the diabetic untreated and vehicle treated rats, whereas in the sulindac (6 mg/kg) treated rats, minimal necrosis was found, with no evidence of necrosis in sulindac (20 mg/kg) group. Our results show for the first time that sulindac has a cardioprotective activity as this agent prevented the development of left ventricular dysfunction in STZ-induced diabetic rats in the 12-week chronic study.

  15. Phospho-sulindac inhibits pancreatic cancer growth: NFATc1 as a drug resistance candidate.

    PubMed

    Murray, Onika T; Wong, Chi C; Vrankova, Kvetoslava; Rigas, Basil

    2014-02-01

    Phospho-sulindac (P-S), a promising anticancer agent, is efficacious in pre-clinical models of human cancer and is apparently safe. Here, we studied the effect of P-S on pancreatic cancer growth. We found that P-S strongly inhibits the growth of human pancreatic cancer cells in vitro, is efficacious in inhibiting the growth of pancreatic xenografts in nude mice, and has an excellent safety profile. Microarray analysis revealed that P-S induced the expression of nuclear factor of activated T-cells, isoform c1 (NFATc1) gene. NFATc1, a calcineurin-responsive transcription factor associated with aggressive pancreatic cancer. The role of increased NFATc1 expression on the growth inhibitory effect of P-S on cancer growth was evaluated by silencing or by overexpressing it both in vitro and in vivo. We found that when the expression of NFATc1 was abrogated by RNAi, pancreatic cancer cells were more responsive to treatment with P-S. Conversely, overexpressing the NFATc1 gene made the pancreatic cancer cells less responsive to treatment with P-S. NFATc1 likely mediates drug resistance to P-S and is an unfavorable prognostic factor that predicts poor tumor response. We also demonstrated that NFATc1-mediated resistance can be overcome by cyclosporin A (CsA), an NFAT inhibitor, and that the combination of P-S and CsA synergistically inhibited pancreatic cancer cell growth. In conclusion, our preclinical data establish P-S as an efficacious drug for pancreatic cancer in preclinical models, which merits further evaluation.

  16. Optimisation and validation of a fast HPLC method for the quantification of sulindac and its related impurities.

    PubMed

    Krier, Fabrice; Brion, Michaël; Debrus, Benjamin; Lebrun, Pierre; Driesen, Aurélie; Ziemons, Eric; Evrard, Brigitte; Hubert, Philippe

    2011-03-25

    The European Pharmacopoeia describes a liquid chromatography (LC) method for the quantification of sulindac, using a quaternary mobile phase including chloroform and with a rather long run time. In the present study, a new method using a short sub-2 μm column, which can be used on a classical HPLC system, was developed. The new LC conditions (without chloroform) were optimised by means of a new methodology based on design of experiments in order to obtain an optimal separation. Four factors were studied: the duration of the initial isocratic step, the percentage of organic modifier at the beginning of the gradient, the percentage of organic modifier at the end of the gradient and the gradient time. The optimal condition allows the separation of sulindac and of its 3 related impurities in 6 min instead of 18 min. Finally, the method was successfully validated using an accuracy profile approach in order to demonstrate its ability to accurately quantify these compounds. Copyright © 2010 Elsevier B.V. All rights reserved.

  17. Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice via suppressing aldo-keto reductase family 1B10 (AKR1B10).

    PubMed

    Li, Haonan; Yang, Allison L; Chung, Yeon Tae; Zhang, Wanying; Liao, Jie; Yang, Guang-Yu

    2013-09-01

    Sulindac has been identified as a competitive inhibitor of aldo-keto reductase 1B10 (AKR1B10), an enzyme that plays a key role in carcinogenesis. AKR1B10 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and exhibits lipid substrate specificity, especially for farnesyl and geranylgeranyl. There have been no studies though showing that the inhibition of PDAC by sulindac is via inhibition of AKR1B10, particularly the metabolism of farnesyl/geranylgeranyl and Kras protein prenylation. To determine the chemopreventive effects of sulindac on pancreatic carcinogenesis, 5-week-old LSL-Kras(G12D)-LSL-Trp53(R172H)-Pdx-1-Cre mice (Pan(kras/p53) mice) were fed an AIN93M diet with or without 200 p.p.m. sulindac (n = 20/group). Kaplan-Meier survival analysis showed that average animal survival in Pan(kras/p53) mice was 143.7 ± 8.8 days, and average survival with sulindac was increased to 168.0 ± 8.8 days (P < 0.005). Histopathological analyses revealed that 90% of mice developed PDAC, 10% with metastasis to the liver and lymph nodes. With sulindac, the incidence of PDAC was reduced to 56% (P < 0.01) and only one mouse had lymph node metastasis. Immunochemical analysis showed that sulindac significantly decreased Ki-67-labeled cell proliferation and markedly reduced the expression of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Raf and mitogen-activated protein kinase kinase 1 and 2. In in vitro experiments with PDAC cells from Pan(kras/p53) mice, sulindac exhibited dose-dependent inhibition of AKR1B10 activity. By silencing AKR1B10 expression through small interfering RNA or by sulindac treatment, these in vitro models showed a reduction in Kras and human DNA-J homolog 2 protein prenylation, and downregulation of phosphorylated C-raf, ERK1/2 and MEK1/2 expression. Our results demonstrate that sulindac inhibits pancreatic carcinogenesis by the inhibition of Kras protein prenylation by targeting AKR1B10.

  18. Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice via suppressing aldo-keto reductase family 1B10 (AKR1B10)

    PubMed Central

    Li, Haonan; Yang, Allison L.; Yang, Guang-Yu

    2013-01-01

    Sulindac has been identified as a competitive inhibitor of aldo-keto reductase 1B10 (AKR1B10), an enzyme that plays a key role in carcinogenesis. AKR1B10 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and exhibits lipid substrate specificity, especially for farnesyl and geranylgeranyl. There have been no studies though showing that the inhibition of PDAC by sulindac is via inhibition of AKR1B10, particularly the metabolism of farnesyl/geranylgeranyl and Kras protein prenylation. To determine the chemopreventive effects of sulindac on pancreatic carcinogenesis, 5-week-old LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice (Pankras/p53 mice) were fed an AIN93M diet with or without 200 p.p.m. sulindac (n = 20/group). Kaplan–Meier survival analysis showed that average animal survival in Pankras/p53 mice was 143.7±8.8 days, and average survival with sulindac was increased to 168.0±8.8 days (P < 0.005). Histopathological analyses revealed that 90% of mice developed PDAC, 10% with metastasis to the liver and lymph nodes. With sulindac, the incidence of PDAC was reduced to 56% (P < 0.01) and only one mouse had lymph node metastasis. Immunochemical analysis showed that sulindac significantly decreased Ki-67-labeled cell proliferation and markedly reduced the expression of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Raf and mitogen-activated protein kinase kinase 1 and 2. In in vitro experiments with PDAC cells from Pankras/p53 mice, sulindac exhibited dose-dependent inhibition of AKR1B10 activity. By silencing AKR1B10 expression through small interfering RNA or by sulindac treatment, these in vitro models showed a reduction in Kras and human DNA-J homolog 2 protein prenylation, and downregulation of phosphorylated C-raf, ERK1/2 and MEK1/2 expression. Our results demonstrate that sulindac inhibits pancreatic carcinogenesis by the inhibition of Kras protein prenylation by targeting AKR1B10. PMID:23689354

  19. Garcinia benzophenones inhibit the growth of human colon cancer cells and synergize with sulindac sulfide and turmeric.

    PubMed

    Einbond, Linda Saxe; Mighty, Jason; Kashiwazaki, Ryota; Figueroa, Mario; Jalees, Filza; Acuna, Ulyana Munoz; Le Gendre, Onica; Foster, David A; Kennelly, Edward J

    2013-12-01

    Previous studies indicate that extracts and purified components from Garcinia species inhibit the growth of human colon cancer cells. Garcinia benzophenones activate the expression of genes in the endoplasmic reticulum and cellular energy stress (mTOR) pathways. This study examines the growth inhibitory and synergistic effects of Garcinia benzophenones, alone or combined with chemopreventive agents, on human colon cancer cells. To find optimal combination treatments, HT29 colon cancer cells were treated with benzophenones alone, or combined with chemopreventive agents, and cell growth measured using the MTT assay. To reveal effects on signaling pathways, we assessed effects of the MEK inhibitor U0126 and the ER IP3 receptor antagonist heparin, as well as effects on the phosphorylation of 4E-BP-1 (mTOR pathway), using Western blot analysis. New and known benzophenones from Garcinia intermedia inhibited the growth of human colon cancer cells; an alcohol extract of Garcinia xanthochymus, as well as purified guttiferones (guttiferone E and xanthochymol), preferentially inhibited the growth of colon cancer versus nonmalignant intestinal epithelial cells. Guttiferone E exhibited synergy with the NSAID sulindac sulfide and xanthochymol, with the spice turmeric. Guttiferone A did not alter phosphorylation of 4E-BP-1, indicating that the mTORC1 pathway is not involved in its action. The effects of xanthochymol were enhanced by U0126, at low doses, and were blocked by heparin, indicating that the MEK pathway is involved, while the ER IP3 receptor is critical for its action. These studies indicate the potential of benzophenones, alone or combined with sulindac sulfide or turmeric, to prevent and treat colon cancer.

  20. Sulindac attenuates valproic acid-induced oxidative stress levels in primary cultured cortical neurons and ameliorates repetitive/stereotypic-like movement disorders in Wistar rats prenatally exposed to valproic acid.

    PubMed

    Zhang, Yinghua; Yang, Cailing; Yuan, Guoyan; Wang, Zhongping; Cui, Weigang; Li, Ruixi

    2015-01-01

    Accumulating evidence suggests that anti-inflammatory agents and antioxidants have neuroprotective properties and may be beneficial in the treatment of neurodevelopental disorders, such as autism. In the present study, the possible neuroprotective properties of sulindac, a non-steroidal anti-inflammatory drug (NSAID), were investigated in vitro using cultured cortical neurons with valproic acid (VPA)-induced neurotoxicity, as well as in vivo through the behavioral analysis of rats prenatally exposed to VPA as a model of autism. VPA induced 4-hydroxynonenal (4-HNE) expression, reactive oxygen species (ROS) generation and decreased cell viability in primary cultured cortical neurons established from timed-pregnant (embryonic day 18) Wistar rat pups. However, co-incubation of the neurons with VPA and sulindac reduced oxidative stress and increased cell viability. The rats were administered an intraperitoneal injection with one of the following: VPA, sulindac, VPA and sulindac, or physiological saline, and their offspring were subjected to the open field test. During the test trials, repetitive/stereotypic-like movements for each rat were recorded and analyzed. The results revealed that treatment with both sulindac and VPA reduced the VPA-induced repetitive/stereotypic-like activity and the sulindac and VPA-treated animals responded better in the open field test compared to the VPA-treated animals. The results from the present study demonstrate that the antioxidant properties of sulindac may prove to be beneficial in the treatment of autism, suggesting that the upregulation of the Wnt/β-catenin signaling pathway disrupts oxidative homeostasis and facilitates susceptibility to autism.

  1. Growth compensatory role of sulindac sulfide-induced thrombospondin-1 linked with ERK1/2 and RhoA GTPase signaling pathways

    PubMed Central

    Moon, Yuseok; Kim, Jeung Il; Yang, Hyun; Eling, Thomas E.

    2009-01-01

    Previously, we reported that non-steroidal anti-inflammatory drugs (NSAIDs) suppress cellular invasion which was mediated by thrombospondin-1 (TSP-1). As the extending study of the previous observation, we investigated the effect of NSAID-induced TSP-1 on the cellular growth and its related signaling transduction of the TSP-1 production. Among diverse NSAIDs, sulindac sulfide was most potent of inducing the human TSP-1 protein expression. Functionally, induced TSP-1 expression was associated with the growth-compensatory action of NSAID. TSP-1 expression was also elevated by mitogenic signals of ERK1/2 and RhoA GTPase pathway which had also growth-promotive capability after sulindac sulfide treatment. These findings suggest the possible mechanism through which tumor cells can survive the chemopreventive action of NSAIDs or the normal epithelium can reconstitute after NSAID-mediated ulceration in a compensatory way. PMID:18261746

  2. Sulindac Sulfide Reverses Aberrant Self-Renewal of Progenitor Cells Induced by the AML-Associated Fusion Proteins PML/RARα and PLZF/RARα

    PubMed Central

    Steinert, Gunnar; Oancea, Claudia; Roos, Jessica; Hagemeyer, Heike; Maier, Thorsten; Ruthardt, Martin; Puccetti, Elena

    2011-01-01

    Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RARα, PLZF/RARα, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RARα and PLZF/RARα or AML-1/ETO activate Wnt signaling by upregulating γ-catenin and β-catenin. In a prospective study, a lower risk of leukemia was observed with aspirin use, which is consistent with numerous studies reporting an inverse association of aspirin with other cancers. Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific. To better investigate whether NSAID treatment is effective, we used Sulindac Sulfide in X-RARα-positive progenitor cell models. Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling. We found that SSi downregulated both β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARα, and it indicates that Sulindac is a valid molecular therapeutic approach that should be further validated using in vivo leukemia models and in clinical settings. PMID:21811629

  3. Suppression of angiogenic activity of sera from diabetic patients with non-proliferative retinopathy by compounds of herbal origin and sulindac sulfone.

    PubMed

    Skopinski, Piotr; Szaflik, Jerzy; Duda-Król, Barbara; Nartowska, Jadwiga; Sommer, Ewa; Chorostowska-Wynimko, Joanna; Demkow, Urszula; Skopinska-Rózewska, Ewa

    2004-10-01

    Angiogenesis, the process of new blood vessel formation, is the key event in the mechanism of several pathological processes including diabetic retinopathy. The physiological control of angiogenesis depends on the balance between stimulatory and inhibitory factors. Therefore, a number of anti-angiogenic approaches has been developed, many of them based on the inhibition of the functional activity of pro-angiogenic factors. The aim of the present study was to compare the anti-angiogenic effectiveness of sulindac sulfone and some herbal compounds in the serum-induced angiogenesis test performed in Balb/c mice. Pooled sera from 35 patients with diabetes type 2 and retinopathy were used as pro-angiogenic stimuli. The strongest inhibitory effect was observed for the sulindac sulfone and ursolic acid in the highest concentration of 200 micro g/ml, as well as for the low-dosage concomitant treatment with 2 micro g/ml of epigallocatechin gallate (EGCG, green tea flavanol), ursolic acid (plant-derived triterpenoid), sulindac sulfone and convalamaroside (steroidal saponin). Combination treatment was significantly more effective than monotherapy with medium (20 micro g/ml) or lowest doses of tested compounds. The present study is the first to demonstrate the potent anti-angiogenic effect of the combination therapy comprising of plant-derived extracts and sulindac sulfone, as tested in the in vivo angiogenesis experimental model with sera of non-proliferative diabetic retinopathy patients used as the pro-angiogenic stimuli. We think that it might be the first step toward application of some of these compounds, in the future, in preventive anti-angiogenic therapy of these patients, as well, as in the treatment of later, proliferative stage of this disease.

  4. Sulindac sulfide reverses aberrant self-renewal of progenitor cells induced by the AML-associated fusion proteins PML/RARα and PLZF/RARα.

    PubMed

    Steinert, Gunnar; Oancea, Claudia; Roos, Jessica; Hagemeyer, Heike; Maier, Thorsten; Ruthardt, Martin; Puccetti, Elena

    2011-01-01

    Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RARα, PLZF/RARα, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RARα and PLZF/RARα or AML-1/ETO activate Wnt signaling by upregulating γ-catenin and β-catenin. In a prospective study, a lower risk of leukemia was observed with aspirin use, which is consistent with numerous studies reporting an inverse association of aspirin with other cancers. Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific. To better investigate whether NSAID treatment is effective, we used Sulindac Sulfide in X-RARα-positive progenitor cell models. Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling. We found that SSi downregulated both β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARα, and it indicates that Sulindac is a valid molecular therapeutic approach that should be further validated using in vivo leukemia models and in clinical settings.

  5. A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy.

    PubMed

    Gurpinar, Evrim; Grizzle, William E; Shacka, John J; Mader, Burton J; Li, Nan; Piazza, Nicholas A; Russo, Suzanne; Keeton, Adam B; Piazza, Gary A

    2013-05-01

    Nonsteroidal anti-inflammatory drugs such as sulindac sulfide have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from COX inhibition limit their use in cancer therapy. We recently described a N,N-dimethylethyl amine derivative of sulindac sulfide, sulindac sulfide amide (SSA), that does not inhibit COX-1 or -2, yet displays potent tumor cell growth-inhibitory activity. Here, we studied the basis for the growth-inhibitory effects of SSA on human lung adenocarcinoma cell lines. SSA potently inhibited the growth of lung tumor cells with IC50 values of 2 to 5 μmol/L compared with 44 to 52 μmol/L for sulindac sulfide. SSA also suppressed DNA synthesis and caused a G0-G1 cell-cycle arrest. SSA-induced cell death was associated with characteristics of autophagy, but significant caspase activation or PARP cleavage was not observed after treatment at its IC50 value. siRNA knockdown of Atg7 attenuated SSA-induced autophagy and cell death, whereas pan-caspase inhibitor ZVAD was not able to rescue viability. SSA treatment also inhibited Akt/mTOR signaling and the expression of downstream proteins that are regulated by this pathway. Overexpression of a constitutively active form of Akt was able to reduce autophagy markers and confer resistance to SSA-induced cell death. Our findings provide evidence that SSA inhibits lung tumor cell growth by a mechanism involving autophagy induction through the suppression of Akt/mTOR signaling. This unique mechanism of action, along with its increased potency and lack of COX inhibition, supports the development of SSA or related analogs for the prevention and/or treatment of lung cancer. ©2013 AACR

  6. Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas

    PubMed Central

    Raj, K P; Zell, J A; Rock, C L; McLaren, C E; Zoumas-Morse, C; Gerner, E W; Meyskens, F L

    2013-01-01

    Background: The polyamine-inhibitory regimen difluoromethylornithine (DFMO)+sulindac has marked efficacy in preventing metachronous colorectal adenomas. Polyamines are synthesised endogenously and obtained from dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial. Methods: Dietary polyamine data were available for 188 of 267 patients completing the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and categorised into two groups: highest (>75–100%) vs the lower three quartiles (0–25, 25–50 and 50–75%). Baseline tissue polyamine concentration and ODC1 genotype were determined. Logistic regression models were used for risk estimation. Results: A significant interaction was detected between dietary polyamine group and treatment with regard to adenoma recurrence (P=0.012). Significant metachronous adenoma risk reduction was observed after DFMO+sulindac treatment in dietary polyamine quartiles 1–3 (risk ratio (RR) 0.19; 95% confidence interval (CI) 0.08–0.42; P<0.0001) but not in quartile 4 (RR 1.51; 95% CI 0.53–4.29; P=0.44). However, a lower number of events in the placebo group within dietary quartile 4 confound the aforementioned risk estimates. Conclusion: These preliminary findings reveal complex relationships between diet and therapeutic prevention, and they support further clinical trial-based investigations where the dietary intervention itself is controlled. PMID:23340449

  7. Structural Mechanism of the Interaction of Alzheimer Disease Aβ Fibrils with the Non-steroidal Anti-inflammatory Drug (NSAID) Sulindac Sulfide.

    PubMed

    Prade, Elke; Bittner, Heiko J; Sarkar, Riddhiman; Lopez Del Amo, Juan Miguel; Althoff-Ospelt, Gerhard; Multhaup, Gerd; Hildebrand, Peter W; Reif, Bernd

    2015-11-27

    Alzheimer disease is the most severe neurodegenerative disease worldwide. In the past years, a plethora of small molecules interfering with amyloid-β (Aβ) aggregation has been reported. However, their mode of interaction with amyloid fibers is not understood. Non-steroidal anti-inflammatory drugs (NSAIDs) are known γ-secretase modulators; they influence Aβ populations. It has been suggested that NSAIDs are pleiotrophic and can interact with more than one pathomechanism. Here we present a magic angle spinning solid-state NMR study demonstrating that the NSAID sulindac sulfide interacts specifically with Alzheimer disease Aβ fibrils. We find that sulindac sulfide does not induce drastic architectural changes in the fibrillar structure but intercalates between the two β-strands of the amyloid fibril and binds to hydrophobic cavities, which are found consistently in all analyzed structures. The characteristic Asp(23)-Lys(28) salt bridge is not affected upon interacting with sulindac sulfide. The primary binding site is located in the vicinity of residue Gly(33), a residue involved in Met(35) oxidation. The results presented here will assist the search for pharmacologically active molecules that can potentially be employed as lead structures to guide the design of small molecules for the treatment of Alzheimer disease.

  8. Inhibitory Effect of Herbal Remedy PERVIVO and Anti-Inflammatory Drug Sulindac on L-1 Sarcoma Tumor Growth and Tumor Angiogenesis in Balb/c Mice

    PubMed Central

    Skopiński, P.; Bałan, B. J.; Kocik, J.; Zdanowski, R.; Lewicki, S.; Niemcewicz, M.; Gawrychowski, K.; Skopińska-Różewska, E.; Stankiewicz, W.

    2013-01-01

    Anticancer activity of many herbs was observed for hundreds of years. They act as modifiers of biologic response, and their effectiveness may be increased by combining multiple herbal extracts . PERVIVO, traditional digestive herbal remedy, contains some of them, and we previously described its antiangiogenic activity. Numerous studies documented anticancer effects of nonsteroidal anti-inflammatory drugs. We were the first to show that sulindac and its metabolites inhibit angiogenesis. In the present paper the combined in vivo effect of multicomponent herbal remedy PERVIVO and nonsteroidal anti-inflammatory drug sulindac on tumor growth, tumor angiogenesis, and tumor volume in Balb/c mice was studied. These effects were checked after grafting cells collected from syngeneic sarcoma L-1 tumors into mice skin. The strongest inhibitory effect was observed in experimental groups treated with PERVIVO and sulindac together. The results of our investigation showed that combined effect of examined drugs may be the best way to get the strongest antiangiogenic and antitumor effect. PMID:23935247

  9. Structural Mechanism of the Interaction of Alzheimer Disease Aβ Fibrils with the Non-steroidal Anti-inflammatory Drug (NSAID) Sulindac Sulfide*

    PubMed Central

    Prade, Elke; Bittner, Heiko J.; Sarkar, Riddhiman; Lopez del Amo, Juan Miguel; Althoff-Ospelt, Gerhard; Multhaup, Gerd; Hildebrand, Peter W.; Reif, Bernd

    2015-01-01

    Alzheimer disease is the most severe neurodegenerative disease worldwide. In the past years, a plethora of small molecules interfering with amyloid-β (Aβ) aggregation has been reported. However, their mode of interaction with amyloid fibers is not understood. Non-steroidal anti-inflammatory drugs (NSAIDs) are known γ-secretase modulators; they influence Aβ populations. It has been suggested that NSAIDs are pleiotrophic and can interact with more than one pathomechanism. Here we present a magic angle spinning solid-state NMR study demonstrating that the NSAID sulindac sulfide interacts specifically with Alzheimer disease Aβ fibrils. We find that sulindac sulfide does not induce drastic architectural changes in the fibrillar structure but intercalates between the two β-strands of the amyloid fibril and binds to hydrophobic cavities, which are found consistently in all analyzed structures. The characteristic Asp23-Lys28 salt bridge is not affected upon interacting with sulindac sulfide. The primary binding site is located in the vicinity of residue Gly33, a residue involved in Met35 oxidation. The results presented here will assist the search for pharmacologically active molecules that can potentially be employed as lead structures to guide the design of small molecules for the treatment of Alzheimer disease. PMID:26416887

  10. Handling Cytotoxic Drugs

    DTIC Science & Technology

    1986-09-01

    Regulations Governing Cytotoxic Drugs-------------------------------- 7 National Institute for Occupational Safety and ke•alth Agency ( NIOSH ) 7...Institute for Occupational Safety and Health ( NIOSH ). Cytotoxic drugs, which are used extensively troughout the health care system to treat cancer, have...foodstufTs, inhalation of drug dusts or droplets, or direct skin contact (1:31). 2 An antineoplastic drug is a cytotoxic chemical substance that is

  11. Response of Apc(min) and A33 (delta N beta-cat) mutant mice to treatment with tea, sulindac, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

    PubMed

    Orner, Gayle A; Dashwood, Wan-Mohaiza; Blum, Carmen A; Díaz, G Darío; Li, Qingjie; Al-Fageeh, Mohamad; Tebbutt, Niall; Heath, Joan K; Ernst, Matthias; Dashwood, Roderick H

    2002-09-30

    There is growing interest in the potential health benefits of tea, and a recent report described the potent antimutagenic activity of white tea in comparison with green tea against several heterocyclic amines, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) [Mutat. Res. 495 (2001) 61]. We compared the inhibitory effects of white and green teas with sulindac, a nonsteroidal anti-inflammatory agent, in two different mouse models of intestinal tumorigenesis. In the Apc(min) mouse, white and green teas given at human-relevant concentrations (1.5% w/v, 2-min brew), and sulindac (80 ppm in the drinking water), each suppressed polyp formation by approximately 50%, and the combination of white tea plus sulindac was more effective than either treatment alone (P=0.05). Mice expressing an N-terminally truncated, oncogenic version of beta-catenin (A 33(delta N beta-cat) mutant mice) developed colonic aberrant crypt foci (ACF) spontaneously, but PhIP treatment increased the incidence and number of ACF per colon. In the normal-looking intestinal mucosa of Apc(min) and A 33(delta N beta-cat) mice, white tea plus sulindac treatment markedly attenuated the expression of beta-catenin protein, and this was recapitulated in vitro in cells transiently transfected with beta-catenin plus Tcf-4 and treated with tea or the major tea polyphenol epigallocatechin-3-gallate (EGCG). Expression of a beta-catenin/Tcf reporter was inhibited by EGCG in the transfected cells, and the beta-catenin/Tcf target genes cyclin D1 and c-jun were downregulated in vivo by tea plus sulindac treatment. Collectively, the data support a chemopreventive role for tea and sulindac against intermediate and late stages of colon cancer, via effects on the beta-catenin/Tcf signaling pathway.

  12. Cytotoxic Drug Dispersal, Cytotoxic Safety, and Cytotoxic Waste Management: Practices and Proposed India-specific Guidelines.

    PubMed

    Capoor, Malini R; Bhowmik, Kumar Tapas

    2017-01-01

    This article deals with practices related to cytotoxic drug dispersal, cytotoxic safety, and cytotoxic waste management and attempts at India-specific guidelines for their dispersal and disposal. The articles related to cytotoxic drug dispersal, cytotoxic safety, and cytotoxic waste management were reviewed from PubMed and their applicability in Indian health-care facilities (HCFs) was also reviewed. All HCFs dealing with cytotoxic drugs should consider cytotoxic policy, patient safety and health-care worker safety, and environmental monitoring program as per the available international guidelines customized as per Indian conditions. Utmost care in handling cytotoxic waste is quintessential. The formation of India-specific cytotoxic guidelines requires the inputs from all stakeholders. Cytotoxic waste, cytotoxic safety, and cytotoxic waste management should be the subject of a national strategy with an infrastructure, cradle-to-grave legislation, competent regulatory authority, and trained personnel.

  13. Cytotoxic Drug Dispersal, Cytotoxic Safety, and Cytotoxic Waste Management: Practices and Proposed India-specific Guidelines

    PubMed Central

    Capoor, Malini R; Bhowmik, Kumar Tapas

    2017-01-01

    This article deals with practices related to cytotoxic drug dispersal, cytotoxic safety, and cytotoxic waste management and attempts at India-specific guidelines for their dispersal and disposal. The articles related to cytotoxic drug dispersal, cytotoxic safety, and cytotoxic waste management were reviewed from PubMed and their applicability in Indian health-care facilities (HCFs) was also reviewed. All HCFs dealing with cytotoxic drugs should consider cytotoxic policy, patient safety and health-care worker safety, and environmental monitoring program as per the available international guidelines customized as per Indian conditions. Utmost care in handling cytotoxic waste is quintessential. The formation of India-specific cytotoxic guidelines requires the inputs from all stakeholders. Cytotoxic waste, cytotoxic safety, and cytotoxic waste management should be the subject of a national strategy with an infrastructure, cradle-to-grave legislation, competent regulatory authority, and trained personnel. PMID:28900329

  14. The sulindac derivatives OSI-461, OSIP486823, and OSIP487703 arrest colon cancer cells in mitosis by causing microtubule depolymerization.

    PubMed

    Xiao, Danhua; Deguchi, Atsuko; Gundersen, Gregg G; Oehlen, Bert; Arnold, Lee; Weinstein, I Bernard

    2006-01-01

    Exisulind (sulindac sulfone) and three highly potent derivatives, OSI-461 (CP461), OSIP486823 (CP248), and OSIP487703, inhibit growth and induce apoptosis in SW480 human colon cancer cells, with IC(50)s of 200, 2, 0.1, and 0.003 micromol/L, respectively. The latter three compounds, but not exisulind, induce marked M-phase cell cycle arrest in these cells. This effect seems to be independent of the known ability of these compounds to cause activation of protein kinase G. When tested at twice their IC(50) concentration for growth inhibition, OSI-461, OSIP486823, and OSIP487703 cause depolymerization of microtubules in interphase cells, inhibit spindle formation in mitotic cells, and induce multinucleated cells. In vitro tubulin polymerization assays indicate that all three compounds interact with tubulin directly to cause microtubule depolymerization and/or inhibit de novo tubulin polymerization. These results suggest that the dual effects of OSI-461, OSIP486823, and OSIP487703 on impairment of microtubule functions and protein kinase G activation may explain the potent antiproliferative and apoptotic effects of these compounds in cancer cells.

  15. Topically applied phospho-sulindac hydrogel is efficacious and safe in the treatment of experimental arthritis in rats.

    PubMed

    Mattheolabakis, George; Mackenzie, Gerardo G; Huang, Liqun; Ouyang, Nengtai; Cheng, Ka Wing; Rigas, Basil

    2013-06-01

    Formulate phospho-sulindac (P-S, OXT-328) in a Pluronic hydrogel to be used as a topical anti-inflammatory agent and study its efficacy, safety and pharmacokinetics in an arthritis model. LEW/crlBR rats with Freund's adjuvant-induced arthritis were treated with P-S formulated in Pluronic hydrogel (PSH). We determined the clinical manifestations of arthritis including the locomotor activity of the rats; evaluated joints for inflammation, bone resorption, cartilage damage, COX-2 expression and NF-κB activation; assayed plasma IL-6 and IL-10 levels; and studied the pharmacokinetics of P-S in rats after topical or oral administration. PSH applied at the onset of arthritis or when arthritis was fully developed, suppressed it by 56-82%, improved the locomotor activity of the rats 2.1-4.4 fold, suppressed synovial inflammation, bone resorption, cartilage damage, NF-κB activation and COX-2 expression but not plasma IL-6 and IL-10 levels. There were no side effects. PSH produced rapidly high local levels of P-S with <14% of P-S reaching the circulation, while orally administered P-S was rapidly metabolized generating much lower joint levels of P-S. Topical application of PSH is efficacious and safe in the treatment of Freund's adjuvant-induced arthritis; has a favorable pharmacokinetic profile; and likely acts by suppressing key pro-inflammatory signaling pathways.

  16. A novel COX-independent mechanism of sulindac sulfide involves cleavage of epithelial cell adhesion molecule protein.

    PubMed

    Liggett, Jason L; Min, Kyung-Won; Smolensky, Dmitriy; Baek, Seung Joon

    2014-08-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are extensively used over the counter to treat headaches and inflammation as well as clinically to prevent cancer among high-risk groups. The inhibition of cyclooxygenase (COX) activity by NSAIDs plays a role in their anti-tumorigenic properties. NSAIDs also have COX-independent activity which is not fully understood. In this study, we report a novel COX-independent mechanism of sulindac sulfide (SS), which facilitates a previously uncharacterized cleavage of epithelial cell adhesion molecule (EpCAM) protein. EpCAM is a type I transmembrane glycoprotein that has been implemented as an over-expressed oncogene in many cancers including colon, breast, pancreas, and prostate. We found EpCAM to be down-regulated by SS in a manner that is independent of COX activity, transcription regulation, de novo protein synthesis, and proteasomal degradation pathway. Our findings clearly demonstrate that SS drives cleavage of the extracellular portion of EpCAM near the N-terminus. This SS driven cleavage is blocked by a deleting amino acids 55-81 as well as simply mutating arginine residues at positions 80 and 81 to alanine of EpCAM. Proteolysis of EpCAM by SS may provide a novel mechanism by which NSAIDs affect anti-tumorigenesis at the post-translational level. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. T helper cell cytotoxicity

    SciTech Connect

    Penna, A.; Glasebrook, A.

    1986-03-01

    It has recently been shown that helper T cells (Lyt2/sup -/, L3T4/sup +/) can express cytolytic activity when activated by antigen (Ag). The authors have studied the phenomenon of T helper cell cytotoxicity using cloned lines of Ag-reactive T cells and T hybrids. Cytotoxicity was determined by coculture of T cells with /sup 51/Cr-labelled Ag presenting cells (APC) and/or non-APC (bystander cells). A high frequency of Ag-specific L3T4/sup +/ T cell clones (> 90%) and hybrids (> 50%) were found to be cytotoxic. Cytotoxicity as determined by /sup 51/Cr release was maximal at 20 hr with little or no cytotoxicity detectable at 6 hr. Target cells, either APC or bystander cells, were killed provided the T cells were stimulated by Ag. Not all of the B cells used as APC were susceptible targets even if able to promote bystander killing. Monoclonal antibodies directed against L3T4, LFA-1 and T cell receptor molecules were able to block the cytotoxicity indicating a requirement for specific activation of the T cells. Cyclosporin A (CsA) reduced the cytotoxic activity of helper T hybrids and clones, while it did not affect the cytotoxic activity of Lyt2/sup +/, L3T4/sup -/ cytolytic T cell (CTL) clones. The delayed expression of cytotoxic activity, the lysis of bystander cells and inhibition by CsA suggest that the cytolytic mechanism is mediated by a soluble factor and different from the cytolytic mechanism of CTL. The phenomenon of cytotoxic T helper cells may be relevant to suppression of B cell immune responses in vivo.

  18. Sulindac and Celecoxib regulate cell cycle progression by p53/p21 up regulation to induce apoptosis during initial stages of experimental colorectal cancer.

    PubMed

    Vaish, Vivek; Rana, Chandan; Piplani, Honit; Vaiphei, Kim; Sanyal, Sankar Nath

    2014-03-01

    In the present study we have elaborated the putative mechanisms could be followed by the non-steroidal anti-inflammatory drugs (NSAIDs) viz. Sulindac and Celecoxib in the regulation of cell cycle checkpoints along with tumor suppressor proteins to achieve their chemopreventive effects in the initial stages of experimental colorectal cancer. Male Sprague-Dawley rats were administered with 1,2-dimethylhydrazine dihydrochloride (DMH) to produce early stages of colorectal carcinogenesis. The mRNA expression profiles of various target genes were analyzed by RT-PCR and validated by quantitative real-time PCR, whereas protein expression was analyzed by Western blotting. Nuclear localization of transcription factors or other nuclear proteins was analyzed by electrophoretic mobility shift assay and immunofluorescence. Flowcytometry was performed to analyze the differential apoptotic events and cell cycle regulation. Molecular docking studies with different target proteins were also performed to deduce the various putative mechanisms of action followed by Sulindac and Celecoxib. We observed that DMH administration has abruptly increased the proliferation of colonic cells which is macroscopically visible in the form of multiple plaque lesions and co-relates with the disturbed molecular mechanisms of cell cycle regulation. However, co-administration of NSAIDs has shown regulatory effects on cell cycle checkpoints via induction of various tumor suppressor proteins. We may conclude that Sulindac and Celecoxib could possibly follow p53/p21 mediated regulation of cell proliferation, where down regulation of NF-κB signaling and activation of PPARγ might serve as important additional events in vivo.

  19. Sulindac inhibits tumor cell invasion by suppressing NF-κB mediated transcription of microRNAs

    PubMed Central

    Li, Xiaobo; Gao, Lin; Cui, Qinghua; Gary, Bernard D.; Dyess, Donna Lynn; Taylor, William; Shevde-Samant, Lalita R.; Samant, Rajeev S.; Dean-Colomb, Windy; Piazza, Gary A.; Xi, Yaguang

    2012-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to display strong efficacy for cancer chemoprevention, although their mechanism of action is poorly understood. The most well documented effects of NSAIDs include inhibition of tumor cell proliferation and induction of apoptosis, but their effect on tumor cell invasion has not been well studied. Here we show that the NSAID, sulindac sulfide (SS) can potently inhibit the invasion of human MDA-MB-231 breast and HCT116 colon tumor cells in vitro at concentrations less than those required to inhibit tumor cell growth. To study the molecular basis for this activity, we investigated the involvement of microRNA (miRNA). A total of 132 miRNAs were found to be altered in response to SS treatment including miR-10b, miR-17, miR-21, and miR-9, which have been previously implicated in tumor invasion and metastasis. We confirmed that these miRNA can stimulate tumor cell invasion and show that SS can attenuate their invasive effects by down-regulating their expression. Employing luciferase and chromatin immunoprecipitation assays, NF-κB was found to bind the promoters of all four miRNAs to suppress their expression at the transcriptional level. We show that SS can inhibit the translocation of NF-κB to the nucleus by decreasing the phosphorylation of IKKβ and IκB. Analysis of the promoter sequences of the miRNAs suppressed by SS revealed that 81 of 115 sequences contained NF-κB binding sites. These results show that SS can inhibit tumor cell invasion by suppressing NF-κB mediated transcription of miRNAs. PMID:22286762

  20. Nonsteroidal anti-inflammatory drug sulindac sulfide suppresses structural protein Nesprin-2 expression in colorectal cancer cells.

    PubMed

    Liggett, Jason L; Choi, Chang Kyoung; Donnell, Robert L; Kihm, Kenneth D; Kim, Jong-Sik; Min, Kyung-Won; Noegel, Angelika Anna; Baek, Seung Joon

    2014-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known for treating inflammatory disease and have been reported to have anti-tumorigenic effects. Their mechanisms are not fully understood, but both cyclooxygenase (COX) dependent and independent pathways are involved. Our goal was to shed further light on COX-independent activity. Human colorectal cancer cells were observed under differential interference contrast microscopy (DICM), fluorescent microscopy, and micro-impedance measurement. Microarray analysis was performed using HCT-116 cells treated with sulindac sulfide (SS). PCR and Western blots were performed to confirm the microarray data and immunohistochemistry was performed to screen for Nesprin-2 expression. Micro-impedance was repeating including Nesprin-2 knock-down by siRNA. HCT-116 cells treated with SS showed dramatic morphological changes under DICM and fluorescent microscopy, as well as weakened cellular adhesion as measured by micro-impedance. Nesprin-2 was selected from two independent microarrays, based on its novelty in relation to cancer and its role in cell organization. SS diminished Nesprin-2 mRNA expression as assessed by reverse transcriptase and real time PCR. Various other NSAIDs were also tested and demonstrated that inhibition of Nesprin-2 mRNA was not unique to SS. Additionally, immunohistochemistry showed higher levels of Nesprin-2 in many tumors in comparison with normal tissues. Further micro-impedance experiments on cells with reduced Nesprin-2 expression showed a proportional loss of cellular adhesion. Nesprin-2 is down-regulated by NSAIDs and highly expressed in many cancers. Our data suggest that Nesprin-2 may be a potential novel oncogene in human cancer cells and NSAIDs could decrease its expression. © 2013.

  1. Colon tumor cell growth inhibitory activity of sulindac sulfide and other NSAIDs is associated with PDE5 inhibition

    PubMed Central

    Tinsley, Heather N.; Gary, Bernard D.; Thaiparambil, Jose; Li, Nan; Lu, Wenyan; Li, Yonghe; Maxuitenko, Yulia Y.; Keeton, Adam B.; Piazza, Gary A.

    2010-01-01

    In experimental studies, nonsteroidal anti-inflammatory drugs (NSAIDs) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here we show that the NSAID, sulindac sulfide (SS) inhibits cGMP phosphodiesterase (PDE) activity in colon tumor cell lysates at concentrations that inhibit colon tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit colon tumor cell growth, while no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cAMP hydrolysis, SS inhibited the cGMP specific PDE5 isozyme and increased cGMP levels in colon tumor cells. Of numerous PDE isozyme specific inhibitors evaluated, only the PDE5 selective inhibitor MY5445 inhibited colon tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in colon tumor cell lines as well as in colon adenomas and adenocarcinomas compared to normal colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs. PMID:20876730

  2. Selenium cytotoxicity in cancer.

    PubMed

    Wallenberg, Marita; Misra, Sougat; Björnstedt, Mikael

    2014-05-01

    Selenium is an essential trace element with growth-modulating properties. Decades of research clearly demonstrate that selenium compounds inhibit the growth of malignant cells in diverse experimental model systems. However, the growth-modulating and cytotoxic mechanisms are diverse and far from clear. Lately, a remarkable tumour selective cytotoxicity of selenium compounds has been shown, indicating the potential of selenium in the treatment of cancer. Of particular interest are the redox-active selenium compounds exhibiting cytotoxic potential to tumour cells. These selenium compounds elicit complex patterns of pharmacodynamics and pharmacokinetics, leading to cell death pathways that differ among compounds. Modern oncology often focuses on targeted ligand-based therapeutic strategies that are specific to their molecular targets. These drugs are initially efficient, but the tumour cells often rapidly develop resistance against these drugs. In contrast, certain redox-active selenium compounds induce complex cascades of pro-death signalling at pharmacological concentrations with superior tumour specificity. The target molecules are often the ones that are important for the survival of cancer cells and often implicated in drug resistance. Therefore, the chemotherapeutic applications of selenium offer great possibilities of multi-target attacks on tumour cells. This MiniReview focuses on the tumour-specific cytotoxic effects of selenium, with special emphasis on cascades of cellular events induced by the major groups of pharmacologically active selenium compounds. Furthermore, the great pharmacological potential of selenium in the treatment of resistant cancers is discussed.

  3. Uncoupling of oxidative phosphorylation and Smac/DIABLO release are not sufficient to account for induction of apoptosis by sulindac sulfide in human colorectal cancer cells.

    PubMed

    Daouphars, Mikael; Koufany, Meriem; Benani, Alexandre; Marchal, Sophie; Merlin, Jean-Louis; Netter, Patrick; Jouzeau, Jean-Yves

    2005-04-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) have shown chemopreventive properties in colorectal cancer, involving both cyclooxygenase (COX)-dependent and -independent mechanisms. Apart from their selectivity for COX isoenzymes, NSAIDs differ in their acidic character which supports ability to uncouple oxidative phosphorylation. To assess the possible contribution of uncoupling to their antineoplastic properties, we compared the effect of sulindac sulfide (SS), an acidic NSAID and NS-398, a non-acidic tricyclic, on mitochondrial function and apoptosis in colorectal cancer cell lines (HT29, Caco-2, HCT15 and HCT116). Although cell lines displayed a different COX status, SS and NS-398 caused growth arrest in a dose-related manner. High dose (10(-4)M) of SS but not of NS-398, increased the percentage of subG1 cell population while reducing mitochondrial transmembrane potential (DeltaPsim). Cyclosporin A (CsA, 1 microM) prevented collapse of DeltaPsim induced by 10(-4)M SS but not by 7.5 microM FCCP used as a protonophoric control. SS and FCCP increased the cytosolic release of Smac/DIABLO which was differently affected by CsA pretreatment depending on the uncoupler. Finally, 7.5 microM FCCP failed to induce apoptosis whereas CsA prevented apoptosis induced by SS from 16% in HCT15 to 41% in HCT116. The present study shows that despite the ability of sulindac sulfide to behave as a protonophoric uncoupler, CsA-sensitive opening of mitochondrial permeability transition pore contributes little to its pro-apoptotic effect in colorectal cancer cells.

  4. A Novel Sulindac Derivative That Does Not Inhibit Cyclooxygenases but Potently Inhibits Colon Tumor Cell Growth and Induces Apoptosis with Antitumor Activity

    PubMed Central

    Piazza, Gary A.; Keeton, Adam B.; Tinsley, Heather N.; Gary, Bernard D.; Whitt, Jason D.; Mathew, Bini; Thaiparambil, Jose; Coward, Lori; Gorman, Gregory; Li, Yonghe; Sani, Brahma; Hobrath, Judith V.; Maxuitenko, Yulia Y.; Reynolds, Robert C.

    2011-01-01

    Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis limits their use for chemoprevention. Previous studies have concluded that the mechanism responsible for their antineoplastic activity may be COX independent. To selectively design out the COX inhibitory activity of sulindac sulfide (SS), in silico modeling studies were done that revealed the crucial role of the carboxylate moiety for COX-1 and COX-2 binding. These studies prompted the synthesis of a series of SS derivatives with carboxylate modifications that were screened for tumor cell growth and COX inhibitory activity. A SS amide (SSA) with a N,N-dimethylethyl amine substitution was found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of human colon tumor cell lines, HT-29, SW480, and HCT116 with IC50 values of 2 to 5 µmol/L compared with 73 to 85 µmol/L for SS. The mechanism of growth inhibition involved the suppression of DNA synthesis and apoptosis induction. Oral administration of SSA was well-tolerated in mice and generated plasma levels that exceeded its in vitro IC50 for tumor growth inhibition. In the human HT-29 colon tumor xenograft mouse model, SSA significantly inhibited tumor growth at a dosage of 250 mg/kg. Combined treatment of SSA with the chemotherapeutic drug, Camptosar, caused a more sustained suppression of tumor growth compared with Camptosar treatment alone. These results indicate that SSA has potential safety and efficacy advantages for colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy. PMID:19470791

  5. A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity.

    PubMed

    Piazza, Gary A; Keeton, Adam B; Tinsley, Heather N; Gary, Bernard D; Whitt, Jason D; Mathew, Bini; Thaiparambil, Jose; Coward, Lori; Gorman, Gregory; Li, Yonghe; Sani, Brahma; Hobrath, Judith V; Maxuitenko, Yulia Y; Reynolds, Robert C

    2009-06-01

    Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis limits their use for chemoprevention. Previous studies have concluded that the mechanism responsible for their antineoplastic activity may be COX independent. To selectively design out the COX inhibitory activity of sulindac sulfide (SS), in silico modeling studies were done that revealed the crucial role of the carboxylate moiety for COX-1 and COX-2 binding. These studies prompted the synthesis of a series of SS derivatives with carboxylate modifications that were screened for tumor cell growth and COX inhibitory activity. A SS amide (SSA) with a N,N-dimethylethyl amine substitution was found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of human colon tumor cell lines, HT-29, SW480, and HCT116 with IC(50) values of 2 to 5 micromol/L compared with 73 to 85 micromol/L for SS. The mechanism of growth inhibition involved the suppression of DNA synthesis and apoptosis induction. Oral administration of SSA was well-tolerated in mice and generated plasma levels that exceeded its in vitro IC(50) for tumor growth inhibition. In the human HT-29 colon tumor xenograft mouse model, SSA significantly inhibited tumor growth at a dosage of 250 mg/kg. Combined treatment of SSA with the chemotherapeutic drug, Camptosar, caused a more sustained suppression of tumor growth compared with Camptosar treatment alone. These results indicate that SSA has potential safety and efficacy advantages for colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy.

  6. A novel sulindac derivative that potently suppresses colon tumor cell growth by inhibiting cGMP phosphodiesterase and β-catenin transcriptional activity.

    PubMed

    Whitt, Jason D; Li, Nan; Tinsley, Heather N; Chen, Xi; Zhang, Wei; Li, Yonghe; Gary, Bernard D; Keeton, Adam B; Xi, Yaguang; Abadi, Ashraf H; Grizzle, William E; Piazza, Gary A

    2012-06-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to inhibit tumor growth by a COX-independent mechanism, although alternative targets have not been well defined or used to develop improved drugs for cancer chemoprevention. Here, we characterize a novel sulindac derivative referred to as sulindac benzylamine (SBA) that does not inhibit COX-1 or COX-2, yet potently inhibits the growth and induces the apoptosis of human colon tumor cells. The basis for this activity appears to involve cyclic guanosine 3',5',-monophosphate phosphodiesterase (cGMP PDE) inhibition as evident by its ability to inhibit cGMP hydrolysis in colon tumor cell lysates and purified cGMP-specific PDE5, increase intracellular cGMP levels, and activate cGMP-dependent protein kinase G at concentrations that suppress tumor cell growth. PDE5 was found to be essential for colon tumor cell growth as determined by siRNA knockdown studies, elevated in colon tumor cells as compared with normal colonocytes, and associated with the tumor selectivity of SBA. SBA activation of PKG may suppress the oncogenic activity of β-catenin as evident by its ability to reduce β-catenin nuclear levels, Tcf (T-cell factor) transcriptional activity, and survivin levels. These events preceded apoptosis induction and appear to result from a rapid elevation of intracellular cGMP levels following cGMP PDE inhibition. We conclude that PDE5 and possibly other cGMP degrading isozymes can be targeted to develop safer and more efficacious NSAID derivatives for colorectal cancer chemoprevention.

  7. A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy

    PubMed Central

    Gurpinar, Evrim; Grizzle, William E.; Shacka, John J.; Mader, Burton J.; Li, Nan; Piazza, Nicholas A.; Russo, Suzanne; Keeton, Adam B.; Piazza, Gary A.

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac sulfide (SS) have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from cyclooxygenase (COX) inhibition limit their use in cancer therapy. We recently described a N, N-dimethylethyl amine derivative of SS, sulindac sulfide amide (SSA), that does not inhibit COX-1 or -2, yet displays potent tumor cell growth inhibitory activity. Here, we studied the basis for the growth inhibitory effects of SSA on human lung adenocarcinoma cell lines. SSA potently inhibited the growth of lung tumor cells with IC50 values of 2–5 μM compared with 44–52 μM for SS. SSA also suppressed DNA synthesis and caused a G0/G1 cell cycle arrest. SSA-induced cell death was associated with characteristics of autophagy, but significant caspase activation or PARP cleavage were not observed after treatment at its IC50 value. siRNA knockdown of Atg7 attenuated SSA-induced autophagy and cell death, while pan-caspase inhibitor ZVAD was not able to rescue viability. SSA treatment also inhibited Akt/mTOR signaling and the expression of downstream proteins that are regulated by this pathway. Overexpression of a constitutively active form of Akt was able to reduce autophagy markers and confer resistance to SSA-induced cell death. Our findings provide evidence that SSA inhibits lung tumor cell growth by a mechanism involving autophagy induction through the suppression of Akt/mTOR signaling. This unique mechanism of action along with its increased potency and lack of cyclooxygenase inhibition support the development of SSA or related analogs for the prevention and/or treatment of lung cancer. PMID:23443799

  8. A Novel Sulindac Derivative that Potently Suppresses Colon Tumor Cell Growth by Inhibiting cGMP Phosphodiesterase and β-Catenin Transcriptional Activity

    PubMed Central

    Whitt, Jason D.; Li, Nan; Tinsley, Heather N.; Chen, Xi; Zhang, Wei; Li, Yonghe; Gary, Bernard D.; Keeton, Adam B.; Xi, Yaguang; Abadi, Ashraf H.; Grizzle, William E.; Piazza, Gary A.

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to inhibit tumor growth by a COX-independent mechanism, although alternative targets have not been well defined or used to develop improved drugs for cancer chemoprevention. Here, we characterize a novel sulindac derivative referred to as sulindac benzylamine (SBA) that does not inhibit COX-1 or COX-2, yet potently inhibits the growth and induces the apoptosis of human colon tumor cells. The basis for this activity appears to involve cyclic guanosine 3′,5′,-monophosphate phosphodiesterase (cGMP PDE) inhibition as evident by its ability to inhibit cGMP hydrolysis in colon tumor cell lysates and purified cGMP-specific PDE5, increase intracellular cGMP levels, and activate cGMP-dependent protein kinase G at concentrations that suppress tumor cell growth. PDE5 was found to be essential for colon tumor cell growth as determined by siRNA knockdown studies, elevated in colon tumor cells as compared with normal colonocytes, and associated with the tumor selectivity of SBA. SBA activation of PKG may suppress the oncogenic activity of β-catenin as evident by its ability to reduce β-catenin nuclear levels, Tcf (T-cell factor) transcriptional activity, and survivin levels. These events preceded apoptosis induction and appear to result from a rapid elevation of intracellular cGMP levels following cGMP PDE inhibition. We conclude that PDE5 and possibly other cGMP degrading isozymes can be targeted to develop safer and more efficacious NSAID derivatives for colorectal cancer chemoprevention. PMID:22556201

  9. Determination of Cytotoxicity.

    PubMed

    2016-01-01

    Cytotoxicity assays are used for drug screening and cytotoxicity tests of chemicals. Nowadays, various reagents are used for cell viability detection. They are based on various cell functions such as enzyme activity, cell membrane permeability, cell adherence, ATP production, co-enzyme production and nucleotide uptake activity. Many have established methods such as colony formation method, crystal violet method, tritium-labelled thymidine uptake method, MTT and WST methods, which are used for counting the number of live cells. Moreover, trypan blue is a widely used assay for staining dead cells. In this method, cell viability must be determined by counting the unstained cells with a microscope or other instruments. This chapter is a collection of all these methods to be followed by researchers in a sequential manner.

  10. Cytotoxicity assay automation

    NASA Technical Reports Server (NTRS)

    Levinthal, E. C.; Payne, R. O.

    1971-01-01

    The design and construction of a system to automatically test HLP antigens are described. Major efforts were made to test and evaluate the performance of such a system, and compare its performance with nonautomatic tissue typing techniques. The system is based on the fluorochromatic cytotoxicity assay. Results show the system will work but is subject to malfunctions after a few samplings, and poses problems in showing correctly the necessary readings.

  11. Cytotoxic effect of orthodontic appliances.

    PubMed

    Grimsdottir, M R; Hensten-Pettersen, A; Kullmann, A

    1992-02-01

    The use of orthodontic appliances may contribute to local gingivitis, often attributed to increased plaque retention. Gingivitis of bacterial origin cannot clinically be distinguished from local tissue irritation caused by corrosion products. The purpose of this investigation was to assess the cytotoxic effect of various metallic components used in orthodontics. Multicomponent devices such as facebows, molar bands, and brackets along with single-component brackets and archwires were tested by the agar overlay cytotoxicity test with mouse fibroblast cells. None of the archwires caused any cytotoxic effect, even though some contained 54 per cent nickel. However, the multi-component devices, which were joined with silver- and copper-based brazing alloys were more cytotoxic than the single-component devices. Copper is more cytotoxic than nickel, which could explain the greater cytotoxic effect of the samples with brazing materials. It is speculated that cytotoxic corrosion products from orthodontic appliances might contribute to localized gingivitis.

  12. Inhibition by nonsteroidal antiinflammatory drugs of luminol-dependent human-granulocyte chemiluminescence and /sup 3/H FMLP binding. Effect of sulindac sulfide, indomethacin metabolite, and optical enantiomers (+) and (-) MK830

    SciTech Connect

    Van Dyke, K.; Peden, D.; Van Dyke, C.; Jones, G.; Castranova, V.; Ma, J.

    1982-03-01

    A system is described to evaluate for nonsteroidal antiinflammatory drugs by means of luminol-dependent human-granulocyte chemiluminescence (CL) is described. The CL is produced using either opsonized zymosan (yeast cells) or the soluble chemotactic peptide f-Met-Leu-Phe as the perturbant of the granulocyte membrane. Using either system, the following drug effects 2 x 10(-5) M were noted: only sulindac sulfide, and not sulindac sulfone or sulindac, displayed marked inhibition of chemiluminescence, following the in vivo data regarding inflammatory effects. The 5-OH indomethacin metabolite was likewise inactive as an inhibitor of CL mirroring in vivo effects. MK(+)410, MK(-)830 and MK835 all showed approximately 50% inhibition of CL, displaying deviation from in vivo data. MK(+)830 markedly stimulated CL, 4-6 times the control (without drug), which is clearly different from its enantiomer, MK(-)830. The reasons for this behavior are unclear. However, receptor binding studies with /sup 3/H FMLP were accomplished in the presence and absence of the various drugs at 2 x 10(-5) M that were effective inhibitors of chemiluminescence (CL). Indomethacin, MK(-)830 and MK(+)410 had equivalent percent control binding and percent control CL. Sulindac sulfide and MK(+)835 both had higher percent control binding than percent control CL, with MK(+)835 displaying apparent increased numbers of available receptors relative to control. MK(+)830, which produces large increases in CL, produced a minor effect on percent control binding. A direct relationship between binding and CL does not exist with each drug. Chemiluminescence is dependent on ion movement and oxidative metabolism and is a secondary event to agonist-receptor occupation.

  13. Cytotoxicity of organophosphate anticholinesterases.

    PubMed

    Cao, C J; Mioduszewski, R J; Menking, D E; Valdes, J J; Katz, E J; Eldefrawi, M E; Eldefrawi, A T

    1999-10-01

    Organophosphate (OP) anticholinesterases were found to modulate metabolic activities of human neuroblastoma cells and hepatocytes, which was detectable by the Cytosensor microphysiometer. The nerve gas ethyl-S-2-diisopropylaminoethyl methylphosphorothiolate (VX), at 10 microM, produced significant reduction in cell metabolism within 2 min, as measured by changes in the acidification rate of the medium. The reduction was dose- and time-dependent and irreversible after 4 h of exposure. Two alkaline degradation products of VX produced no cytotoxicity. Exposure for 24 h to 3 microM VX caused 36% and 94% irreversible loss of metabolism in hepatocytes and neuroblastoma cells, respectively. The insecticides parathion and chlorpyrifos stimulated hepatocyte metabolism but inhibited neuroblastoma cells. Their oxons were more active. Exposure of neuroblastoma cells for 4 h to VX, parathion, paraoxon, diisopropylfluorophosphate or chlorpyrifos gave an LC50 of 65, 775, 640, 340, or 672 microM, respectively, whereas 24 h gave an LC50 of 0.7, 3.7, 2.5, 29, and 31 microM, respectively. Preincubation of hepatocytes with phenobarbital enhanced their response to parathion and VX due to metabolic bioactivation. Atropine partially blocked the effects of VX and paraoxon on both cell types, which suggests the involvement of a muscarinic receptor as the target for cytotoxicity. There was no correlation between OP in vivo neurotoxicity and in vitro cytotoxicity. It is suggested that the former results from their cholinesterase inhibition, while the latter results from action on different targets and requires much higher concentrations.

  14. Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a randomized, double-blind, Phase III trial.

    PubMed

    Burke, Carol A; Dekker, Evelien; Samadder, N Jewel; Stoffel, Elena; Cohen, Alfred

    2016-08-02

    Molecular studies suggest inhibition of colorectal mucosal polyamines (PAs) may be a promising approach to prevent colorectal cancer (CRC). Inhibition of ornithine decarboxylase (ODC) using low-dose eflornithine (DFMO, CPP-1X), combined with maximal PA export using low-dose sulindac, results in greatly reduced levels of normal mucosal PAs. In a clinical trial, this combination (compared with placebo) reduced the 3-year incidence of subsequent high-risk adenomas by >90 %. Familial Adenomatous Polyposis (FAP) is characterized by marked up-regulation of ODC in normal intestinal epithelial and adenoma tissue, and therefore PA reduction might be a potential strategy to control progression of FAP-related intestinal polyposis. CPP FAP-310, a randomized, double-blind, Phase III trial was designed to examine the safety and efficacy of sulindac and DFMO (alone or in combination) for preventing a clinically relevant FAP-related progression event in individuals with FAP. Eligible adults with FAP will be randomized to: CPP-1X 750 mg and sulindac 150 mg, CPP-1X placebo and sulindac 150 mg, or CPP-1X 750 mg and sulindac placebo once daily for 24 months. Patients will be stratified based on time-to-event prognosis into one of the three treatment arms: best (ie, longest time to first FAP-related event [rectal/pouch polyposis]), intermediate (duodenal polyposis) and worst (pre-colectomy). Stage-specific, "delayed time to" FAP-related events are the primary endpoints. Change in polyp burden (upper and/or lower intestine) is a key secondary endpoint. The trial is ongoing. As of February 1, 2016, 214 individuals have been screened; 138 eligible subjects have been randomized to three treatment groups at 15 North American sites and 6 European sites. By disease strata, 26, 80 and 32 patients are included for assessment of polyp burden in the rectum/pouch, duodenal polyposis and pre-colectomy groups, respectively. Median age is 40 years; 59 % are men. The most common reasons for

  15. Autoxidation and cytotoxicity

    SciTech Connect

    Borg, D C; Schaich, K M; Elmore, Jr, J J

    1980-01-01

    A comprehensive synthesis, or reaction schema, to relate autoxidations of non-lipid compounds to lipid chain peroxidation in vivo is presented. This is done in the context of cytotoxic autoxidation reactions, and it is concluded that hydroxyl radicals produced by iron-dependent Fenton reactions serve as both primary toxicants and as sources of secondary toxicants. The latter stem from lipid chain peroxidation initiated by the Fenton-derived hydroxyl radicals, which are visualized as the obligate coupling step linking enzyme-dependent and non-enzymic autoxidations to potentially toxic outcomes.

  16. Cytotoxicity of denture adhesives.

    PubMed

    de Gomes, Pedro Sousa; Figueiral, Maria Helena; Fernandes, Maria Helena R; Scully, Crispian

    2011-12-01

    Ten commercially available denture adhesives, nine soluble formulations (six creams, three powders) and one insoluble product (pad), were analyzed regarding the cytotoxicity profile in direct and indirect assays using L929 fibroblast cells. In the direct assay, fibroblasts were seeded over the surface of a thick adhesive gel (5%, creams; 2.5%, powders and pad). In the indirect assay, cells were cultured in the presence of adhesive extracts prepared in static and dynamic conditions (0.5-2%, creams; 0.25-1%, powders and pad). Cell toxicity was assessed for cell viability/proliferation (MTT assay) and cell morphology (observation of the F-actin cytoskeleton organization by confocal laser scanning microscopy). Direct contact of the L929 fibroblasts with the thick adhesive gels caused no, or only a slight, decrease in cell viability/proliferation. The adhesive extracts (especially those prepared in dynamic conditions) caused significantly higher growth inhibition of fibroblasts and, in addition, caused dose- and time-dependent effects, throughout the 6-72 h exposure time. Also, dose-dependent effects on cell morphology, with evident disruption of the F-actin cytoskeleton organization, were seen in the presence of most adhesives. In conclusion, the adhesives possessed different degrees of cytotoxicity, but similar dose- and time-dependent biological profiles.

  17. Fluorinated Nanocarbons Cytotoxicity.

    PubMed

    Teo, Wei Zhe; Chua, Chun Kiang; Sofer, Zdenek; Pumera, Martin

    2015-09-07

    As the research in nanotechnology progresses, there will eventually be an influx in the number of commercial products containing different types of nanomaterials. This phenomenon might damage our health and environment if the nanomaterials used are found to be toxic and they are released into the waters when the products degrade. In this study, we investigated the cytotoxicity of fluorinated nanocarbons (CXFs), a group of nanomaterials which can find applications in solid lubricants and lithium primary batteries. Our cell viability findings indicated that the toxicological effects induced by the CXF are dependent on the dose, size, shape, and fluorine content of the CXF. In addition, we verified that CXFs have insignificant interactions with the cell viability assays-methylthiazolyldiphenyl-tetrazolium bromide (MTT) and water-soluble tetrazolium salt (WST-8), thus suggesting that the cytotoxicity data obtained are unlikely to be affected by CXF-induced artifacts and the results will be reliable. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Gold Nanoparticles Cytotoxicity

    NASA Astrophysics Data System (ADS)

    Mironava, Tatsiana

    Over the last two decades gold nanoparticles (AuNPs) have been used for many scientific applications and have attracted attention due to the specific chemical, electronic and optical size dependent properties that make them very promising agents in many fields such as medicine, imagine techniques and electronics. More specifically, biocompatible gold nanoparticles have a huge potential for use as the contrast augmentation agent in X-ray Computed Tomography and Photo Acoustic Tomography for early tumor diagnostic as well these nanoparticles are extensively researched for enhancing the targeted cancer treatment effectiveness such as photo-thermal and radiotherapy. In most biomedical applications biocompatible gold nanoparticles are labeled with specific tumor or other pathology targeting antibodies and used for site specific drug delivery. However, even though gold nanoparticles poses very high level of anti cancer properties, the question of their cytotoxicity ones they are released in normal tissue has to be researched. Moreover, the huge amount of industrially produced gold nanoparticles raises the question of these particles being a health hazard, since the penetration is fairly easy for the "nano" size substances. This study focuses on the effect of AuNPs on a human skin tissue, since it is fall in both categories -- the side effects for biomedical applications and industrial workers and users' exposure during production and handling. Therefore, in the present project, gold nanoparticles stabilized with the biocompatible agent citric acid were generated and characterized by Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM). The cytotoxic effect of AuNPs release to healthy skin tissue was modeled on 3 different cell types: human keratinocytes, human dermal fibroblasts, and human adipose derived stromal (ADS) cells. The AuNPs localization inside the cell was found to be cell type dependent. Overall cytotoxicity was found to be dependent

  19. Cytotoxicity of halogenated graphenes

    NASA Astrophysics Data System (ADS)

    Teo, Wei Zhe; Khim Chng, Elaine Lay; Sofer, Zdeněk; Pumera, Martin

    2013-12-01

    Graphene and its family of derivatives possess unique and remarkable physicochemical properties which make them valuable materials for applications in many areas like electronics, energy storage and biomedicine. In response to the possibility of its large-scale manufacturing as commercial products in the future, an investigation was conducted to determine the cytotoxicity of one particular family of graphene derivatives, the halogenated graphenes, for the first time. Halogenated graphenes were prepared through thermal exfoliation of graphite oxide in gaseous chlorine, bromine or iodine atmospheres to yield chlorine- (TRGO-Cl), bromine- (TRGO-Br) and iodine-doped graphene (TRGO-I) respectively. 24 h exposure of human lung carcinoma epithelial cells (A549) to the three halogenated graphenes and subsequent cell viability assessments using methylthiazolyldiphenyl-tetrazolium bromide (MTT) and water-soluble tetrazolium salt (WST-8) assays revealed that all the halogenated graphenes examined are rather cytotoxic at the concentrations tested (3.125 μg mL-1 to 200 μg mL-1) and the effects are dose-dependent, with TRGO-Cl reducing the cell viability to as low as 25.7% at the maximum concentration of 200 μg mL-1. Their levels of cytotoxicity can be arranged in the order of TRGO-Cl > TRGO-Br > TRGO-I, and it is suggested that the amount of halogen present in the graphene material is the determining factor for the observed trend. Control experiments were carried out to test for possible nanomaterial-induced interference as a consequence of reaction between the halogenated graphenes and the viability markers (MTT/WST-8 reagent) or binding of the formazan products under cell-free conditions. The data obtained eliminate the probability of significant influence by these interferents as the change in the normalized percentage of formazan formed is relatively small and thorough washings were performed prior to the viability assessments to reduce the amount of halogenated

  20. Phospho-sulindac (OXT-328) Inhibits the Growth of Human Lung Cancer Xenografts in Mice: Enhanced Efficacy and Mitochondria Targeting by Its Formulation in Solid Lipid Nanoparticles

    PubMed Central

    Zhu, Rongrong; Cheng, Ka-Wing; Mackenzie, Gerardo; Huang, Liqun; Sun, Yu; Xie, Gang; Vrankova, Kveta; Rigas, Basil; Constantinides, Panayiotis P.

    2013-01-01

    Purpose To evaluate the antitumor efficacy of solid lipid nanoparticle–encapsulated phospho-sulindac (SLN-PS) in human lung cancer. Methods PS was incorporated into SLNs using the emulsion evaporation technique. We determined the antitumor activity of SLN-PS in cultured lung cancer cells. The performance of SLN-PS was further evaluated by pharmacokinetic studies in mice and in a model of human lung cancer xenografts in nude mice. Results SLN-PS was >4-fold more potent than PS in inhibiting the growth of A549 and H510 cells in vitro. SLN-PS enhanced cellular uptake and facilitated PS accumulation in mitochondria, leading to oxidative stress and apoptosis via the mitochondrial-apoptosis pathway. SLN-PS was highly effective in suppressing the growth of A549 xenografts (78% inhibition compared to control, p < 0.01); while PS had no significant effect. Formulation of PS in SLNs resulted in improved pharmacokinetics in mice and an enhanced (~14-fold) accumulation of PS and its metabolites in A549 xenografts. Finally, SLN-PS enhanced urinary F2-isoprostane uniquely in mice bearing A549 xenografts compared to untreated controls, suggesting that SLN-PS specifically induced oxidative stress in tumors. Conclusions Our results show that SLN-PS is efficacious in suppressing the growth of lung cancer and merits further evaluation. PMID:22723123

  1. Effect of Sulindac Binary System on In Vitro and In Vivo Release Profiles: An Assessment of Polymer Type and Its Ratio

    PubMed Central

    2016-01-01

    The bioavailability of sulindac (SDC), a nonsteroidal anti-inflammatory drug, is low due to poor aqueous solubility and poor dissolution rate. For this reason it is necessary to enhance the solubility and enhance dissolution of the drug by dispersing SDC in polyethylene glycols 6000 (PEG 6000) and polyvinyl pyrrolidone 40000 (PVP 40000) matrices using the coevaporation technique. Studying the influence of SDC to polymer ratio on drug content, percent yield, particle size, and in vitro release was performed. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy were used to characterize any change in crystal habit of SDC in the prepared formulae. The anti-inflammatory effect of SDC was studied using the hind paw edema model. It was found that incorporation of SDC in PEG 6000 and PVP 40000 matrices resulted in improving the dissolution rate, which was found to depend on the polymer and its weight ratio of the drug. It is clearly obvious that the dissolution rate was remarkably improved in drug PVP 40000 molecular dispersions when compared to drug PEG 6000 systems. Solid dispersion of SDC in PEG and PVP improved the anti-inflammatory effect of SDC and it was found that formula SDV5 exhibited a more pronounced inhibition of swelling than other formulae. PMID:27840824

  2. Effect of Sulindac Binary System on In Vitro and In Vivo Release Profiles: An Assessment of Polymer Type and Its Ratio.

    PubMed

    Shazly, Gamal A

    2016-01-01

    The bioavailability of sulindac (SDC), a nonsteroidal anti-inflammatory drug, is low due to poor aqueous solubility and poor dissolution rate. For this reason it is necessary to enhance the solubility and enhance dissolution of the drug by dispersing SDC in polyethylene glycols 6000 (PEG 6000) and polyvinyl pyrrolidone 40000 (PVP 40000) matrices using the coevaporation technique. Studying the influence of SDC to polymer ratio on drug content, percent yield, particle size, and in vitro release was performed. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy were used to characterize any change in crystal habit of SDC in the prepared formulae. The anti-inflammatory effect of SDC was studied using the hind paw edema model. It was found that incorporation of SDC in PEG 6000 and PVP 40000 matrices resulted in improving the dissolution rate, which was found to depend on the polymer and its weight ratio of the drug. It is clearly obvious that the dissolution rate was remarkably improved in drug PVP 40000 molecular dispersions when compared to drug PEG 6000 systems. Solid dispersion of SDC in PEG and PVP improved the anti-inflammatory effect of SDC and it was found that formula SDV5 exhibited a more pronounced inhibition of swelling than other formulae.

  3. Phospho-sulindac (OXT-328) inhibits the growth of human lung cancer xenografts in mice: enhanced efficacy and mitochondria targeting by its formulation in solid lipid nanoparticles.

    PubMed

    Zhu, Rongrong; Cheng, Ka-Wing; Mackenzie, Gerardo; Huang, Liqun; Sun, Yu; Xie, Gang; Vrankova, Kveta; Constantinides, Panayiotis P; Rigas, Basil

    2012-11-01

    To evaluate the antitumor efficacy of solid lipid nanoparticle-encapsulated phospho-sulindac (SLN-PS) in human lung cancer. PS was incorporated into SLNs using the emulsion evaporation technique. We determined the antitumor activity of SLN-PS in cultured lung cancer cells. The performance of SLN-PS was further evaluated by pharmacokinetic studies in mice and in a model of human lung cancer xenografts in nude mice. SLN-PS was >4-fold more potent than PS in inhibiting the growth of A549 and H510 cells in vitro. SLN-PS enhanced cellular uptake and facilitated PS accumulation in mitochondria, leading to oxidative stress and apoptosis via the mitochondrial-apoptosis pathway. SLN-PS was highly effective in suppressing the growth of A549 xenografts (78% inhibition compared to control, p < 0.01); while PS had no significant effect. Formulation of PS in SLNs resulted in improved pharmacokinetics in mice and an enhanced (≈ 14-fold) accumulation of PS and its metabolites in A549 xenografts. Finally, SLN-PS enhanced urinary F2-isoprostane uniquely in mice bearing A549 xenografts compared to untreated controls, suggesting that SLN-PS specifically induced oxidative stress in tumors. Our results show that SLN-PS is efficacious in suppressing the growth of lung cancer and merits further evaluation.

  4. Sulindac sulfide inhibits sarcoendoplasmic reticulum Ca2+ ATPase, induces endoplasmic reticulum stress response, and exerts toxicity in glioma cells: relevant similarities to and important differences from celecoxib.

    PubMed

    White, M C; Johnson, G G; Zhang, W; Hobrath, J V; Piazza, G A; Grimaldi, M

    2013-03-01

    Malignant gliomas have low survival expectations regardless of current treatments. Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent cell transformation and slow cancer cell growth by mechanisms independent of cyclooxygenase (COX) inhibition. Certain NSAIDs trigger the endoplasmic reticulum stress response (ERSR), as revealed by upregulation of molecular chaperones such as GRP78 and C/EBP homologous protein (CHOP). Although celecoxib (CELE) inhibits the sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA), an effect known to induce ERSR, sulindac sulfide (SS) has not been reported to affect SERCA. Here, we investigated these two drugs for their effects on Ca(2+) homeostasis, ERSR, and glioma cell survival. Our findings indicate that SS is a reversible inhibitor of SERCA and that both SS and CELE bind SERCA at its cyclopiazonic acid binding site. Furthermore, CELE releases additional Ca(2+) from the mitochondria. In glioma cells, both NSAIDS upregulate GRP78 and activate ER-associated caspase-4 and caspase-3. Although only CELE upregulates the expression of CHOP, it appears that CHOP induction could be associated with mitochondrial poisoning. In addition, CHOP induction appears to be uncorrelated with the gliotoxicity of these NSAIDS in our experiments. Our data suggest that activation of ERSR is primarily responsible for the gliotoxic effect of these NSAIDS. Because SS has good brain bioavailability, has lower COX-2 inhibition, and has no mitochondrial effects, it represents a more appealing molecular candidate than CELE to achieve gliotoxicity via activation of ERSR. Copyright © 2012 Wiley Periodicals, Inc.

  5. CYTOTOXIC PHOSPHOLIPID OXIDATION PRODUCTS

    PubMed Central

    Chen, Rui; Yang, Lili; McIntyre, Thomas M.

    2008-01-01

    Phospholipid oxidation products accumulate in the necrotic core of atherosclerotic lesions, in apoptotic cells, and circulate in oxidized LDL. Phospholipid oxidation generates toxic products, but little is known about which specific products are cytotoxic, their receptors, or the mechanism(s) that induces cell death. We find the most common phospholipid oxidation product of oxidized LDL, phosphatidylcholine with esterified sn-2 azelaic acid, induced apoptosis at low micromolar concentrations. The synthetic ether phospholipid hexadecyl azelaoyl phosphatidylcholine (HAzPC) was rapidly internalized, and over-expression of PLA2g7 (PAF acetylhydrolase) that specifically hydrolyzes such oxidized phospholipids suppressed apoptosis. Internalized HAzPC associated with mitochondria, and cytochrome C and apoptosis-inducing factor escaped from mitochondria to the cytoplasm and nucleus, respectively, in cells exposed to HAzPC. Isolated mitochondria exposed to HAzPC rapidly swelled, and released cytochrome C and apoptosis-inducing factor. Other phospholipid oxidation products induced swelling, but HAzPC was the most effective and was twice as effective as its diacyl homolog. Cytoplasmic cytochrome C completes the apoptosome, and activated caspase 9 and 3 were present in cells exposed to HAzPC. Irreversible inhibition of caspase 9 blocked downstream caspase 3 activation, and prevented apoptosis. Mitochondrial damage initiated this apoptotic cascade because over-expression of Bcl-XL, an anti-apoptotic protein localized to mitochondria, blocked cytochrome C escape, and apoptosis. Thus, exogenous phospholipid oxidation products target intracellular mitochondria to activate the intrinsic apoptotic cascade. PMID:17597068

  6. Are diamond nanoparticles cytotoxic?

    PubMed

    Schrand, Amanda M; Huang, Houjin; Carlson, Cataleya; Schlager, John J; Omacr Sawa, Eiji; Hussain, Saber M; Dai, Liming

    2007-01-11

    Finely divided carbon particles, including charcoal, lampblack, and diamond particles, have been used for ornamental and official tattoos since ancient times. With the recent development in nanoscience and nanotechnology, carbon-based nanomaterials (e.g., fullerenes, nanotubes, nanodiamonds) attract a great deal of interest. Owing to their low chemical reactivity and unique physical properties, nanodiamonds could be useful in a variety of biological applications such as carriers for drugs, genes, or proteins; novel imaging techniques; coatings for implantable materials; and biosensors and biomedical nanorobots. Therefore, it is essential to ascertain the possible hazards of nanodiamonds to humans and other biological systems. We have, for the first time, assessed the cytotoxicity of nanodiamonds ranging in size from 2 to 10 nm. Assays of cell viability such as mitochondrial function (MTT) and luminescent ATP production showed that nanodiamonds were not toxic to a variety of cell types. Furthermore, nanodiamonds did not produce significant reactive oxygen species. Cells can grow on nanodiamond-coated substrates without morphological changes compared to controls. These results suggest that nanodiamonds could be ideal for many biological applications in a diverse range of cell types.

  7. Cytotoxicity of Hymenocallis expansa alkaloids.

    PubMed

    Antoun, M D; Mendoza, N T; Ríos, Y R; Proctor, G R; Wickramaratne, D B; Pezzuto, J M; Kinghorn, A D

    1993-08-01

    From the bulbs and leaves of Hymenocallis expansa (Amaryllidaceae), three alkaloid constituents were identified: (+)-tazettine, (+)-hippeastrine, and (-)-haemanthidine. These alkaloids demonstrated significant cytotoxicity when tested against a panel of human and murine tumor cell lines.

  8. Secretory Defect and Cytotoxicity

    PubMed Central

    Li, Songhua; Yang, Zhihui; Hu, Jane; Gordon, William C.; Bazan, Nicolas G.; Haas, Arthur L.; Bok, Dean; Jin, Minghao

    2013-01-01

    Interphotoreceptor retinoid-binding protein (IRBP) secreted by photoreceptors plays a pivotal role in photoreceptor survival and function. Recently, a D1080N mutation in IRBP was found in patients with retinitis pigmentosa, a frequent cause of retinal degeneration. The molecular and cellular bases for pathogenicity of the mutation are unknown. Here, we show that the mutation abolishes secretion of IRBP and results in formation of insoluble high molecular weight complexes via disulfide bonds. Co-expression of protein disulfide isomerase A2 that regulates disulfide bond formation or introduction of double Cys-to-Ala substitutions at positions 304 and 1175 in D1080N IRBP promoted secretion of the mutated IRBP. D1080N IRBP was not transported to the Golgi apparatus, but accumulated in the endoplasmic reticulum (ER), bound with the ER-resident chaperone proteins such as BiP, protein disulfide isomerase, and heat shock proteins. Splicing of X-box-binding protein-1 mRNA, expression of activating transcription factor 4 (ATF4), and cleavage of ATF6 were significantly increased in cells expressing D1080N IRBP. Moreover, D1080N IRBP induced up-regulation and nuclear translocation of the C/EBP homologous protein, a proapoptotic transcription factor associated with the unfolded protein response. These results indicate that loss of normal function (nonsecretion) and gain of cytotoxic function (ER stress) are involved in the disease mechanisms of D1080N IRBP. Chemical chaperones and low temperature, which help proper folding of many mutated proteins, significantly rescued secretion of D1080N IRBP, suggesting that misfolding is the molecular basis for pathogenicity of D1080N substitution and that chemical chaperones are therapeutic candidates for the mutation-caused blinding disease. PMID:23486466

  9. Hydrogen sulfide-mediated myocardial pre- and post-conditioning

    PubMed Central

    Predmore, Benjamin L; Lefer, David J

    2011-01-01

    Coronary artery disease is a major cause of morbidity and mortality in the Western world. Acute myocardial infarction, resulting from coronary artery atherosclerosis, is a serious and often fatal consequence of coronary artery disease, resulting in cell death in the myocardium. Pre- and post-conditioning of the myocardium are two treatment strategies that reduce the amount of cell death significantly. Hydrogen sulfide has recently been identified as a potent cardioprotective signaling molecule, which is a highly effective pre- and post-conditioning agent. The cardioprotective signaling pathways involved in hydrogen sulfide-based pre- and post-conditioning will be explored in this article. PMID:21373204

  10. Ricin. Mechanisms of cytotoxicity.

    PubMed

    Lord, Michael J; Jolliffe, Nicholas A; Marsden, Catherine J; Pateman, Cassandra S; Smith, Daniel C; Spooner, Robert A; Watson, Peter D; Roberts, Lynne M

    2003-01-01

    or if inhaled, has identified this protein toxin as a potential biological warfare agent. Therapeutically, its cytotoxicity has encouraged the use of ricin in 'magic bullets' to specifically target and destroy cancer cells, and the unusual intracellular trafficking properties of ricin potentially permit its development as a vaccine vector. Combining our understanding of the ricin structure with ways to cripple its unwanted properties (its enzymatic activity and promotion of vascular leak whilst retaining protein stability and important immunodominant epitopes), will also be crucial in the development of a long awaited protective vaccine against this toxin.

  11. Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin mediated transcription in human breast tumor cells

    PubMed Central

    Tinsley, Heather N.; Gary, Bernard D.; Keeton, Adam B.; Lu, Wenyan; Li, Yonghe; Piazza, Gary A.

    2011-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac sulfide (SS) display promising antineoplastic properties, but toxicities resulting from cyclooxygenase (COX) inhibition limit their clinical use. While COX inhibition is responsible for the anti-inflammatory activity of SS, recent studies suggest that phosphodiesterase (PDE) 5 inhibition and activation of cGMP signaling are closely associated with its ability to induce apoptosis of tumor cells. However, the underlying mechanisms responsible for apoptosis induction, factors that influence sensitivity of tumor cells to SS, and the importance of PDE5 for breast tumor cell growth have not been established. Here we show that SS can induce apoptosis of breast tumor cells, which predominantly rely on PDE5 for cGMP hydrolysis, but not normal mammary epithelial cells, which rely on PDE isozymes other than PDE5 for cGMP hydrolysis. Inhibition of PDE5 and activation of PKG by SS was associated with increased β-catenin phosphorylation, decreased β-catenin mRNA and protein levels, reduced β-catenin nuclear localization, decreased Tcf/Lef promoter activity, and decreased expression of Wnt/β-catenin regulated proteins. Suppression of PDE5 with siRNA or known PDE5 inhibitors was sufficient to selectively induce apoptosis and attenuate β-catenin mediated transcription in breast tumor cells with minimal effects on normal mammary epithelial cells. These findings provide evidence that SS induces apoptosis of breast tumor cells through a mechanism involving inhibition of PDE5 and attenuation of oncogenic Wnt/β-catenin mediated transcription. We conclude that PDE5 represents a novel molecular target for the discovery of safer and more efficacious drugs for breast cancer chemoprevention. PMID:21505183

  12. Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin-mediated transcription in human breast tumor cells.

    PubMed

    Tinsley, Heather N; Gary, Bernard D; Keeton, Adam B; Lu, Wenyan; Li, Yonghe; Piazza, Gary A

    2011-08-01

    Nonsteroidal anti-inflammatory drugs (NSAID) such as sulindac sulfide (SS) display promising antineoplastic properties, but toxicities resulting from COX inhibition limit their clinical use. Although COX inhibition is responsible for the anti-inflammatory activity of SS, recent studies suggest that phosphodiesterase (PDE) 5 inhibition and activation of cyclic guanosine monophosphate (cGMP) signaling are closely associated with its ability to induce apoptosis of tumor cells. However, the underlying mechanisms responsible for apoptosis induction, factors that influence sensitivity of tumor cells to SS, and the importance of PDE5 for breast tumor cell growth have not been established. Here we show that SS can induce apoptosis of breast tumor cells, which predominantly rely on PDE5 for cGMP hydrolysis but not normal mammary epithelial cells, which rely on PDE isozymes other than PDE5 for cGMP hydrolysis. Inhibition of PDE5 and activation of protein kinase G (PKG) by SS was associated with increased β-catenin phosphorylation, decreased β-catenin mRNA and protein levels, reduced β-catenin nuclear localization, decreased T-cell factor/lymphoid enhancer factor (Tcf/Lef) promoter activity, and decreased expression of Wnt/β-catenin-regulated proteins. Suppression of PDE5 with siRNA or known PDE5 inhibitors was sufficient to selectively induce apoptosis and attenuate β-catenin-mediated transcription in breast tumor cells with minimal effects on normal mammary epithelial cells. These findings provide evidence that SS induces apoptosis of breast tumor cells through a mechanism involving inhibition of PDE5 and attenuation of oncogenic Wnt/β-catenin-mediated transcription. We conclude that PDE5 represents a novel molecular target for the discovery of safer and more efficacious drugs for breast cancer chemoprevention.

  13. Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition.

    PubMed

    Tinsley, Heather N; Gary, Bernard D; Thaiparambil, Jose; Li, Nan; Lu, Wenyan; Li, Yonghe; Maxuitenko, Yulia Y; Keeton, Adam B; Piazza, Gary A

    2010-10-01

    Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here, we show that the NSAID sulindac sulfide (SS) inhibits cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase (PDE) activity in colon tumor cell lysates at concentrations that inhibit colon tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs also inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit colon tumor cell growth, whereas no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cyclic AMP hydrolysis, SS inhibited the cGMP-specific PDE5 isozyme and increased cGMP levels in colon tumor cells. Of numerous PDE isozyme-specific inhibitors evaluated, only the PDE5-selective inhibitor MY5445 inhibited colon tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin-mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in colon tumor cell lines as well as in colon adenomas and adenocarcinomas compared with normal colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs.

  14. Sulindac, 3,3'-diindolylmethane and curcumin reduce carcinogenesis in the Pirc rat, an Apc-driven model of colon carcinogenesis.

    PubMed

    Femia, Angelo Pietro; Soares, Paulo Victoria; Luceri, Cristina; Lodovici, Maura; Giannini, Augusto; Caderni, Giovanna

    2015-09-03

    Recently, we showed that Sulindac (SU; 320 ppm) reduces precancerous lesions in the colon of Pirc rats, mutated in the Apc gene. Surprisingly, previous data in Apc-mutated mice showed that SU, with reported efficacy in Familial Adenomatous Polyposis (FAP), increases colon carcinogenesis. Therefore, we assessed the effect of SU 320 ppm in a long-term carcinogenesis experiment in Pirc rats. Moreover, since side effects of SU hamper its chronic use and a combination of drugs could be more effective and less toxic than single agents, we also studied whether two natural compounds, 3,3'-diindolylmethane (DIM; 250 ppm) and curcumin (CUR; 2000 ppm), with or without lower doses of SU could affect carcinogenesis Pirc rats were fed an AIN76 diet containing SU, DIM and CUR and sacrificed at 8 months of age to measure intestinal tumours. Apoptosis and proliferation in the normal colon mucosa, as well as gene expression profile were studied Colon tumours were significantly reduced by SU 320 ppm (62 % reduction over Controls), by DIM and CUR without or with SU 80 and 160 ppm (50, 53 and 58 % reduction, respectively) but not by SU 80 ppm alone. Total tumours (colon and small intestine) were reduced by SU (80 and 320 ppm) and by DIM and CUR. Apoptosis in the normal mucosa was significantly increased by SU 320 ppm, and slightly increased by DIM and CUR with or without SU. A slight reduction in Survivin-Birc5 expression was observed with all the treatments compared to Controls. Proliferative activity was not varied The results on SU reinforce the validity of Pirc rats to identify chemopreventive products. Moreover, the efficacy of the DIM and CUR combination to lower colon tumours, suggests an alternative strategy to be exploited in patients at risk.

  15. Cytotoxic quassinoids from Ailanthus altissima.

    PubMed

    Wang, Yan; Wang, Wen-Jing; Su, Chang; Zhang, Dong-Mei; Xu, Li-Peng; He, Rong-Rong; Wang, Lei; Zhang, Jian; Zhang, Xiao-Qi; Ye, Wen-Cai

    2013-02-01

    Two new quassinoids, altissinol A (1) and B (7), together with 12 known quassinoids, were isolated from the 95% ethanol extract of the barks of Ailanthus altissima. The structures of the new compounds (1 and 7) were determined on the basis of the spectroscopic methods including UV, IR, HR-ESI-MS, 1D and 2D NMR. The cytotoxic potential of all isolates were evaluated in vitro against three human hepatoma cell lines. Quassinoids 1-7 displayed potent cytotoxic activities against human hepatoma Hep3B and HepG2 cell lines. Interestingly, compounds 2, 3, and 5 exhibited cytotoxic activity against multidrug resistance HepG2/ADM cell line with IC(50) value 4.3-fold more sensitive to Doxorubicin (DOX). Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Cytotoxic activity of Aeromonas hydrophila.

    PubMed Central

    Donta, S T; Haddow, A D

    1978-01-01

    Most strains of Aeromonas hydrophila tested demonstrated cytotoxic activity on several tissue-cultured cell lines. The cytotoxin is heat-labile, non-dialyzable, and immunologically distinct from that of Shigella dysenteriae and Clostridium perfringens. None of the aeromonas isolates was found to be enterotoxigenic by either tissue culture or rabbit ileal loop assays. Images PMID:711344

  17. Saponins as cytotoxic agents: a review

    PubMed Central

    Galanty, Agnieszka; Sobolewska, Danuta

    2010-01-01

    Saponins are natural glycosides which possess a wide range of pharmacological properties including cytotoxic activity. In this review, the recent studies (2005–2009) concerning the cytotoxic activity of saponins have been summarized. The correlations between the structure and the cytotoxicity of both steroid and triterpenoid saponins have been described as well as the most common mechanisms of action. PMID:20835386

  18. Cytotoxicity of zinc in vitro.

    PubMed

    Borovanský, J; Riley, P A

    1989-01-01

    The effect of zinc ions on B16 mouse melanoma lines, HeLa cells and I-221 epithelial cells was investigated in vitro in order to ascertain whether sensitivity to Zn2+ is a general feature of cells in vitro and in an attempt to elucidate the mechanism(s) of zinc cytotoxicity. The proliferation of B16, HeLa and I-221 cell lines was inhibited by 1.25 x 10(-4), 1.50 x 10(-4) and 1.50 x 10(-4) mol/l Zn2+, respectively. The free radical scavengers, methimazole and ethanol, did not suppress the toxicity of Zn2+, neither did superoxide dismutase or catalase. The addition of the chelating agent EDTA reduced the zinc cytotoxicity. It was possible to suppress the cytotoxicity of zinc by increasing the concentration of either Fe2+ or Ca2+ but not Mg2+, which suggests that a prerequisite for the toxic action of zinc is entry into cells using channels that are shared with iron or calcium. This view was supported by experiments in which transferrin intensified the cytotoxic action of zinc in serum-free medium. Another agent facilitating zinc transport, prostaglandin E2, inhibited the proliferation of the B16 melanoma cell line. There were no conspicuous differences in zinc toxicity to pigmented and unpigmented cells. The toxic effect of zinc in the cell systems studied exceeded that of iron, copper, manganese and cobalt in the same concentration range. In vitro, Zn2+ should be regarded as a dangerous cation.

  19. Cytotoxic geranylflavonoids from Bonannia graeca

    PubMed Central

    Rosselli, Sergio; Bruno, Maurizio; Maggio, Antonella; Raccuglia, Rosa Angela; Safder, Muhammad; Lai, Chin-Yu; Bastow, Kenneth F.; Lee, Kuo-Hsiung

    2011-01-01

    The analysis of the aerial parts of Bonannia graeca led to the isolation and characterization of two new polar geranylated flavonoids (6 and 7). The structure elucidation was performed by extensive spectroscopic methods (1D and 2D NMR) and comparison with literature data. All natural flavonoids isolated from B. graeca (1–7) and some synthetic derivatives (8–11) were tested for cytotoxic activity against four human tumor cell lines. Preliminary structure-activity relationship correlations are discussed. PMID:21459391

  20. Triterpenes as potentially cytotoxic compounds.

    PubMed

    Chudzik, Malwina; Korzonek-Szlacheta, Ilona; Król, Wojciech

    2015-01-19

    Triterpenes are compounds of natural origin, which have numerously biological activities: anti-cancer properties, anti-inflammatory, anti-oxidative, anti-viral, anti-bacterial and anti-fungal. These substances can be isolated from plants, animals or fungi. Nowadays, when neoplasms are main cause of death, triterpenes can become an alternative method for treating cancer because of their cytotoxic properties and chemopreventive activities.

  1. Cytotoxic coumarins from Mammea harmandii.

    PubMed

    Reutrakul, Vichai; Leewanich, Pornsiri; Tuchinda, Patoomratana; Pohmakotr, Manat; Jaipetch, Thaworn; Sophasan, Samaisukh; Santisuk, Thawatchai

    2003-11-01

    Two new naturally occurring coumarins, isomesuol (1) and mammearin A (2), together with nine known Mammea coumarins 3-11 were isolated from the EtOAc extract of the leaves and twigs of Mammea harmandii. Coumarins 1, 3 and 4 showed cytotoxicity against a panel of mammalian cancer cell lines. Their structures were determined by spectroscopic methods. The assignments of 13C-NMR signals of isomesuol (1), which was isolated for the first time as a natural product, have been revised.

  2. Cell Proliferation and Cytotoxicity Assays.

    PubMed

    Adan, Aysun; Kiraz, Yağmur; Baran, Yusuf

    Cell viability is defined as the number of healthy cells in a sample and proliferation of cells is a vital indicator for understanding the mechanisms in action of certain genes, proteins and pathways involved cell survival or death after exposing to toxic agents. Generally, methods used to determine viability are also common for the detection of cell proliferation. Cell cytotoxicity and proliferation assays are generally used for drug screening to detect whether the test molecules have effects on cell proliferation or display direct cytotoxic effects. Regardless of the type of cell-based assay being used, it is important to know how many viable cells are remaining at the end of the experiment. There are a variety of assay methods based on various cell functions such as enzyme activity, cell membrane permeability, cell adherence, ATP production, co-enzyme production, and nucleotide uptake activity. These methods could be basically classified into different categories: (I) dye exclusion methods such as trypan blue dye exclusion assay, (II) methods based on metabolic activity, (III) ATP assay, (IV) sulforhodamine B assay, (V) protease viability marker assay, (VI) clonogenic cell survival assay, (VII) DNA synthesis cell proliferation assays and (V) raman micro-spectroscopy. In order to choose the optimal viability assay, the cell type, applied culture conditions, and the specific questions being asked should be considered in detail. This particular review aims to provide an overview of common cell proliferation and cytotoxicity assays together with their own advantages and disadvantages, their methodologies, comparisons and intended purposes.

  3. Cytotoxic Compounds from Brucea mollis

    PubMed Central

    Tung, Mai Hung Thanh; Đuc, Ho Viet; Huong, Tran Thu; Duong, Nguyen Thanh; Phuong, Do Thi; Thao, Do Thi; Tai, Bui Huu; Kim, Young Ho; Bach, Tran The; Cuong, Nguyen Manh

    2013-01-01

    Ten compounds, including soulameanone (1), isobruceine B (2), 9-methoxy-canthin-6-one (3), bruceolline F (4), niloticine (5), octatriacontan-1-ol (6), bombiprenone (7), α-tocopherol (8), inosine (9), and apigenin 7-O-β-D-glucopyranoside (10), were isolated from the leaves, stems, and roots of Brucea mollis Wall. ex Kurz. Their structures were determined using one-and two-dimensional NMR spectroscopy and mass spectrometry. All compounds were evaluated for their cytotoxic activity against KB (human carcinoma of the mouth), LU-1 (human lung adenocarcinoma), LNCaP (human prostate adeno-carcinoma), and HL-60 (human promyelocytic leukemia) cancer cell lines. Compound 2 showed significant cytotoxic activity against KB, LU-1, LNCaP, and HL-60 cancer cells with IC50 values of 0.39, 0.40, 0.34, and 0.23 μg/mL, respectively. In addition, compounds 3 and 5 showed significant cytotoxic activity against KB, LU-1, LNCaP, and HL-60 cancer cells with IC50 values around 1–4 μg/mL. Compounds 9-methoxycanthin-6-one (3) and niloticine (5) have been discovered for the first time from the Brucea genus. PMID:24106661

  4. Comparative cytotoxicity of periodontal bacteria

    SciTech Connect

    Stevens, R.H.; Hammond, B.F.

    1988-11-01

    The direct cytotoxicity of sonic extracts (SE) from nine periodontal bacteria for human gingival fibroblasts (HGF) was compared. Equivalent dosages (in terms of protein concentration) of SE were used to challenge HGF cultures. The cytotoxic potential of each SE was assessed by its ability to (1) inhibit HGF proliferation, as measured by direct cell counts; (2) inhibit 3H-thymidine incorporation in HGF cultures; or (3) cause morphological alterations of the cells in challenged cultures. The highest concentration (500 micrograms SE protein/ml) of any of the SEs used to challenge the cells was found to be markedly inhibitory to the HGFs by all three of the criteria of cytotoxicity. At the lowest dosage tested (50 micrograms SE protein/ml); only SE from Actinobacillus actinomycetemcomitans, Bacteroides gingivalis, and Fusobacterium nucleatum caused a significant effect (greater than 90% inhibition or overt morphological abnormalities) in the HGFs as determined by any of the criteria employed. SE from Capnocytophaga sputigena, Eikenella corrodens, or Wolinella recta also inhibited cell proliferation and thymidine incorporation at this dosage; however, the degree of inhibition (5-50%) was consistently, clearly less than that of the first group of three organisms named above. The SE of the three other organisms tested (Actinomyces odontolyticus, Bacteroides intermedius, and Streptococcus sanguis) had little or no effect (0-10% inhibition) at this concentration. The data suggest that the outcome of the interaction between bacterial components and normal resident cells of the periodontium is, at least in part, a function of the bacterial species.

  5. Long-term outcome of sporadic and FAP-associated desmoid tumors treated with high-dose selective estrogen receptor modulators and sulindac: a single-center long-term observational study in 134 patients.

    PubMed

    Quast, Daniel Robert; Schneider, Ralph; Burdzik, Emanuel; Hoppe, Steffen; Möslein, Gabriela

    2016-01-01

    Aim of this study is to evaluate the outcome of long-term conservative treatment with sulindac and high-dose selective estrogen receptor modulators (SERMs) for sporadic and FAP-associated desmoid tumors. Desmoids are very rare tumors in the general population but occur frequently in FAP patients, being encountered in 23-38 %. Treatment of desmoids is still most controversial since response cannot be predicted and they are prone to develop recurrence. This study included all desmoid patients that were treated and followed at our institution and had completed at least 1 year of treatment. Response was defined as stable size or regression of desmoid size between two CT or MRI scans. A total of 134 patients were included. 64 (47.8 %) patients had a confirmed diagnosis of FAP, 69 (51.5 %) patients were sporadic. Overall 114 (85.1 %) patients showed regressive or stable desmoid size. Patients with previous history of multiple desmoid-related surgeries showed less-favorable response. The mean time to reach at least stable size was 14.9 (±9.1) months. After regression or stabilization, medication was tapered in 69 (60.5 %) of the treated patients with only one long-term recurrence after >10 years. The results of this study fortify the role of sulindac and high-dose SERMs as an effective and safe treatment for both, sporadic and FAP-associated desmoid tumors. While invasive treatment frequently results in high recurrence rates, high morbidity and high mortality, this conservative treatment is successful in most patients. The recurrence rate is negligible with no desmoid-related mortality in this large series. Therefore surgical resection, especially for mesenteric desmoids, should be deferred favoring this convincingly effective, well tolerated regimen.

  6. Liposomal formulations of cytotoxic drugs.

    PubMed

    Janknegt, R

    1996-07-01

    Liposomes are microscopic particles of lipid bilayer membrane that enclose aqueous internal compartments. These drug-delivery systems offer a very interesting opportunity for delivering cytotoxic drugs with equal or improved clinical efficacy and reduced toxicity. The most important clinical application of liposomes until now has been the inclusion of amphotericin B. At the same dose level, liposomal amphotericin B is as effective or slightly less effective than the conventional formulation, but much higher dosages, up to 5-7 mg kg-1day-1, can be given with acceptable toxicity. There are three preparations of cytotoxic drugs in an advanced stage of commercial development. Two of these (Doxil and TLD D99) contain doxorubicin and the other (DaunoXome) contains daunorubicin. The cardiac toxicity of the three preparations under clinical evaluation appears to be low in comparison with conventional doxorubicin or daunorubicin. No direct comparisons between the new formulations are available, so it is not yet possible to make any statements concerning their relative efficacy and toxicity. DaunoXome is the only drug that is approved in any country, and is also the best documented. It is too early to make recommendations concerning the place of these drugs in therapy. The marked increase in concentrations at the site of the tumour has yet to lead to increased therapeutic efficacy. These findings need further investigation. The efficacy of liposomal preparations in Kaposi's sarcoma appears to be similar to that of standard therapy and the clinical tolerance is good. Perhaps combination therapy with other cytotoxic agents could result in improved clinical efficacy. Their cost will probably be high in comparison with standard therapies.

  7. Cytotoxic constituents of Saussurea lappa.

    PubMed

    Jung, J H; Kim, Y; Lee, C O; Kang, S S; Park, J H; Im, K S

    1998-04-01

    The crude extract of Saussurea lappa displayed significant lethality to brine shrimp larvae. Investigation of the causative components by bioactivity-directed fractionation resulted in the isolation of three C17-polyene alcohols. Based on various nmr spectral data, these compounds were identified as shikokiols which had been previously isolated from Cirsium nipponicum and/or Centaurea aegyptica. These C17-polyene alcohols exhibited moderate cytotoxicities against the human tumor cell lines, A549, SK-OV-3, SK-MEL-2, XF498, and HCT15.

  8. Cytotoxic diterpenoids from Salvia yunnanensis.

    PubMed

    Wu, Chun-Yan; Liao, Yang; Yang, Zi-Gang; Yang, Xing-Wei; Shen, Xiao-Ling; Li, Rong-Tao; Xu, Gang

    2014-10-01

    Forty-six abietane type diterpenoids possessing nine different fused ring systems were characterized from the roots of Salvia yunnanensis, six of which (salyunnanins A-F, 1-6) had different nor-abietane, homo-abietane, seco-abietane, and normal abietane architectures. Their structures were elucidated by comprehensive NMR and MS spectroscopic analyses. The inhibitory activities of these isolates against six human tumor lines were tested in vitro. Several of the compounds exhibited substantial cytotoxicity with IC50 values of 0.86-10.1μM.

  9. Cytotoxic dinorditerpenoids from Drypetes perreticulata.

    PubMed

    Ge, Ying-Zi; Zhang, Hua; Liu, Hong-Chun; Dong, Lei; Ding, Jian; Yue, Jian-Min

    2014-04-01

    Four hitherto unknown dinorditerpenoids, dryperreins A-D of the pimarane class, together with eight known triterpenoids, were isolated from twigs and leaves of Drypetes perreticulata. The structures of dryperreins A-D were elucidated on the basis of detailed spectroscopic analysis as (10S)-11,12-dihydroxy-6-methoxy-15,16-dinorpimara-5,8,11,13-tetraene-3,7-dione, (10S)-6,11,12-trihydroxy-15,16-dinorpimara-5,8,11,13-tetraene-3,7-dione, (10S)-11,12-dihydroxy-6-methoxy-15,16-dinorpimara-1,5,8,11,13-pentaene-3,7-dione, and (10S)-6,11,12-trihydroxy-15,16-dinorpimara-1,5,8,11,13-pentaene-3,7-dione, respectively. Dryperreins C and D exhibited strong cytotoxicity in vitro against HL-60 human tumor cell line. The structure-activity relationship of the cytotoxic compounds was briefly discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. A cytotoxic substance from Sangre de Grado.

    PubMed

    Itokawa, H; Ichihara, Y; Mochizuki, M; Enomori, T; Morita, H; Shirota, O; Inamatsu, M; Takeya, K

    1991-04-01

    Taspine has been isolated as a cytotoxic substance from Sangre de Grado, sap of Croton palanostigma (Euphorbiaceae), by bioassay guided fractionation. The cytotoxicity (IC50) of taspine was found to be 0.39 microgram/ml against KB cells and 0.17 microgram/ml against V-79 cells.

  11. Cytotoxic Potential of Silver Nanoparticles

    PubMed Central

    Zhang, Tianlu; Wang, Liming

    2014-01-01

    Silver nanoparticles (AgNPs) have been widely used in industrial, household, and healthcare-related products due to their excellent antimicrobial activity. With increased exposure of AgNPs to human beings, the risk of safety has attracted much attention from the public and scientists. In review of recent studies, we discuss the potential impact of AgNPs on individuals at the cell level. In detail, we highlight the main effects mediated by AgNPs on the cell, such as cell uptake and intracellular distribution, cytotoxicity, genotoxicity, and immunological responses, as well as some of the major factors that influence these effects in vivo and in vivo, such as dose, time, size, shape, surface chemistry, and cell type. At the end, we summarize the main influences on the cell and indicate the challenges in this field, which may be helpful for assessing the risk of AgNPs in future. PMID:24532494

  12. Cytotoxic and antibacterial effects of orthodontic appliances.

    PubMed

    Grimsdottir, M R; Hensten-Pettersen, A

    1993-08-01

    The cytotoxic and antibacterial effects of orthodontic appliances were assessed. Metallic devices used in orthodontics, such as molar bands, brackets, and archwires were tested by the agar overlay cytotoxicity test with mouse fibroblast cells. The same devices were tested for antibacterial effect with Streptococcus mutans and S. sanguis. The multicomponent devices, which are bonded with silver- and copper-based brazing alloys, were more cytotoxic than the single-component devices, probably because copper is more cytotoxic than nickel. The devices had a definite, but low, antibacterial effect, as compared with the 0.05% chlorhexidine positive control. A cytotoxic effect of the devices per se might contribute to a localized gingivitis. It is uncertain whether orthodontic devices have any significant inhibitory effect on dental plaque viability.

  13. Serial dilution microchip for cytotoxicity test

    NASA Astrophysics Data System (ADS)

    Bang, Hyunwoo; Lim, Sun Hee; Lee, Young Kyung; Chung, Seok; Chung, Chanil; Han, Dong-Chul; Chang, Jun Keun

    2004-08-01

    Today's pharmaceutical industry is facing challenges resulting from the vast increases in sample numbers produced by high-throughput screening (HTS). In addition, the bottlenecks created by increased demand for cytotoxicity testing (required to assess compound safety) are becoming a serious problem. We have developed a polymer PDMS (polydimethylsiloxane) based microfluidic device that can perform a cytotoxicity test in a rapid and reproducible manner. The concept that the device includes is well adjustable to automated robots in huge HTS systems, so we can think of it as a potential dilution and delivery module. Cytotoxicity testing is all about the dilution and dispensing of a drug sample. Previously, we made a PDMS based microfluidic device which automatically and precisely diluted drugs with a buffer solution with serially increasing concentrations. This time, the serially diluted drug solution was directly delivered to 96 well plates for cytotoxicity testing. Cytotoxic paclitaxel solution with 2% RPMI 1640 has been used while carrying out cancerous cell based cytotoxicity tests. We believe that this rapid and robust use of the PDMS microchip will overcome the growing problem in cytotoxicity testing for HTS.

  14. Cytotoxic Effects of Bangladeshi Medicinal Plant Extracts

    PubMed Central

    Uddin, Shaikh J.; Grice, I. Darren; Tiralongo, Evelin

    2011-01-01

    To investigate the cytotoxic effect of some Bangladeshi medicinal plant extracts, 16 Bangladeshi medicinal plants were successively extracted with n-hexane, dichloromethane, methanol and water. The methanolic and aqueous extracts were screened for cytotoxic activity against healthy mouse fibroblasts (NIH3T3) and three human cancer-cell lines (gastric: AGS; colon: HT-29; and breast: MDA-MB-435S) using the MTT assay. Two methanolic extracts (Hygrophila auriculata and Hibiscus tiliaceous) and one aqueous extract (Limnophila indica) showed no toxicity against healthy mouse fibroblasts, but selective cytotoxicity against breast cancer cells (IC50 1.1–1.6 mg mL−1). Seven methanolic extracts from L. indica, Clerodendron inerme, Cynometra ramiflora, Xylocarpus moluccensis, Argemone mexicana, Ammannia baccifera and Acrostichum aureum and four aqueous extracts from Hygrophila auriculata, Bruguiera gymnorrhiza, X. moluccensis and Aegiceras corniculatum showed low toxicity (IC50 > 2.5 mg mL−1) against mouse fibroblasts but selective cytotoxicity (IC50 0.2–2.3 mg mL−1) against different cancer cell lines. The methanolic extract of Blumea lacera showed the highest cytotoxicity (IC50 0.01–0.08 mg mL−1) against all tested cell lines among all extracts tested in this study. For some of the plants their traditional use as anticancer treatments correlates with the cytotoxic results, whereas for others so far unknown cytotoxic activities were identified. PMID:19706693

  15. Cytotoxic effects of bangladeshi medicinal plant extracts.

    PubMed

    Uddin, Shaikh J; Grice, I Darren; Tiralongo, Evelin

    2011-01-01

    To investigate the cytotoxic effect of some Bangladeshi medicinal plant extracts, 16 Bangladeshi medicinal plants were successively extracted with n-hexane, dichloromethane, methanol and water. The methanolic and aqueous extracts were screened for cytotoxic activity against healthy mouse fibroblasts (NIH3T3) and three human cancer-cell lines (gastric: AGS; colon: HT-29; and breast: MDA-MB-435S) using the MTT assay. Two methanolic extracts (Hygrophila auriculata and Hibiscus tiliaceous) and one aqueous extract (Limnophila indica) showed no toxicity against healthy mouse fibroblasts, but selective cytotoxicity against breast cancer cells (IC(50) 1.1-1.6 mg mL(-1)). Seven methanolic extracts from L. indica, Clerodendron inerme, Cynometra ramiflora, Xylocarpus moluccensis, Argemone mexicana, Ammannia baccifera and Acrostichum aureum and four aqueous extracts from Hygrophila auriculata, Bruguiera gymnorrhiza, X. moluccensis and Aegiceras corniculatum showed low toxicity (IC(50) > 2.5 mg mL(-1)) against mouse fibroblasts but selective cytotoxicity (IC(50) 0.2-2.3 mg mL(-1)) against different cancer cell lines. The methanolic extract of Blumea lacera showed the highest cytotoxicity (IC(50) 0.01-0.08 mg mL(-1)) against all tested cell lines among all extracts tested in this study. For some of the plants their traditional use as anticancer treatments correlates with the cytotoxic results, whereas for others so far unknown cytotoxic activities were identified.

  16. Cytotoxic chalcones from some Indonesian Cryptocarya

    NASA Astrophysics Data System (ADS)

    Kurniadewi, F.; Syah, Y. M.; Juliawaty, L. D.; Hakim, E. H.; Koyama, K.; Kinoshita, K.

    2017-07-01

    Malignant tumors are one of the main causes of death in the world. Until now the search for cytotoxic (antitumor) compounds from nature, particularly from plants, is being a continuation activities. One group of plants that produce potential cytotoxic compounds is the Cryptocarya, one of the large genera of the Lauraceae family. As a part of our chemical and cytotoxic evaluation of the Cryptocarya species, we examined three species of Indonesian Cryptocarya. The sample of the wood of C. konishii hayata was collected from Cibodas Botanical Garden, West Java while the stem bark of C. phoebeopsis and C. cagayanensis were obtained from Sorong, Papua. Our investigation of flavonoid constituents on these species afforded three chalcone compounds i.e. desmethylinfectocaryone (1), infectocaryone (2) and cryptocaryone (3). The molecular structures of the isolated compounds were determined based on spectroscopic data, including UV, IR, 1D and 2D NMR. Cytotoxic effects of the compounds were evaluated using MTT [3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide] assay. Compound 1, 2 and 3 displayed strong cytotoxic properties (IC50 < 2 μg/mL) against Murine Leukemia P388 and HL 60 (blood premyelocytic leukemia) cells whereas 2 and 3 exhibited strong cytotoxicity properties against HCT116 (colon cancer). Cryptocaryone (3) also showed moderate cytotoxic properties (IC50 < 10 μg/mL) towards A549 (human lung adenocarcinoma epithelial) cells.

  17. Cytotoxic constituents of Alocasia macrorrhiza.

    PubMed

    Elsbaey, Marwa; Ahmed, Kadria F M; Elsebai, Mahmoud F; Zaghloul, Ahmed; Amer, Mohamed M A; Lahloub, Mohamed-Farid I

    2017-01-01

    An indole alkaloid, 2-(5-hydroxy-1H-indol-3-yl)-2-oxo-acetic acid (1) isolated for the first time from nature, in addition to the nine known compounds 5-hydroxy-1H-indole-3-carboxylic acid methyl ester (2), alocasin B (3), hyrtiosin B (4), α-monopalmitin (5), 1-O-β-D-glucopyranosyl-(2S, 3R, 4E, 8Z)-2-[(2(R)-hydroctadecanoyl) amido]-4,8-octadecadiene-1,3-diol (6), 3-epi-betulinic acid (7), 3-epi-ursolic acid (8), β-sitosterol (9) and β-sitosterol 3-O-β-D-glucoside (10) were isolated from the rhizomes of Alocasia macrorrhiza (Araceae). Their structures were elucidated by 1D and 2D NMR spectroscopic data. Of these compounds, 6 exhibited the strongest cytotoxicity against the four tested human cancer cell lines (IC50 of about 10 µM against Hep-2 larynx cancer cells).

  18. Cytotoxic glucosyltransferases of Legionella pneumophila.

    PubMed

    Belyi, Yury; Jank, Thomas; Aktories, Klaus

    2013-01-01

    Legionella is a gram-negative bacterium and the causative pathogen of legionellosis-a severe pneumonia in humans. A large number of Legionella effectors interfere with numerous host cell functions, including intracellular vacuole trafficking and maturation, phospholipid metabolism, protein ubiquitination, pro-/anti-apoptotic balances or inflammatory responses. Moreover, eukaryotic protein synthesis is affected by L. pneumophila glucosyltransferases Lgt1, Lgt2, and Lgt3. Structurally, these enzymes are similar to large clostridial cytotoxins, use UDP-glucose as a co-substrate and modify a conserved serine residue (Ser-53) in elongation factor 1A (eEF1A). The ternary complex consisting of eEF1A, GTP, and aminoacylated-tRNA seems to be the substrate for Lgts. Studies with Saccharomyces cerevisiae corroborated that eEF1A is the major target responsible for Lgt-induced cytotoxic activity. In addition to Lgt proteins, Legionella produces other effector glycosyltransferase, including the modularly composed protein SetA, which displays tropism for early endosomal compartments, subverts host cell vesicle trafficking and demonstrates toxic activities toward yeast and mammalian cells. Here, our current knowledge about both groups of L. pneumophila glycosylating effectors is reviewed.

  19. Engineering Polymeric Aptamers for Selective Cytotoxicity

    PubMed Central

    Yang, Liu; Meng, Ling; Zhang, Xiaobing; Chen, Yan; Zhu, Guizhi; Liu, Haipeng; Xiong, Xiangling; Sefah, Kwame; Tan, Weihong

    2011-01-01

    Chemotherapy strategies thus far reported can result in both side effects and drug resistance. To address both of these issues at the cellular level, we report a molecular engineering strategy which employs polymeric aptamers to induce selective cytotoxicity inside target cells. The polymeric aptamers, composed of both multiple cell-based aptamers and a high ratio of dye-labeled short DNA, exploit the target recognition capability of the aptamer, enhanced cell internalization via multivalent effects, and cellular disruption by the polymeric conjugate. Importantly, the polymer backbone built into the conjugate is cytotoxic only inside cells. As a result, selective cytotoxicity is achieved equally in both normal cancer cells and drug-resistant cells. Control assays have confirmed the nontoxicity of the aptamer itself, but they have also shown that the physical properties of the polymer backbone contribute to target cell cytotoxicity. Therefore, our approach may shed new light on drug design and drug delivery. PMID:21702469

  20. The cytotoxic activity of ursolic acid derivatives.

    PubMed

    Ma, Chao-Mei; Cai, Shao-Qing; Cui, Jing-Rong; Wang, Rui-Qing; Tu, Peng-Fei; Hattori, Masao; Daneshtalab, Mohsen

    2005-06-01

    Ursolic acid and 2alpha-hydroxyursolic acid isolated from apple peels were found to show growth inhibitory activity against four tumor cell lines, HL-60, BGC, Bel-7402 and Hela. Structural modifications were performed on the C-3, C-28 and C-11 positions of ursolic acid and the cytotoxicity of the derivatives was evaluated. The SAR revealed that the triterpenes possessing two hydrogen-bond forming groups (an H-donor and a carbonyl group) at positions 3 and 28 exhibit cytotoxic activity. The configuration at C-3 was found to be important for the activity. Introduction of an amino group increased the cytotoxicity greatly. A 3beta-amino derivative was 20 times more potent than the parent ursolic acid. The 28-aminoalkyl dimer compounds showed selective cytotoxicity.

  1. Avoiding accidental exposure to intravenous cytotoxic drugs.

    PubMed

    Meade, Elizabeth

    Many cytotoxic drugs have been shown to be mutagenic, teratogenic and carcinogenic with second malignancies known to be associated with several specific cancer drugs. Occupational exposure to cytotoxic drugs presents a signification danger to healthcare staff and unwarranted handling of these drugs should be avoided. Guidelines have been established for the safe handling of hazardous drugs but not all professionals are adhering to these recommendations. Recent environmental studies have demonstrated measurable drug contamination on surfaces even when recommended guidelines are followed. It is therefore imperative that healthcare workers are aware of the potential hazards of antineoplastic agents and employ the recommended precautions to minimise exposure. This article outlines the potential risks associated with exposure to cytotoxic drugs for healthcare staff. The safe-handling precautions required in the storage, preparation, transport, administration and waste disposal of cytotoxic drugs are presented.

  2. Recommendations for handling cytotoxic drugs in hospitals.

    PubMed

    Stolar, M H; Power, L A; Viele, C S

    1983-07-01

    Recommended procedures for handling cytotoxic drugs in hospitals are presented. The recommended procedures are designed to reduce the number of opportunities for unnecessary contact with cytotoxic agents (CYTAs) by hospital personnel and to prevent contamination of the hospital environment and staff with cytotoxic agents. The recommendations incorporate elements of previously published and unpublished guidelines; they admittedly are based on informed judgment as well. Three sets of recommended procedures are presented, each offering a varying degree of protection. The number of cytotoxic drug doses prepared and administered is suggested as the determinant of which level of protection is followed. The cytotoxic workload index, defined as the number of CYTAs prepared or administered (or both) divided by the number of available staff hours, is proposed as a quantitative method of deciding which level of protection is required for a particular work station or work shift. The recommended procedures cover the following seven topic areas: general guidelines; apparel, equipment, and facilities; drug preparation; drug administration; housekeeping, waste disposal, and management of spills and contamination; medical surveillance of staff; and legal and personnel considerations. The recommended procedures and associated equipment are considered to be practical and to adequately protect hospital personnel from risks associated with handling cytotoxic agents.

  3. Oxidative Mechanisms of Monocyte-Mediated Cytotoxicity

    NASA Astrophysics Data System (ADS)

    Weiss, Stephen J.; Lobuglio, Albert F.; Kessler, Howard B.

    1980-01-01

    Human monocytes stimulated with phorbol myristate acetate were able to rapidly destroy autologous erythrocyte targets. Monocyte-mediated cytotoxicity was related to phorbol myristate acetate concentration and monocyte number. Purified preparations of lymphocytes were incapable of mediating erythrocyte lysis in this system. The ability of phorbol myristate acetate-stimulated monocytes to lyse erythrocyte targets was markedly impaired by catalase or superoxide dismutase but not by heat-inactivated enzymes or albumin. Despite a simultaneous requirement for superoxide anion and hydrogen peroxide in the cytotoxic event, a variety of hydroxyl radical and singlet oxygen scavengers did not effect cytolysis. However, tryptophan significantly inhibited cytotoxicity. The myeloperoxidase inhibitor cyanide enhanced erythrocyte destruction, whereas azide reduced it modestly. The inability of cyanide to reduce cytotoxicity coupled with the protective effect of superoxide dismutase suggests that cytotoxicity is independent of the classic myeloperoxidase system. We conclude that monocytes, stimulated with phorbol myristate acetate, generate superoxide anion and hydrogen peroxide, which together play an integral role in this cytotoxic mechanism.

  4. Cytotoxicity of four categories of dental cements.

    PubMed

    Schmid-Schwap, Martina; Franz, Alexander; König, Franz; Bristela, Margit; Lucas, Trevor; Piehslinger, Eva; Watts, David C; Schedle, Andreas

    2009-03-01

    Assessment of dental material biocompatibility is gaining increasing importance for both patients and dentists. Dental cements may be in contact with oral soft tissues for prolonged periods of time and play an important role in prosthetic rehabilitation. The aim of the present study was to evaluate eight dental cements using a standardized L929-fibroblast cell culture test. For each material, fresh specimens (added to the cultures immediately after preparation) and specimens preincubated for 7 days in cell culture medium were prepared according to the manufacturers' recommendations. After exposure to test specimens, cell numbers were compared to glass controls. The main outcome was a two-sided 95% confidence interval for the mean value of the standardized cell number for each substance investigated. Fresh specimens of all tested cements showed significant cytotoxicity, which diminished after 7 days preincubation. Cytotoxicity of fresh adhesive and self-adhesive resin cements was lower when specimens were dual-cured compared to self-cured. A rank order of cytotoxicity was established based on mean values: Nexus 2 (dual-cured) showed least cytotoxicity, followed by Variolink II (dual-cured), Nexus 2 (self-cured), Harvard, RelyxUnicem (dual-cured), Panavia 21, Fujicem, Durelon, Variolink II (self-cured), RelyxUnicem (self-cured), Maxcem (dual-cured) and Maxcem (self-cured). When bondings were added to Nexus 2 or Variolink II specimens, a slight increase in cytotoxicity was observed. Adhesive resin cements showed less cytotoxicity than self-adhesive and chemically setting cements. Bonding only slightly influenced cytotoxicity of the adhesive resin cements. Dual-cured specimens of adhesive and self-adhesive resin cements showed significantly less toxicity than self-cured specimens.

  5. The cytotoxicity study of praziquantel enantiomers.

    PubMed

    Sun, Qian; Mao, Ruifeng; Wang, Dongling; Hu, Changyan; Zheng, Yang; Sun, Dequn

    2016-01-01

    Praziquantel (PZQ) is prescribed as a racemic mixture (racemic-PZQ, rac-PZQ), which is composed of (R)-PZQ and (S)-PZQ. In this work, the cytotoxicity of rac-PZQ and its two enantiomers (R)-PZQ and (S)-PZQ on eight cell lines (L-02, HepG2, prf-plc-5, SH-SY5Y, HUVEC, A549, HCT-15, Raw264.7) was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-nyltetrazolium bromide and lactate dehydrogenase assays. The morphology of apoptotic cells was studied by fluorescence microscope using Hoechst 33342 staining, and the cytotoxicity of the compounds was also tested by lactate dehydrogenase assay. Results revealed that (R)-PZQ had negligible cytotoxicity against L-02, SH-SY5Y, HUVEC, A549, HCT-15, and Raw264.7 cells but selectively inhibited tumor cell lines (prf-plc-5 and HepG2). However, in contrast to (R)-PZQ, the (S)-isomer showed higher cytotoxicity against L-02 cells and lower inhibition on prf-plc-5 and HepG2 cells. Besides, (R)-PZQ showed lower cytotoxicity on SH-SY5Y cells than (S)-PZQ. Meanwhile, (R)-PZQ at <80 μM concentration could promote proliferation of macrophage cells (Raw264.7). Our research revealed that (R)-PZQ has lower cytotoxicity than (S)-PZQ and has similar cytotoxicity with rac-PZQ. (S)-PZQ is the principal enantiomer to cause side effects on human definitive hosts. These findings gave the reasonable reasons for World Health Organization to produce (R)-PZQ as a replacement for rac-PZQ for the treatment of schistosomiasis.

  6. Cytotoxic effects of acrylates and methacrylates: relationships of monomer structures and cytotoxicity.

    PubMed

    Yoshii, E

    1997-12-15

    Thirty-nine acrylates and methacrylates that had been used in dental resin materials were evaluated by a cytotoxicity test, and the relationships between their structures and cytotoxicity were studied to predict cytotoxic levels of dental resin materials in order to develop new low-toxic resin materials. All the acrylates evaluated were more toxic than corresponding methacrylates. In both the acrylates and methacrylates, a hydroxyl group seemed to enhance cytotoxicity. Dimethacrylates with 14 or fewer oxyethylene chains showed similar cytotoxicity while dimethacrylates with 23 oxyethylene chains showed lower cytotoxicity. The cytotoxicity ranking of monomers widely used in dental resin materials was bisphenol A bis 2-hydroxypropyl methacrylate (bisGMA) > urethane dimethacrylate (UDMA) > triethyleneglycol dimethacrylate (3G) > 2-hydroxyethyl methacrylate (HEMA) > methyl methacrylate (MMA). In acrylates, methacrylates, and ethylmethacrylates with either substituents, the lipophilicity of substituents affected their cytotoxicity, and an inverse correlation between IC50 and logP was observed. These results will be useful in developing new resin materials with low toxic monomer compositions.

  7. Cytotoxicity of Odorous Compounds from Poultry Manure

    PubMed Central

    Nowak, Adriana; Matusiak, Katarzyna; Borowski, Sebastian; Bakuła, Tadeusz; Opaliński, Sebastian; Kołacz, Roman; Gutarowska, Beata

    2016-01-01

    Long-term exposure and inhalation of odorous compounds from poultry manure can be harmful to farm workers and the surrounding residents as well as animals. The aim of the present study was to determine the cytotoxicity and IC50 values of common odorous compounds such as ammonium, dimethylamine, trimethylamine, butyric acid, phenol, and indole in the chick liver hepatocellular carcinoma cell line LMH (Leghorn Male Hepatoma), in vitro, using MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) and PrestoBlue cytotoxicity assays. The cells were microscopically examined for any morphological changes post treatment. Dimethylamine exhibited the strongest cytotoxic effect on LMH cells with an IC50 value of 0.06% and 0.04% after an exposure of 24 h and 48 h, respectively. Both ammonium and trimethylamine had comparable cytotoxicity and their IC50 values were 0.08% and 0.04% after 24 h and 48 h, respectively. Of note, indole had the lowest cytotoxicity as the majority of cells were viable even after 72 h exposure. Thus, the IC50 for indole was not calculated. Results achieved from both MTT and PrestoBlue assays were comparable. Moreover, the morphological changes induced by the tested odours in LMH cells resulted in monolayer destruction, cytoplasm vacuolisation, chromatin condensation, and changes in nucleus and cell shape. Our study showed harmful effects of odorous compounds in chick tissues. PMID:27792203

  8. Safe handling of cytotoxics: guideline recommendations

    PubMed Central

    Easty, A.C.; Coakley, N.; Cheng, R.; Cividino, M.; Savage, P.; Tozer, R.; White, R.E.

    2015-01-01

    Background This evidence-based practice guideline was developed to update and address new issues in the handling of cytotoxics, including the use of oral cytotoxics; the selection and use of personal protective equipment; and treatment in diverse settings, including the home setting. Methods The guideline was developed primarily from an adaptation and endorsement of an existing guideline and from three systematic reviews. Before publication, the guideline underwent a series of peer and external reviews to gather feedback. All comments were addressed, and the guideline was amended when required. The guideline applies to health care workers who could come into contact with cytotoxic drugs at any point in the medication circuit. The intended users are hospital administrators, educators, and managers; occupational health and safety services; and pharmacy and health care workers. Results The recommendations represent a reasonable and practical set of procedures that the intended users of this guideline should implement to minimize opportunities for accidental exposure. They are not limited to just the point of care; they cover the entire chain of cytotoxics handling from the time such agents enter the institution until they leave in the patient or as waste. Conclusions Reducing the likelihood of accidental exposure to cytotoxic agents within the medication circuit is the main objective of this evidenced-based guideline. The recommendations differ slightly from earlier guidelines because of the availability of new evidence. PMID:25684994

  9. Cytotoxicity of Dental Adhesives In Vitro

    PubMed Central

    Koulaouzidou, Elisabeth A.; Helvatjoglu-Antoniades, Maria; Palaghias, George; Karanika-Kouma, Artemis; Antoniades, Dimitrios

    2009-01-01

    Objectives The purpose of this study was to evaluate the cytotoxic effect of six dental adhesives (Admira Bond, Clearfil Liner Bond 2V, ED Primer II, Fuji Bond LC, Gluma Comfort Bond, and NanoBond) applied to cell cultures. Methods The experiments were performed on two cell lines, rat pulp cells (RPC-C2A) and human lung fibroblasts (MRC5). Samples of the adhesives were light-cured and placed in culture medium for 24 hours. The extraction media was applied on the RPC-C2A and the MRC5 cells. Complete medium was used as a control. Cytotoxicity was evaluated with a modified sulforhodamine B (SRB) assay after 24 hours of exposure. Results The cell survival of RPC-C2A cells exposed to Fuji Bond LC, NanoBond, Clearfil Liner Bond 2V, ED Primer II, Admira Bond and Gluma Comfort Bond was 73%, 67%, 50%, 20%, 18% and 5% respectively, relative to the cell survival with the control medium. In the MRC5 cell line, the relative survival was 98%, 80%, 72%, 41%, 19% and 7% after exposure to NanoBond, Fuji Bond LC, Clearfil Liner Bond 2V, ED Primer II, Admira Bond and Gluma Comfort Bond, respectively. Conclusions Different types of dental adhesives showed different cytotoxic effects on cells in vitro. The self-etch adhesives were superior in terms of cytotoxicity. The different cytotoxic effects of dental adhesives should be considered when selecting an appropriate adhesive for operative restorations. PMID:19262725

  10. Cytotoxic activities of phytochemicals from Ferula species.

    PubMed

    Valiahdi, Seied Mojtaba; Iranshahi, Mehrdad; Sahebkar, Amirhossein

    2013-05-23

    Ferula species are reputed in folk medicine for the treatment of a variety of disorders. There have been sporadic reports on the chemopreventive and chemosensitizing activities of some terpenoid coumarin derivatives from the genus Ferula. The present study investigated the cytotoxic activity of 11 phytochemicals (conferone, farnesiferol A, acantrifoside E, mogoltadone, diversin, galbanic acid, herniarin, 7-isopentenyloxycoumarin, umbelliprenin, stylosin and tschimgine) from Ferula species together with a newly synthesized prenylated derivative of curcumin (gercumin II). Cytotoxic activity of phytochemicals was evaluated against ovarian carcinoma (CH1), lung cancer (A549) and melanoma (SK-MEL-28) cell lines using MTT assay. Overall, moderate cytotoxic activity was observed from the tested compounds with IC50 values in the micromolar range. The highest activity against CH1 and A549 lines was from conferone while stylosin and tschimgine were the most potent compounds against SK-MEL-28 line. In conclusion, the findings of the present investigation did not support a potent cytotoxic activity of the tested phytochemicals against CH1, A549 and SK-MEL-28 cell lines. With respect to previous reports, the beneficial impact of these phytochemicals in cancer therapy may be more attributable to their chemopreventive or chemosensitizing activity rather than direct cytotoxic effects.

  11. Cytotoxic activities of phytochemicals from Ferula species

    PubMed Central

    2013-01-01

    Background Ferula species are reputed in folk medicine for the treatment of a variety of disorders. There have been sporadic reports on the chemopreventive and chemosensitizing activities of some terpenoid coumarin derivatives from the genus Ferula. The present study investigated the cytotoxic activity of 11 phytochemicals (conferone, farnesiferol A, acantrifoside E, mogoltadone, diversin, galbanic acid, herniarin, 7-isopentenyloxycoumarin, umbelliprenin, stylosin and tschimgine) from Ferula species together with a newly synthesized prenylated derivative of curcumin (gercumin II). Methods Cytotoxic activity of phytochemicals was evaluated against ovarian carcinoma (CH1), lung cancer (A549) and melanoma (SK-MEL-28) cell lines using MTT assay. Results and conclusion Overall, moderate cytotoxic activity was observed from the tested compounds with IC50 values in the micromolar range. The highest activity against CH1 and A549 lines was from conferone while stylosin and tschimgine were the most potent compounds against SK-MEL-28 line. In conclusion, the findings of the present investigation did not support a potent cytotoxic activity of the tested phytochemicals against CH1, A549 and SK-MEL-28 cell lines. With respect to previous reports, the beneficial impact of these phytochemicals in cancer therapy may be more attributable to their chemopreventive or chemosensitizing activity rather than direct cytotoxic effects. PMID:23701832

  12. Cytotoxicity of Odorous Compounds from Poultry Manure.

    PubMed

    Nowak, Adriana; Matusiak, Katarzyna; Borowski, Sebastian; Bakuła, Tadeusz; Opaliński, Sebastian; Kołacz, Roman; Gutarowska, Beata

    2016-10-26

    Long-term exposure and inhalation of odorous compounds from poultry manure can be harmful to farm workers and the surrounding residents as well as animals. The aim of the present study was to determine the cytotoxicity and IC50 values of common odorous compounds such as ammonium, dimethylamine, trimethylamine, butyric acid, phenol, and indole in the chick liver hepatocellular carcinoma cell line LMH (Leghorn Male Hepatoma), in vitro, using MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) and PrestoBlue cytotoxicity assays. The cells were microscopically examined for any morphological changes post treatment. Dimethylamine exhibited the strongest cytotoxic effect on LMH cells with an IC50 value of 0.06% and 0.04% after an exposure of 24 h and 48 h, respectively. Both ammonium and trimethylamine had comparable cytotoxicity and their IC50 values were 0.08% and 0.04% after 24 h and 48 h, respectively. Of note, indole had the lowest cytotoxicity as the majority of cells were viable even after 72 h exposure. Thus, the IC50 for indole was not calculated. Results achieved from both MTT and PrestoBlue assays were comparable. Moreover, the morphological changes induced by the tested odours in LMH cells resulted in monolayer destruction, cytoplasm vacuolisation, chromatin condensation, and changes in nucleus and cell shape. Our study showed harmful effects of odorous compounds in chick tissues.

  13. Cytotoxicity of titanium and titanium alloying elements.

    PubMed

    Li, Y; Wong, C; Xiong, J; Hodgson, P; Wen, C

    2010-05-01

    It is commonly accepted that titanium and the titanium alloying elements of tantalum, niobium, zirconium, molybdenum, tin, and silicon are biocompatible. However, our research in the development of new titanium alloys for biomedical applications indicated that some titanium alloys containing molybdenum, niobium, and silicon produced by powder metallurgy show a certain degree of cytotoxicity. We hypothesized that the cytotoxicity is linked to the ion release from the metals. To prove this hypothesis, we assessed the cytotoxicity of titanium and titanium alloying elements in both forms of powder and bulk, using osteoblast-like SaOS(2) cells. Results indicated that the metal powders of titanium, niobium, molybdenum, and silicon are cytotoxic, and the bulk metals of silicon and molybdenum also showed cytotoxicity. Meanwhile, we established that the safe ion concentrations (below which the ion concentration is non-toxic) are 8.5, 15.5, 172.0, and 37,000.0 microg/L for molybdenum, titanium, niobium, and silicon, respectively.

  14. The mechanism of asbestos-induced cytotoxicity

    SciTech Connect

    Goodglick, L.A.

    1988-01-01

    Crocidolite asbestos fibers constitute a serious environmental pollutant capable of causing pleural scarring and cancer. This thesis addresses three questions: (1) what is the mechanism of asbestos-induced cytotoxicity in vitro and in vivo (2) What is the influence of fiber size on cytotoxicity in vitro and in vivo (3) What is the chronic response of the peritoneal cavity to asbestos fibers of varying lengths Macrophages release reactive oxygen metabolites when exposed to crocidolite in vitro or in vivo. Crocidolite-induced cytotoxicity is prevented with superoxide dismutase (SOD) and catalase. In addition, presoaking crocidolite fibers in deferoxamine, prevents cytotoxicity in vitro and in vivo. In vitro, macrophages exposed to crocidolite also lose mitochondrial membrane potential and undergo lipid peroxidation. Neither of these changes in itself, however, is responsible for macrophage death. We also examined the role of crocidolite fiber size in cytoxicity. Both long and short crocidolite fibers are toxic to macrophages in vitro via an oxidant dependent mechanism. Within the periotoneal cavity long crocidolite fibers are acutely cytotoxic and inflammatory while short fibers are not. Weekly intraperitoneal injections of long and native crocidolite asbestos fibers produced mesotheliomas in 20-40% of mice after 35-50 weeks. Neoplastic and preneoplastic cells were obtained from these mice, cultured, and characterized for in vitro transformation and in vivo tumorigenicity.

  15. Cytotoxic edema: mechanisms of pathological cell swelling

    PubMed Central

    Liang, Danny; Bhatta, Sergei; Gerzanich, Volodymyr; Simard, J. Marc

    2009-01-01

    Cerebral edema is caused by a variety of pathological conditions that affect the brain. It is associated with two separate pathophysiological processes with distinct molecular and physiological antecedents: those related to cytotoxic (cellular) edema of neurons and astrocytes, and those related to transcapillary flux of Na+ and other ions, water, and serum macromolecules. In this review, the authors focus exclusively on the first of these two processes. Cytotoxic edema results from unchecked or uncompensated influx of cations, mainly Na+, through cation channels. The authors review the different cation channels that have been implicated in the formation of cytotoxic edema of astrocytes and neurons in different pathological states. A better understanding of these molecular mechanisms holds the promise of improved treatments of cerebral edema and of the secondary injury produced by this pathological process. PMID:17613233

  16. Cytotoxic falcarinol oxylipins from Dendropanax arboreus.

    PubMed

    Bernart, M W; Cardellina, J H; Balaschak, M S; Alexander, M R; Shoemaker, R H; Boyd, M R

    1996-08-01

    The crude organic extract of Dendropanax arboreus was selected as a candidate for bioassayguided fractionation on the basis of its relatively selective cytotoxicity to a subset of cell lines within the National Cancer Institute's disease-oriented in vitro tumor-screening panel. The major compound responsible for the in vitro cytotoxicity was falcarinol (1). Several other known compounds were isolated and found to be cytotoxic, including dehydrofalcarinol (2), a diyenne (3), falcarindiol (4), and dehydrofalcarindiol (5). In addition, two novel polyacetylenes, dendroarboreols A (6) and B (7), were isolated and characterized by standard and inverse-detected NMR methods. Compounds were selected from this series for absolute stereochemical determination using the modified Mosher method and preliminary in vivo evaluation using a LOX melanoma mouse xenograft model.

  17. Cytotoxicity and bonding property of dental ceramics.

    PubMed

    Uo, Motohiro; Sjögren, Göran; Sundh, Anders; Watari, Fumio; Bergman, Maud; Lerner, Ulf

    2003-09-01

    Yttria partially stabilized zirconia (YPSZ) ceramic is suitable for dental and medical use because of its high fracture toughness and chemical durability. The purpose of this study was to estimate the cytotoxicity and bonding property of zirconia ceramic compared to other dental ceramics. Eight commercial dental ceramics including Denzir (YPSZ) are used in this cytotoxicity test. The human gingival fibroblast (GF) cells were cultured using extraction solutions of ceramics. The cytotoxicity was estimated by two different methods. The bonding strength of Denzir was compared to Empress2 using zinc phosphate, glass ionomer, and adhesive resin cements. A brass plate was prepared with drilled tapered holes and ceramic specimens were prepared to fit the holes and bonded. The bonding strength was estimated by the punching test. No significant (p>0.05) cytotoxicity was observed in all ceramic extractions. The two evaluation methods showed no significant differences. Denzir and Empress2 showed similar bonding strength with zinc phosphate or glass ionomer cement bonding. For both Empress2 and Denzir the glass ionomer cement showed significantly (p<0.001) higher bonding strength compared to the zinc phosphate cement. Empress2 showed significantly higher bonding strength with adhesive resin cement. However, the Denzir showed lower bonding strength with adhesive resin cement. No ceramic extractions showed any evidence of cytotoxicity. Therefore, the low in vitro cytotoxicity of ceramic extractions including Denzir was confirmed. Denzir showed a similar bonding strength to Empress2 with zinc phosphate or glass ionomer cement bonding with this testing method and lower bonding strength with adhesive resin cement than with Empress2.

  18. Cytotoxicity associated with electrospun polyvinyl alcohol.

    PubMed

    Pathan, Saif G; Fitzgerald, Lisa M; Ali, Syed M; Damrauer, Scott M; Bide, Martin J; Nelson, David W; Ferran, Christiane; Phaneuf, Tina M; Phaneuf, Matthew D

    2015-11-01

    Polyvinyl alcohol (PVA) is a synthetic, water-soluble polymer, with applications in industries ranging from textiles to biomedical devices. Research on electrospinning of PVA has been targeted toward optimizing or finding novel applications in the biomedical field. However, the effects of electrospinning on PVA biocompatibility have not been thoroughly evaluated. In this study, the cytotoxicity of electrospun PVA (nPVA) which was not crosslinked after electrospinning was assessed. PVA polymers of several molecular weights were dissolved in distilled water and electrospun using the same parameters. Electrospun PVA materials with varying molecular weights were then dissolved in tissue culture medium and directly compared against solutions of nonelectrospun PVA polymer in human coronary artery smooth muscle cells and human coronary artery endothelial cells cultures. All nPVA solutions were cytotoxic at a threshold molar concentration that correlated with the molecular weight of the starting PVA polymer. In contrast, none of the nonelectrospun PVA solutions caused any cytotoxicity, regardless of their concentration in the cell culture. Evaluation of the nPVA material by differential scanning calorimetry confirmed that polymer degradation had occurred after electrospinning. To elucidate the identity of the nPVA component that caused cytotoxicity, nPVA materials were dissolved, fractionated using size exclusion columns, and the different fractions were added to HCASMC and human coronary artery endothelial cells cultures. These studies indicated that the cytotoxic component of the different nPVA solutions were present in the low-molecular-weight fraction. Additionally, the amount of PVA present in the 3-10 kg/mol fraction was approximately sixfold greater than that in the nonelectrospun samples. In conclusion, electrospinning of PVA resulted in small-molecular-weight fractions that were cytotoxic to cells. This result demonstrates that biocompatibility of electrospun

  19. Cytotoxic anthraquinone derivatives from Picramnia antidesma.

    PubMed

    Hernández-Medel, María del Rosario; Pereda-Miranda, Rogelio

    2002-06-01

    Activity-guided investigation of crude extracts prepared from the root bark of Picramnia antidesma, a medicinal plant long used for the treatment of malaria in tropical areas of the Americas, when tested on KB cells led to the isolation of a new compound, 10-epi-uveoside, from a cytotoxic fraction containing a rich mixture of anthrone glycosides. The antiplasmodial activity proved to be a result of the high levels of cytotoxicity displayed by the anthraquinone derivatives and therefore infusions from this crude drug lack the selectivity index needed to be an effective antimalarial agent.

  20. Cytotoxicity of pregnane glycosides of Cynanchum otophyllum.

    PubMed

    Zhang, Mi; Li, Xiang; Xiang, Cheng; Qin, Yi; He, Jing; Li, Bao-Cai; Li, Peng

    2015-12-01

    Fourteen new pregnane glycosides, including nine caudatin glycosides (1-9), three qinyangshengenin glycosides (10-12), one kidjoranin glycosides (13) and one gagaminin glycosides (14), along with twelve known analogs (15-26) were isolated from roots of Cynanchum otophyllum Schneid. Their structures were deduced by detailed analysis of 1D and 2D NMR spectra, as well as HRESIMS. In this study, all pregnane glycosides obtained (1-26) were evaluated for their cytotoxic activities using three cancer cell lines (HepG2, Hela, U251). As results, except 6 and 10, other twenty-four pregnane glycosides showed cytotoxicities at different degrees against three cell lines.

  1. Natural cytotoxic macrophages in the peritoneal cavity of mice.

    PubMed Central

    Pels, E.; Den Otter, W.

    1979-01-01

    Many strains of mice from various breeding institutes have natural cytotoxic macrophages. These macrophages can also be present in nude mice, suggesting that this cytotoxicity can be acquired without invovlvement of T cells. The natural cytotoxicity was non-specific for tumour cells, was not sensitive to trypsin treatment, was lost after 5 days incubation, but could be enhanced by foetal bovine serum. The presence of cytotoxic macrophages in the peritoneal cavity was not genetically or age controlled. Natural cytotoxic macrophages did not occur in germ-free mice. The possible causes of natural cytotoxicity are discussed. PMID:526427

  2. Correlation between luminescence intensity and cytotoxicity in cell-based cytotoxicity assay using luciferase.

    PubMed

    Wakuri, S; Yamakage, K; Kazuki, Y; Kazuki, K; Oshimura, M; Aburatani, S; Yasunaga, M; Nakajima, Y

    2017-04-01

    The luciferase reporter assay has become one of the conventional methods for cytotoxicity evaluation. Typically, the decrease of luminescence expressed by a constitutive promoter is used as an index of cytotoxicity. However, to our knowledge, there have been no reports of the correlation between cytotoxicity and luminescence intensity. In this study, to accurately verify the correlation between them, beetle luciferase was stably expressed in human hepatoma HepG2 cells harboring the multi-integrase mouse artificial chromosome vector. We showed that the cytotoxicity assay using luciferase does not depend on the stability of luciferase protein and the kind of constitutive promoter. Next, HepG2 cells in which green-emitting beetle luciferase was expressed under the control of CAG promoter were exposed to 58 compounds. The luminescence intensity and cytotoxicity curves of cells exposed to 48 compounds showed similar tendencies, whereas those of cells exposed to 10 compounds did not do so, although the curves gradually approached each other with increasing exposure time. Finally, we demonstrated that luciferase expressed under the control of a constitutive promoter can be utilized both as an internal control reporter for normalizing a test reporter and for monitoring cytotoxicity when two kinds of luciferases are simultaneously used in the cytotoxicity assay. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Cytotoxicity associated with prolonged room temperature storage of serum and proposed methods for reduction of cytotoxicity.

    PubMed

    Shiraishi, Rikiya; Hirayama, Norio

    2015-12-01

    Canine serum preserved at room temperature (25°C) for longer than 24h is known to exhibit significant cytotoxicity. This phenomenon is one of the major reasons for the failure of virus neutralization tests. In this study, a method for reducing this cytotoxicity was investigated by applying several treatments to dog, cat and human serum prior to room temperature storage. Additionally, the identity of the cytotoxic factor generated during room temperature storage was investigated. Heat-inactivation at 56°C or 65°C and the addition of protease inhibitor prior to storage were found to be effective for reducing cytotoxicity in the serum. Furthermore, heat-inactivation at 65°C reduced the cytotoxicity that was induced under room temperature storage. Several protein factors in serum were suspected to play a role in the observed cytotoxicity. According to this study, the membrane-attack-complex in serum was not involved in the cytotoxicity. This study provides useful information for development and improvement of cell culture and virus neutralization tests. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Incipient cytotoxicity: A time-independent measure of cytotoxic potency in vitro.

    PubMed

    Gülden, Michael; Kähler, Daria; Seibert, Hasso

    2015-09-01

    Time is an important determinant of toxicity but largely ignored in in vitro toxicity assays where exposure times chosen are rather arbitrary. To investigate the impact of time on the cytotoxic potency of chemicals in vitro, the concentration dependent cytotoxic action of selected chemicals (surfactants, metals, oxidative stressors, a mitochondrial poison) was determined after various exposure times (1-72 h) in cultures of Balb/c 3T3 cells. Time affected the cytotoxic potency as well as the cytotoxic efficacy. The median cytotoxic concentrations, EC50, decreased and in most cases approached an "incipient" value, EC50,∞, within 72 h. Cytotoxicity due to mitochondrial insult occurred after a threshold time which was dependent on the medium glucose concentration. Within the chemicals studied the extent of potency change with time ranged from 3- to >1000-fold and the "time to incipient cytotoxicity", tic, from 4 to >72 h. Hence, also the relative cytotoxic potencies depend on exposure time. Ignoring this may lead to severe bias in toxicological hazard and risk assessment. Therefore it is recommended to determine the incipient cytotoxic potency of chemical compounds, represented by, e.g., the incipient median effect (EC50,∞), no effect (NEC∞) or lowest effect concentrations (LEC∞) instead of measures obtained after arbitrary exposure times. If this is not possible, the 72 h-potency measurements appear to be useful surrogates. These time-independent incipient potency values can be reasonably compared between substances, endpoints, cells and biological test systems and may serve to define points of departure for quantitative in vitro-in vivo extrapolations.

  5. Natural deep eutectic solvents: cytotoxic profile.

    PubMed

    Hayyan, Maan; Mbous, Yves Paul; Looi, Chung Yeng; Wong, Won Fen; Hayyan, Adeeb; Salleh, Zulhaziman; Mohd-Ali, Ozair

    2016-01-01

    The purpose of this study was to investigate the cytotoxic profiles of different ternary natural deep eutectic solvents (NADESs) containing water. For this purpose, five different NADESs were prepared using choline chloride as a salt, alongside five hydrogen bond donors (HBD) namely glucose, fructose, sucrose, glycerol, and malonic acid. Water was added as a tertiary component during the eutectics preparation, except for the malonic acid-based mixture. Coincidentally, the latter was found to be more toxic than any of the water-based NADESs. A trend was observed between the cellular requirements of cancer cells, the viscosity of the NADESs, and their cytotoxicity. This study also highlights the first time application of the conductor-like screening model for real solvent (COSMO-RS) software for the analysis of the cytotoxic mechanism of NADESs. COSMO-RS simulation of the interactions between NADESs and cellular membranes' phospholipids suggested that NADESs strongly interacted with cell surfaces and that their accumulation and aggregation possibly defined their cytotoxicity. This reinforced the idea that careful selection of NADESs components is necessary, as it becomes evident that organic acids as HBD highly contribute to the increasing toxicity of these neoteric mixtures. Nevertheless, NADESs in general seem to possess relatively less acute toxicity profiles than their DESs parents. This opens the door for future large scale utilization of these mixtures.

  6. Cytotoxicity Potentials of Eleven Bangladeshi Medicinal Plants

    PubMed Central

    Haque, Tania; Akter, Mahfuja; Akter, Subarna; Jhumur, Afrin

    2014-01-01

    Various forms of cancer are rising all over the world, requiring newer therapy. The quest of anticancer drugs both from natural and synthetic sources is the demand of time. In this study, fourteen extracts of different parts of eleven Bangladeshi medicinal plants which have been traditionally used for the treatment of different types of carcinoma, tumor, leprosy, and diseases associated with cancer were evaluated for their cytotoxicity for the first time. Extraction was conceded using methanol. Phytochemical groups like reducing sugars, tannins, saponins, steroids, gums, flavonoids, and alkaloids were tested using standard chromogenic reagents. Plants were evaluated for cytotoxicity by brine shrimp lethality bioassay using Artemia salina comparing with standard anticancer drug vincristine sulphate. All the extracts showed potent to moderate cytotoxicity ranging from LC50 2 to 115 µg/mL. The highest toxicity was shown by Hygrophila spinosa seeds (LC50 = 2.93 µg/mL) and the lowest by Litsea glutinosa leaves (LC50 = 114.71 µg/mL) in comparison with standard vincristine sulphate (LC50 = 2.04 µg/mL). Among the plants, the plants traditionally used in different cancer and microbial treatments showed highest cytotoxicity. The results support their ethnomedicinal uses and require advanced investigation to elucidate responsible compounds as well as their mode of action. PMID:25431796

  7. Cytotoxic effect of endodontic irrigants in vitro.

    PubMed

    Bajrami, Donika; Hoxha, Veton; Gorduysus, Omer; Muftuoglu, Sevda; Zeybek, Nacije Dilara; Küçükkaya, Selen

    2014-03-10

    Cytotoxicity of root canal irrigants is important due to their close contact with host tissues. The aim of this study was to assess the cytotoxic effect of NaOCl 3%, Chx 2%, and MTAD on rat periodontal ligament fibroblasts, at 0.1 and 100 µl/mL, using WST-1 colorimetric method. Rat ligamental fibroblasts were exposed to the irrigants and their viability was assessed after 1, 24, 48, and 72 h. The measurements were determined using WST-1 assay, using a micro ELISA reader. At 100 ml/L all 3 irrigants were strongly cytotoxic, although CHX was less so than NaOCl and MTAD. At the 0.1 ml/L concentration, NaOCl and MTAD were only moderately cytotoxic, whereas Chx was highly deleterious to cell viability at all time points. There was a significant influence of the dilution rate of the substance, because the odds ratio for cell viability being over 50% was increased 51 times between the 100 ml/L and 0.1 ml/L dilutions. It seems that irrigating solutions should be used at lower concentrations to enhance cell viability.

  8. Cytotoxic effect of endodontic irrigants in vitro

    PubMed Central

    Bajrami, Donika; Hoxha, Veton; Gorduysus, Omer; Muftuoglu, Sevda; Zeybek, Naciye Dilara; Küçükkaya, Selen

    2014-01-01

    Background Cytotoxicity of root canal irrigants is important due to their close contact with host tissues. The aim of this study was to assess the cytotoxic effect of NaOCl 3%, Chx 2%, and MTAD on rat periodontal ligament fibroblasts, at 0.1 and 100 μl/mL, using WST-1 colorimetric method. Material/Method Rat ligamental fibroblasts were exposed to the irrigants and their viability was assessed after 1, 24, 48, and 72 h. The measurements were determined using WST-1 assay, using a micro ELISA reader. Results At 100 ml/L all 3 irrigants were strongly cytotoxic, although CHX was less so than NaOCl and MTAD. At the 0.1 ml/L concentration, NaOCl and MTAD were only moderately cytotoxic, whereas Chx was highly deleterious to cell viability at all time points. There was a significant influence of the dilution rate of the substance, because the odds ratio for cell viability being over 50% was increased 51 times between the 100 ml/L and 0.1 ml/L dilutions. Conclusions It seems that irrigating solutions should be used at lower concentrations to enhance cell viability. PMID:24614571

  9. Ethanol cytotoxic effect on trophoblast cells.

    PubMed

    Clave, S; Joya, X; Salat-Batlle, J; Garcia-Algar, O; Vall, O

    2014-03-03

    Prenatal ethanol exposure may cause both, altered fetal neurodevelopment and impaired placental function. These disturbances can lead to growth retardation, which is one of the most prevalent features in Fetal Alcohol Syndrome (FAS). It is not known whether there is a specific pattern of cytotoxicity caused by ethanol that can be extrapolated to other cell types. The aim of this study was to determine the cytotoxic effects caused by sustained exposure of trophoblast cells to ethanol. The cytotoxic effect of sustained exposure to standard doses of ethanol on an in vitro human trophoblast cell line, JEG3, was examined. Viable cell count by exclusion method, total protein concentration, lactate dehydrogenase (LDH) activity and activation of apoptotic markers (P-H2AX, caspase-3 and PARP-1) were determined. Sustained exposure to ethanol decreased viable cell count and total protein concentration. LDH activity did not increased in exposed cells but apoptotic markers were detected. In addition, there was a dose-dependent relationship between ethanol concentration and apoptotic pathways activation. Sustained ethanol exposure causes cellular cytotoxicity by apoptotic pathways induction as a result of DNA damage. This apoptotic induction may partially explain the altered function of placental cells and the damage previously detected in other tissues.

  10. Cytotoxic effects of gutta-percha solvents.

    PubMed

    Barbosa, S V; Burkard, D H; Spångberg, L S

    1994-01-01

    Cytotoxicity of commonly used gutta-percha solvents was evaluated. Gutta-percha dissolved by chloroform, halothane, or turpentine was evaluated with the radiochromium release method using L929 mouse fibroblast cells. All solvents were toxic. Turpentine was most toxic followed by halothane and chloroform, which caused similar levels of cell injury.

  11. Cytotoxic oxoisoaporphine alkaloids from Menispermum dauricum.

    PubMed

    Yu, B W; Meng, L H; Chen, J Y; Zhou, T X; Cheng, K F; Ding, J; Qin, G W

    2001-07-01

    Four new oxoisoaporphine alkaloids, daurioxoisoporphines A-D (1-4), were isolated from the rhizomes of Menispermum dauricum. The structures of these alkaloids were established by spectroscopic methods. The cytotoxic evaluation of 1 and 2 is reported against four cancer cell lines.

  12. Cytotoxic activity of four Mexican medicinal plants.

    PubMed

    Vega-Avila, Elisa; Espejo-Serna, Adolfo; Alarcón-Aguilar, Francisco; Velasco-Lezama, Rodolfo

    2009-01-01

    Ibervillea sonorae Greene, Cucurbita ficifolia Bouché, Tagetes lucida Cav and Justicia spicigera Scheltdd are Mexican native plants used in the treatment of different illnesses. The ethanolic extract of J. spicigera and T. lucida as well as aqueous extracts from I. sonorae, C. ficifolia, T. lucida and J. spicigera were investigated using sulforhodamine B assay. These extracts were assessed using two cell line: T47D (Human Breast cancer) and HeLa (Human cervix cancer). Colchicine was used as the positive control. Data are presented as the dose that inhibited 50% control growth (ED50). All of the assessed extracts were cytotoxic (ED50 < 20 microg/ml) against T47D cell line, meanwhile only the aqueous extract from T. lucida and the ethanolic extract from J. spicigera were cytotoxic to HeLa cell line. Ethanolic extract from J. spicigera presented the best cytotoxic effect. The cytotoxic activity of J. spicigera correlated with one of the popular uses, the treatment of cancer.

  13. [Study of cytotoxic and antiviral effects of some eye drops].

    PubMed

    Dediulescu, Lucreţia; Dediulescu, Daniela Florentina

    2008-01-01

    The study of the cytotoxic and antiviral effect of six commercial mixtures, eye drops type, underlined the advantages of using eye drops with Indomethacin for Herpetic Keratitis, due to the antiviral effect and also for the lack of cytotoxicity.

  14. Assessment of cytotoxicity by emerging impedance spectroscopy

    SciTech Connect

    Xiao Caide; Luong, John H.T. . E-mail: john.luong@cnrc-nrc.gc.ca

    2005-08-07

    An on-line and continuous technique based on electric cell substrate impedance sensing (ECIS) was developed for measuring the concentration and time response function of fibroblastic V79 cells exposed to toxicants. Mercury chloride (HgCl{sub 2}), cadmium chloride (CdCl{sub 2}), benzalkonium chloride (BAK), sodium arsenate (Na{sub 2}HAsO{sub 4}), and trinitrobenzene (TNB) were used as five test models. The first four chemicals serve as a model for acute toxicants, and TNB represents a model for long-term cytotoxicity effects. Adhesion, spreading, and proliferation of V79 fibroblastic cells cultured on a microarray of small gold electrodes precoated with fibronectin were detected as resistance changes. The response function was derived to reflect the resistance change as a result of cell attachment, spreading, mitosis and cytotoxicity effect. Exposure of V79 cells to toxicants led to alterations in cell behavior, and therefore, chemical cytotoxicity was easily screened by measuring the response function of the attached and spread cells in the presence of inhibitor. The half inhibition concentration, the required concentration to achieve 50% inhibition, was obtained from the response function to provide dynamic information about cytotoxicity during the course of the assay. A simple mathematical model was developed to describe the responses of ECIS that were related to the adhesion, spreading, and proliferation of V79 fibroblastic cells. The novel results of this paper are mainly characterized by the systematic study of several parameters including the cell number, detection limit, sensor sensitivity, and cytotoxicity, and they may motivate further research and study of ECIS sensors.

  15. Assessment of cytotoxicity by emerging impedance spectroscopy.

    PubMed

    Xiao, Caide; Luong, John H T

    2005-08-07

    An on-line and continuous technique based on electric cell substrate impedance sensing (ECIS) was developed for measuring the concentration and time response function of fibroblastic V79 cells exposed to toxicants. Mercury chloride (HgCl(2)), cadmium chloride (CdCl(2)), benzalkonium chloride (BAK), sodium arsenate (Na(2)HAsO(4)), and trinitrobenzene (TNB) were used as five test models. The first four chemicals serve as a model for acute toxicants, and TNB represents a model for long-term cytotoxicity effects. Adhesion, spreading, and proliferation of V79 fibroblastic cells cultured on a microarray of small gold electrodes precoated with fibronectin were detected as resistance changes. The response function was derived to reflect the resistance change as a result of cell attachment, spreading, mitosis and cytotoxicity effect. Exposure of V79 cells to toxicants led to alterations in cell behavior, and therefore, chemical cytotoxicity was easily screened by measuring the response function of the attached and spread cells in the presence of inhibitor. The half inhibition concentration, the required concentration to achieve 50% inhibition, was obtained from the response function to provide dynamic information about cytotoxicity during the course of the assay. A simple mathematical model was developed to describe the responses of ECIS that were related to the adhesion, spreading, and proliferation of V79 fibroblastic cells. The novel results of this paper are mainly characterized by the systematic study of several parameters including the cell number, detection limit, sensor sensitivity, and cytotoxicity, and they may motivate further research and study of ECIS sensors.

  16. Protection and potentiation of nitrogen mustard cytotoxicity by WR-2721

    SciTech Connect

    Valeriote, F.; Tolen, S.

    1982-11-01

    The radioprotective agent WR-2721 was examined for its effects on modifying the cytotoxicity of HN2 against normal and tumor cells in the AKR mouse. Quantitation was carried out by the spleen colony assay for both normal hematopoietic stem cells and AKR leukemia cells. Protection from drug toxicity and normal cell cytotoxicity was noted. Potentiation of cytotoxicity to AKR leukemia was found.

  17. Gold Nanoparticles Inhibit Matrix Metalloproteases without Cytotoxicity.

    PubMed

    Hashimoto, M; Sasaki, J I; Yamaguchi, S; Kawai, K; Kawakami, H; Iwasaki, Y; Imazato, S

    2015-08-01

    Nanoparticles (NPs) are currently the focus of considerable attention for dental applications; however, their biological effects have not been fully elucidated. The long-term, slow release of matrix metalloproteases (MMPs) digests collagen fibrils within resin-dentin bonds. Therefore, MMP inhibitors can prolong the durability of resin-dentin bonds. However, there have been few reports evaluating the combined effect of MMP inhibition and the cytotoxic effects of NPs for dentin bonding. The aim of this study was to evaluate MMP inhibition and cytotoxic responses to gold (AuNPs) and platinum nanoparticles (PtNPs) stabilized by polyvinylpyrrolidone (PVP) in cultured murine macrophages (RAW264) by using MMP inhibition assays, measuring cell viability and inflammatory responses (quantitative reverse transcription polymerase chain reaction [RT-qPCR]), and conducting a micromorphological analysis by fluorescence and transmission electron microscopy. Cultured RAW264 cells were exposed to metal NPs at various concentrations (1, 10, 100, and 400 µg/mL). AuNPs and PtNPs markedly inhibited MMP-8 and MMP-9 activity. Although PtNPs were cytotoxic at high concentrations (100 and 400 µg/mL), no cytotoxic effects were observed for AuNPs at any concentration. Transmission electron microscopy images showed a significant nonrandom intercellular distribution for AuNPs and PtNPs, which were mostly observed to be localized in lysosomes but not in the nucleus. RT-qPCR analysis demonstrated inflammatory responses were not induced in RAW264 cells by AuNPs or PtNPs. The cytotoxicity of nanoparticles might depend on the core metal composition and arise from a "Trojan horse" effect; thus, MMP inhibition could be attributed to the surface charge of PVP, which forms the outer coating of NPs. The negative charge of the surface coating of PVP binds to Zn(2+) from the active center of MMPs by chelate binding and results in MMP inhibition. In summary, AuNPs are attractive NPs that effectively

  18. Cytotoxic constituents of ethyl acetate fraction from Dianthus superbus.

    PubMed

    Ding, Chengli; Zhang, Wu; Li, Jie; Lei, Jiachuan; Yu, Jianqing

    2013-01-01

    The ethyl acetate fraction (EE-DS) from Dianthus superbus was found to possess the cytotoxic activity against cancer cells in previous study. To investigate cytotoxic constituents, the bioassay-guided isolation of compounds from EE-DS was performed. Two dianthramides (1 and 2), three flavonoids (3-5), two coumarins (6 and 7) and three other compounds (8-10) were obtained. Structures of isolated compounds were identified by spectroscopic analysis. Cytotoxicity of the compounds against HepG2 cells was evaluated. Compound 1 showed the strongest cytotoxicity, compounds 10, 4, 3 and 5 had moderate cytotoxicity.

  19. In vivo Cytotoxicity Studies of Amaryllidaceae Alkaloids.

    PubMed

    Nair, Jerald J; Bastida, Jaume; van Staden, Johannes

    2016-01-01

    The plant family Amaryllidaceae is recognizable for its esthetic floral characteristics, its widespread usage in traditional medicine as well as its unique alkaloid principles. Few alkaloid-producing families rival the Amaryllidaceae in terms of the diversity of its structures as well as their wide applicability on the biological landscape. In particular, cytotoxic effects have come to be a dominant theme in the biological properties of Amaryllidacea alkaloids. To this extent, a significant number of structures have been subjected to in vitro studies in numerous cell lines from which several targets have been identified as promising chemotherapeutics. By contrast, in vivo models of study involving these alkaloids have been carried out to a lesser extent and should prove crucial in the continued development of a clinical target such as pancratistatin. This survey examines the cytotoxic effects of Amaryllidaceae alkaloids in vivo and contrasts these against the corresponding in vitro effects.

  20. [Cytotoxic T lymphocytes in cancer and autoimmunity].

    PubMed

    Prado-García, Heriberto; Avila-Moreno, Federico; López-González, José Sullivan

    2004-01-01

    Cytotoxic T lymphocytes (CTLs) are cells of the immune system that recognize and kill cells that have been infected with intracellular pathogens, allogenic cells or tumor cells. It has been reported that CTLs participate in the pathogenesis of some autoimmune diseases. After stimulation with the antigen, CTLs undergo an activation process highly regulated, which leads to the cell to acquire an effector or memory function. In this review, we indicate the cellular markers associated with the different stages of CTL-differentiation (naive, memory and effector); we indicate the distinct models of CTLs differentiation; also, the mechanisms of CTLs cytotoxicity are mentioned. Furthermore, we describe the participation of CTLs in cancer and autoimmunity; the implications of CTLs in the progression of these diseases are discussed.

  1. Synthesis and cytotoxicity properties of amiodarone analogues.

    PubMed

    Bigler, Laurent; Spirli, Carlo; Fiorotto, Romina; Pettenazzo, Andrea; Duner, Elena; Baritussio, Aldo; Follath, Ferenc; Ha, Huy Riem

    2007-06-01

    Amiodarone (AMI) is a potent antiarrhythmic agent; however, its clinical use is limited due to numerous side effects. In order to investigate the structure--cytotoxicity relationship, AMI analogues were synthesized, and then, using rabbit alveolar macrophages, were tested for viability and for the ability to interfere with the degradation of surfactant protein A (SP-A) and with the accumulation of an acidotropic dye. Our data revealed that modification of the diethylamino-beta-ethoxy group of the AMI molecule may affect viability, the ability to degrade SP-A and vacuolation differently. In particular, PIPAM (2d), an analogue with a piperidyl moiety, acts toward the cells in a similar manner to AMI, but is less toxic. Thus, it would be possible to reduce the cytotoxicity of AMI by modifying its chemical structure.

  2. Cytotoxic polycyclic polyprenylated acylphloroglucinols from Hypericum attenuatum.

    PubMed

    Zhou, Zhong-bo; Zhang, Yang-mei; Pan, Ke; Luo, Jian-guang; Kong, Ling-yi

    2014-06-01

    Six new polycyclic polyprenylated acylphloroglucinols, attenuatumiones A-F (1-6), together with twelve known analogs (7-18) were isolated from the whole plant of Hypericum attenuatum. Their structures were elucidated by spectroscopic methods, and the absolute configuration of C-13 in attenuatumione C (3) was deduced via the circular dichroism datum of the in situ formed [Rh2(OCOCF3)4] complexes. All isolates were evaluated for the cytotoxic activities on three human cancer cell lines. Compound 3 showed moderate cytotoxic activities with IC50 values of 10.12 and 10.56 μM against SMMC7721 and U2OS, respectively. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. New pyrazolic compounds as cytotoxic agents.

    PubMed

    Bouabdallah, Ibrahim; M'Barek, Lahcen Ait; Zyad, Abdelmajid; Ramdani, Abdelkrim; Zidane, Ismail; Melhaoui, Ahmed

    2007-04-01

    The evaluation of the in vitro cytotoxic properties of two pyrazole compounds: 1-(4-nitrophényl)-3,5-diméthylpyrazole (1) and 1,1'-di(4-nitrophényl)-5,5'-diisopropyl-3,3'-bipyrazole (2) was investigated against Hep cell line (Human laryngeal carcinoma). These two compounds showed an important cytotoxic activity on the Hep cell line, with IC(50): 8.25 microg mL(-1) for the compound 1; IC(50): 10.20 microg mL(-1) for the compound 2 while the IC(50) for adriamycine used as positive control was 3.62 microg mL(-1).

  4. Cytotoxic activity of selected Nigerian plants.

    PubMed

    Sowemimo, A; van de Venter, M; Baatjies, L; Koekemoer, T

    2009-07-03

    Cancer is one of the most prominent human diseases which has stimulated scientific and commercial interest in the discovery of new anticancer agents from natural sources. The current study investigates the cytotoxic activity of ethanolic extracts of sixteen Nigerian plants used locally for the treatment of cancer using the MTT assay on the HeLa cell line. Sapium ellipticum leaves showed activity comparable to the reference compound Cisplatin and greater cytotoxic activity than Combretum paniculatum, Celosia trigyna, Drymaria cordata, Cyathula achyranthoides and Cyathula prostata. Justica extensa, Pupalia lappacea, Hedranthera barteri leaves, Alternanthera sessilis, Ethulia conyzoides leaves, Combretum zenkeri root, Sapium ellipticum stembark and Lannea nigritana stembark showed very low activity while Combretum molle, Adenanthera parvoniana and Lannea acida showed no activity. The results justify the use of Sapium, Combretum, Celosia, Drymaria and Cyathula in traditional treatment of cancer.

  5. L-arginine independent macrophage tumor cytotoxicity

    SciTech Connect

    Klostergaard, J.; Leroux, M.E. )

    1989-12-29

    We have investigated the role of L-arginine in macrophage tumor cytotoxicity in coculture. L929, EMT-6, MCA-26, and P815 targets were all susceptible to cytolysis by activated macrophages when cocultured in medium containing L-arginine. When cocultured in arginine-free medium, these targets displayed comparable or even higher levels of lysis. L1210 targets were lytically resistant under either condition. However, 59Fe release from this target did reflect strong dependence on the presence of arginine. The structural analogue, NG-monomethyl-L-arginine, was an effective inhibitor of iron-release from L1210 targets cocultured with activated macrophages, whereas it had minimal inhibitory effects on release of 51Cr from cocultured L929 cells. These results suggest that the L-arginine requiring cytotoxic pathway of activated macrophage is independent of major effector mechanisms involved in tumor cell lysis.

  6. Cytotoxic compounds from endemic Arnebia purpurea.

    PubMed

    Yuzbasioglu, Merve; Kuruuzum-Uz, Ayse; Guvenalp, Zuhal; Simon, András; Tóth, Gabór; Harput, U Sebnem; Kazaz, Cavit; Bilgili, Bilgehan; Duman, Hayri; Saracoglu, Iclal; Demirezer, L Omur

    2015-04-01

    Phytochemical studies of the roots and aerial parts of endemic Arnebia purpurea S. Erik & H. Sumbul resulted in the isolation and characterization of four naphthoquinones [isovalerylalkannin (1), α-methyl-n-butanoyl alkannin (2), acetylalkannin (3), and alkannin (4)], a triterpene derivative [3-O-acetyl-oleanolic acid (5)], a steroid [β-sitosterol (6)], three flavonoid glycosides [isorhamnetin-3-O-rutinoside (7), kaempferol-3-O-rutinoside (8), kaempferol 3-O-(5"-acetyl) apiofuranoside 7-O-rhamnopyranoside (9)] and a phenolic acid [rosmarinic acid (10)]. 3-O-Acetyl-oleanolic acid, isorhamnetin-3-O-rutinoside, kaempferol-3-O-mrutinoside, and kaempferol 3-O-(5"-acetyl) apiofuranoside 7-O-rhamnopyranoside are reported from an Arnebia species for the first time. Cytotoxic activities on L929 murine fibrosarcoma cell line of the isolated compounds were investigated using MTT assay. Naphthoquinones (1-4) showed intermediate cytotoxic activity in comparison with the standard, doxorubicin.

  7. Cytotoxic steroidal saponins from Agave sisalana.

    PubMed

    Chen, Pi-Yu; Chen, Chin-Hui; Kuo, Ching-Chuan; Lee, Tzong-Huei; Kuo, Yueh-Hsiung; Lee, Ching-Kuo

    2011-06-01

    Two new steroidal saponins, 8 and 10, along with 7 known steroidal sapogenins and saponins (1-7) and a furostanol saponin (9) were isolated from Agave sisalana Perrine ex Engelm. The structures of these two new compounds were identified and characterized by 1D and 2D NMR spectroscopy and mass spectrometry. In addition, acid hydrolysis and GC-FID were used to confirm the sugar moieties of 8 and 10. The cytotoxic effects of 1-10 on MCF-7, NCI-H460, and SF-268 cancer cells were evaluated, and among them, compound 10 proved to be the most cytotoxic with IC₅₀ values of 1.2, 3.8, and 1.5 µM, respectively.

  8. Increase of cytotoxicity during wastewater chlorination: Impact factors and surrogates.

    PubMed

    Du, Ye; Wu, Qian-Yuan; Lu, Yun; Hu, Hong-Ying; Yang, Yang; Liu, Rui; Liu, Feng

    2017-02-15

    Toxic and harmful disinfection byproducts (DBPs) were formed during wastewater chlorination. It was recently suggested that cytotoxicity to mammalian cells reflects risks posed by chlorinated wastewater. Here, ATP assays were performed to evaluate the cytotoxicity to mammalian cells. Chlorination significantly increased cytotoxicity of treated wastewater. Factors affecting cytotoxicity formation during wastewater chlorination were investigated. Quenching with sodium thiosulfate and ascorbic acid decreased the formed cytotoxicity, while ammonium kept the cytotoxicity stable. The chlorine dose required for the maximum cytotoxicity increase was dramatically affected by DOC and ammonia concentrations. The maximum cytotoxicity increase, defined as the cytotoxicity formation potential (CtFP), occurred when wastewater was treated for 48h with a chlorine dose of 2·DOC+11·NH3N+10 (mg-Cl2/L). During chlorination, the amounts of AOX formation was found to be significantly correlated with cytotoxicity formation when no DBPs were destroyed. AOX formation could be used as a surrogate to estimate cytotoxicity increase during wastewater chlorination. Besides, the CtFP of 14 treated wastewater samples was assessed ranged from 5.4-20.4mg-phenol/L. The CtFP could be estimated from UV254 of treated wastewater because CtFP and UV254 were strongly correlated.

  9. Novel cytotoxic annonaceous acetogenins from Annona muricata.

    PubMed

    Chang, F R; Wu, Y C

    2001-07-01

    Seven new annonaceous acetogenins, muricins A-G (1-7), as well as five known compounds, a mixture of muricatetrocin A (8) and muricatetrocin B (9), longifolicin (10), corossolin (11), and corossolone (12), were isolated from the seeds of Annona muricata. The structures of all isolates were elucidated and characterized by spectral and chemical methods. These acetogenins showed significantly selective in vitro cytotoxicities toward the human hepatoma cell lines Hep G(2) and 2,2,15.

  10. Therapeutic implications of iodine-125 cytotoxicity

    SciTech Connect

    Bloomer, W.D.; McLaughlin, W.H.; Adelstein, S.J.

    1982-11-01

    The biological consequences of differential subcellular radionuclide accumulation within nuclear stuctures have important implications for the design and development of new therapeutic agents for cancer management. A growing body of experimental data demonstrates that localization of /sup 125/I within the genome results in marked cytotoxicity. Investigations of iodine-125 labeled iododeoxyuridine, DNA intercalators and tamoxifen are reviewed as representative of this new group of potential radiotherapeutic agents.

  11. Therapeutic implications of iodine-125 cytotoxicity

    SciTech Connect

    Bloomer, W.D.; McLaughlin, W.H.; Adelstein, S.J.

    1982-11-01

    The biological consequences of differential subcellular radionuclide accumulation within nuclear structures have important implications for the design and development of new therapeutic agents for cancer management. A growing body of experimental data demonstrates that localization of /sup 125/I within the genome results in marked cytotoxicity. Investigations of iodine-125 labeled iododeoxyuridine, DNA intercalators and tamoxifen are reviewed as representative of this new group of potential radiotherapeutic agents.

  12. Arecoline is cytotoxic for human endothelial cells.

    PubMed

    Ullah, Mafaz; Cox, Stephen; Kelly, Elizabeth; Boadle, Ross; Zoellner, Hans

    2014-11-01

    Oral submucous fibrosis is a pre-malignant fibrotic condition caused by areca nut use and involves reduced mucosal vascularity. Arecoline is the principal areca nut alkaloid and is cytotoxic for epithelium and fibroblasts. Endothelial cell cycle arrest is reported on exposure to arecoline, as is cytotoxicity for endothelial-lung carcinoma hybrid cells. We here describe cytotoxicity for primary human endothelial cultures from seven separate donors. Human umbilical vein endothelial cells were exposed to increasing concentrations of arecoline and examined by: phase-contrast microscopy, haemocytometer counts, transmission electron microscopy, lactate dehydrogenase release and the methyl-thiazol-tetrazolium assay. Vacuolation and detachment of endothelium were observed at and above arecoline concentrations of 333 μg/ml or more. Ultrastructural features of cellular stress were seen after 24-h treatment with 111 μg/ml arecoline and included reduced ribosomal studding of endoplasmic reticulum, increased autophagolysosomal structures, increased vacuolation and reduced mitochondrial cristae with slight swelling. Similar changes were seen at 4 h with arecoline at 333 μg/ml or above, but with more severe mitochondrial changes including increased electron density of mitochondrial matrix and greater cristal swelling, while by 24 h, these cells were frankly necrotic. Haemocytometer counts were paralleled by both lactate dehydrogenase release and the methyl-thiazol-tetrazolium assays. Arecoline is cytotoxic via necrosis for endothelium, while biochemical assays indicate no appreciable cellular leakage before death and detachment, as well as no clear effect on mitochondrial function in viable cells. Arecoline toxicity may thus contribute to reduced vascularity in oral submucous fibrosis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. A cytotoxic diacetylene from Dendropanax arboreus.

    PubMed

    Setzer, W N; Green, T J; Whitaker, K W; Moriarity, D M; Yancey, C A; Lawton, R O; Bates, R B

    1995-10-01

    The crude ethanol extract from the leaves of Dendropanax arboreus (Araliaceae) from Monteverde, Costa Rica, exhibits cytotoxic activity against Hep-G2, A-431, H-4IIE, and L-1210 tumor cell lines, but is not toxic against normal hepatocytes. The active component has been isolated by activity-directed separation and identified by 1H- and 13C-NMR spectroscopy as the acetylenic compound cis-1,9,16-heptadecatriene-4,6-diyne-3,8-diol.

  14. Four new cytotoxic xanthones from Garcinia nujiangensis.

    PubMed

    Tang, Zhong-Yan; Xia, Zheng-Xiang; Qiao, Shi-Ping; Jiang, Chao; Shen, Guo-Rong; Cai, Mei-Xiang; Tang, Xiao-Yan

    2015-04-01

    Bioassay-guided fractionation of the acetone extract of the twigs of Garcinia nujiangensis resulted in the isolation of four new prenylated xanthones, nujiangexanthones C-F (1-4), and ten known related analogues. The structures of compounds 1-4 were elucidated by interpretation of their spectroscopic data. The compounds isolated were evaluated for their cytotoxic effects against three cancer cell lines, the test substances demonstrated selectivity toward the cancer cells.

  15. Mycoplasma pneumoniae induces cytotoxic activity in guinea pig bronchoalveolar cells

    SciTech Connect

    Kist, M.; Koester, H.; Bredt, W.

    1985-06-01

    Precultured guinea pig alveolar macrophages (AM) and freshly harvested alveolar cells (FHAC) activated by interaction with Mycoplasma pneumoniae were cytotoxic for xenogeneic /sup 75/selenomethionine-labeled tumor target cells. Phagocytosis of whole opsonized or nonopsonized M. pneumoniae cells was more effective in eliciting cytotoxicity than uptake of sonicated microorganisms. The addition of living mycoplasma cells to the assay system enhanced the cytotoxic effect considerably. Target cells were significantly more susceptible to the cytotoxic action of phagocytes if they were coated with mycoplasma antigen or cocultured together with M. pneumoniae. The activation of the phagocytes could be inhibited by 2-deoxy-D-glucose but not by antimicrobial substances suppressing mycoplasma protein synthesis. It was accompanied by /sup 51/Cr release without detectable signs of cell damage. The supernatants of activated cells were cytotoxic for approximately 24 h. Inhibition, release, and cytotoxic activity indicate the necessity of an intact metabolism of the effector cells and suggest a secretion of cytotoxic substances.

  16. Initial cytotoxicity of novel titanium alloys.

    PubMed

    Koike, M; Lockwood, P E; Wataha, J C; Okabe, T

    2007-11-01

    We assessed the biological response to several novel titanium alloys that have promising physical properties for biomedical applications. Four commercial titanium alloys [Super-TIX(R) 800, Super-TIX(R) 51AF, TIMETAL(R) 21SRx, and Ti-6Al-4V (ASTM grade 5)] and three experimental titanium alloys [Ti-13Cr-3Cu, Ti-1.5Si and Ti-1.5Si-5Cu] were tested. Specimens (n = 6; 5.0 x 5.0 x 3.0 mm(3)) were cast in a centrifugal casting machine using a MgO-based investment and polished to 600 grit, removing 250 mum from each surface. Commercially pure titanium (CP Ti: ASTM grade 2) and Teflon (polytetrafluoroethylene) were used as positive controls. The specimens were cleaned and disinfected, and then each cleaned specimen was placed in direct contact with Balb/c 3T3 fibroblasts for 72 h. The cytotoxicity [succinic dehydrogenase (SDH) activity] of the extracts was assessed using the MTT method. Cytotoxicity of the metals tested was not statistically different compared to the CP Ti and Teflon controls (p > 0.05). These novel titanium alloys pose cytotoxic risks no greater than many other commonly used alloys, including commercially pure titanium. The promising short-term biocompatibility of these Ti alloys is probably due to their excellent corrosion resistance under static conditions, even in biological environments.

  17. Triterpenoid pyrazines and benzopyrazines with cytotoxic activity.

    PubMed

    Urban, Milan; Sarek, Jan; Kvasnica, Miroslav; Tislerova, Iva; Hajduch, Marian

    2007-04-01

    Twelve lupane, 18alpha-oleanane, and des-E-lupane derivatives (1a-5b) were either extracted from natural sources or synthesized from betulinic acid (1a) and betulin (2). Compounds 1b, 1c, 3b, 3c, 4b, 4c, 5a, and 5b were then used as starting materials for further synthesis of a series of pyrazines and benzopyrazines (6a-18); 20 of them are new (6a-6e, 7a-7d, and 10a-18). Activity of pyrazine 6a against the T-lymphoblastic leukemia cell line CEM encouraged us to synthesize several new esters (6b-6d) to study structure-activity relationships with respect to substitution of the carboxyl group at position 28. The synthesized compounds were tested for cytotoxicity against a variety of cancer cell lines of different histogenetic origin, and the results were compared with cytotoxicity of the known starting compounds. Significant cytotoxic activity against A 549, K 562, and multidrug-resistant K 562-tax cell lines was found in pyrazines 6a, 6d, and 6e.

  18. Biological microdosimetry based on radiation cytotoxicity data.

    PubMed

    Scott, B R; Hutt, J; Lin, Y; Padilla, M T; Gott, K M; Potter, C A

    2013-01-01

    Researchers in the field of radiation microdosimetry have attempted to explain the relative biological effectiveness (RBE) of different ionising photon radiation sources on the basis of the singly stochastic, microdose metric lineal energy y, which only addresses physical stochasticity related to energy (ε) deposition via single events in the critical targets (cell nuclei assumed here). Biological stochasticity related to variable nuclei geometries and cell orientations (relative to the incoming radiation) is usually not addressed. Here a doubly stochastic microdose metric, the single-event hit size q (=ε/T), is introduced which allows the track length T to be stochastic. The new metric is used in a plausible model of metabolic-activity-based in vitro cytotoxicity of low-dose ionising photon radiation. The cytotoxicity model has parameters E{q} (average single-event hit size with q assumed to be exponentially distributed) and E{α}, which is the average value of the cellular response parameter α. E{α} is referred to as the biological signature and it is independent of q. Only E{q} is needed for determination of RBE. The model is used to obtain biological-microdosimetry-based q spectra for 320-kV X-rays and (137)Cs gamma rays and the related RBE for cytotoxicity. The spectra are similar to published lineal energy y spectra for 200-kV X-rays and (60)Co gamma rays for 1-μm biological targets.

  19. Mutagenic and cytotoxic activities of benfuracarb insecticide.

    PubMed

    Eren, Yasin; Erdoğmuş, Sevim Feyza; Akyıl, Dilek; Özkara, Arzu

    2016-08-01

    Benfuracarb is a carbamate insecticide used to control insect pests in vegetables and it has anti-acetylcholinesterase activity lower than other carbamates. Cytotoxic effects of benfuracarb were evaluated by using root growth inhibition (EC50), mitotic index (MI), and mitotic phase determinations on the root meristem cells of Allium cepa and mutagenic effects were determined in Salmonella typhymurium Ames test by TA98 and TA100 strains with and without metabolic activation. In Allium test, 1 % DMSO was used as negative control group and 10 ppm MMS was used as positive control group. 75 ppm concentration of benfuracarb was found as EC50. In MI and mitotic phases determination study, 37.5, 75 and 150 ppm doses of benfuracarb were used. Dose-dependent cytotoxic activity was found by root growth inhibition and MI studies. It was identified that mitotic inhibition activity of benfuracarb was higher than 10 ppm MMS. In Ames test, mutagenic activity was not observed and over 200 µg/plate of benfuracarb was determined as cytotoxic to S. typhymurium strains. Benfuracarb can be called as "mitotic inhibitor" but not called as mutagen.

  20. Iron oxide nanoparticle enhancement of radiation cytotoxicity

    NASA Astrophysics Data System (ADS)

    Mazur, Courtney M.; Tate, Jennifer A.; Strawbridge, Rendall R.; Gladstone, David J.; Hoopes, P. Jack

    2013-02-01

    Iron oxide nanoparticles (IONPs) have been investigated as a promising means for inducing tumor cell-specific hyperthermia. Although the ability to generate and use nanoparticles that are biocompatible, tumor specific, and have the ability to produce adequate cytotoxic heat is very promising, significant preclinical and clinical development will be required for clinical efficacy. At this time it appears using IONP-induced hyperthermia as an adjunct to conventional cancer therapeutics, rather than as an independent treatment, will provide the initial IONP clinical treatment. Due to their high-Z characteristics, another option is to use intracellular IONPs to enhance radiation therapy without excitation with AMF (production of heat). To test this concept IONPs were added to cell culture media at a concentration of 0.2 mg Fe/mL and incubated with murine breast adenocarcinoma (MTG-B) cells for either 48 or 72 hours. Extracellular iron was then removed and all cells were irradiated at 4 Gy. Although samples incubated with IONPs for 48 hrs did not demonstrate enhanced post-irradiation cytotoxicity as compared to the non-IONP-containing cells, cells incubated with IONPs for 72 hours, which contained 40% more Fe than 48 hr incubated cells, showed a 25% decrease in clonogenic survival compared to their non-IONP-containing counterparts. These results suggest that a critical concentration of intracellular IONPs is necessary for enhancing radiation cytotoxicity.

  1. Cytotoxic Constituents and Mechanism from Peganum harmala.

    PubMed

    Wang, Chunhua; Zhang, Zhenxue; Wang, Yihai; He, Xiangjiu

    2016-07-01

    Peganum harmala L. is a traditional Chinese and Uygur medicine used to treat cancer. Bioactivity-guided fractionation was applied to determine the cytotoxic constituents from P. harmala. A novel triterpenoid and a phenolic glycoside were isolated and identified, as well as seven known compounds. The novel metabolites were elucidated to be 3α-acetoxy-27-hydroxyolean-12-en-28-oic acid methyl ester (1, OA) and N-acetyl-9-syringinoside (9). Some compounds exhibited potent cytotoxicity against human tumor cells. Among them, OA showed the highest cytotoxicity against human lung cancer cells A549 with an IC50 value of 8.03 ± 0.81 μm. OA had a potent anti-NSCLC cell activity by interfering with the epidermal growth factor receptor (EGFR) activation and its downstream signaling, and could exert an antiproliferative effect by inactivation of EGFR-driven antiapoptotic pathway followed by the release of mitochondrial cytochrome c, which might prove to be a promising leading compound for the development of an anti-lung cancer drug.

  2. Synthesis, Characterization and Cytotoxicity of Alkylated Quercetin Derivatives

    PubMed Central

    Bao, Xin-Ran; Liao, Han; Qu, Jiao; Sun, Yong; Guo, Xin; Wang, En-Xia; Zhen, Yu-Hong

    2016-01-01

    Quercetin, a ubiquitous flavonol, represents a promising leading drug for development of new chemotherapeutic agents. However, its limited cytotoxicity to cancer cells hampers its clinical use. In order to obtain novel quercetin derivatives with superior cytotoxicity, seven alkylated quercetin derivatives were synthesized. Solubility of these derivatives was determined by turbidimetry. Cytotoxicity of the high-soluble derivatives against MCF-7 cells and caco-2 cells was determined using MTT assay. Among these seven products, 7-O-butylquercetin had the highest solubility in DMEM medium and 7-O-geranylquercetin had the most potent cytotoxicity. Further study on cytotoxicity of 7-O-geranylquercetin on NCI-H446, A549, MGC-803 and SGC-7901 cell lines revealed potential antiproliferative effects. The 7-O-geranylquercetin is a broad spectrum cytotoxic agent and it may be a promising leading drug for cancer chemotherapy. PMID:27980567

  3. Cytotoxic activities of several geranyl-substituted flavanones.

    PubMed

    Smejkal, Karel; Svacinová, Jana; Slapetová, Tereza; Schneiderová, Kristýna; Dall'acqua, Stefano; Innocenti, Gabbriella; Závalová, Veronika; Kollár, Peter; Chudík, Stanislav; Marek, Radek; Julínek, Ondrej; Urbanová, Marie; Kartal, Murat; Csöllei, Marek; Dolezal, Karel

    2010-04-23

    Nine geranylated flavanones isolated from the fruits of Paulownia tomentosa (4-12) and two from the roots of Morus alba (13 and 14) were examined for cytotoxicity to selected human cancer cell lines and normal human fibroblasts. Cytotoxicity was determined in vitro using a calcein AM cytotoxicity assay. Cytotoxicity for the THP-1 monocytic leukemia cell line was tested using erythrosin B cell staining. The geranylated compounds tested were compared with the known simple flavanone standards taxifolin (1), naringenin (2), and hesperetin (3) and with the standard anticancer drugs olomoucine II, diaziquone, and oxaliplatin and the antineoplastic compound camptothecin, and showed different levels of cytotoxicity. The effects of structural changes on cytotoxic activity, including geranyl substitution of the flavanone skeleton and the oxidation pattern of ring B of the flavanones, are discussed.

  4. Orthodontic rare earth magnets--in vitro assessment of cytotoxicity.

    PubMed

    Bondemark, L; Kurol, J; Wennberg, A

    1994-11-01

    The aim of this study was to assess and compare in vitro the cytotoxic effects of uncoated and parylene-coated rare earth magnets, used in orthodontics. Cytotoxicity of samarium-cobalt magnets (SmCo5 and Sm2Co17) and neodymium-iron-boron magnets (Nd2Fe14B) was assessed by two in vitro methods, the millipore filter method and an extraction method. Orthodontic stainless steel brackets served as controls. Uncoated SmCo5-magnets showed high cytotoxicity while uncoated Sm2Co17-magnets demonstrated moderate cytotoxicity. Uncoated neodymium-iron-boron magnets, as well as parylene coated Sm2Co17-magnets and parylene-coated neodymium-iron-boron magnets, showed negligible cytotoxicity. Short-term exposure to a static magnetic field did not cause any cytotoxic effect on the cells.

  5. Virulence and cytotoxicity of seafood borne Aeromonas hydrophila

    PubMed Central

    Illanchezian, Seethalakshmi; Jayaraman, SathishKumar; Manoharan, Muthu Saravanan; Valsalam, Saritha

    2010-01-01

    The present study was conducted to determine the virulence and cytotoxicity of Aeromonas hydrophila strains isolated from seafood samples collected from 5 major fish markets in Chennai, Tamil Nadu, India. Among 73 A. hydrophila strains isolated from fish and shrimp samples, 86.3% exhibited haemolysis, 78.1% produced slime, 98.63% produced protease and also demonstrated cytotoxicity on Vero cells. Cell shrinkage, detachment and rounding of Vero cells were recorded as cytotoxic changes. Only one strain did not show haemolysis, slime production, proteolytic activity and cytotoxicity on treatment with Vero cells. Positive correlation was observed between proteolytic activity and cytotoxicity irrespective of haemolytic activity of the strains. These results demonstrated the presence of wide spread, pathogenically characterized, cytotoxic seafood borne A. hydrophila in Chennai. PMID:24031577

  6. Synthesis, Characterization and Cytotoxicity of Alkylated Quercetin Derivatives.

    PubMed

    Bao, Xin-Ran; Liao, Han; Qu, Jiao; Sun, Yong; Guo, Xin; Wang, En-Xia; Zhen, Yu-Hong

    2016-01-01

    Quercetin, a ubiquitous flavonol, represents a promising leading drug for development of new chemotherapeutic agents. However, its limited cytotoxicity to cancer cells hampers its clinical use. In order to obtain novel quercetin derivatives with superior cytotoxicity, seven alkylated quercetin derivatives were synthesized. Solubility of these derivatives was determined by turbidimetry. Cytotoxicity of the high-soluble derivatives against MCF-7 cells and caco-2 cells was determined using MTT assay. Among these seven products, 7-O-butylquercetin had the highest solubility in DMEM medium and 7-O-geranylquercetin had the most potent cytotoxicity. Further study on cytotoxicity of 7-O-geranylquercetin on NCI-H446, A549, MGC-803 and SGC-7901 cell lines revealed potential antiproliferative effects. The 7-O-geranylquercetin is a broad spectrum cytotoxic agent and it may be a promising leading drug for cancer chemotherapy.

  7. New Cytotoxic Tigliane Diterpenoids from Croton caudatus.

    PubMed

    Chen, Ying-Ying; Yang, Kun-Xian; Yang, Xing-Wei; Khan, Afsar; Liu, Lu; Wang, Bei; Zhao, Yun-Li; Liu, Ya-Ping; Li, Yan; Luo, Xiao-Dong

    2016-05-01

    Three new tigliane-type diterpenoids were isolated from the methanolic extract of the twigs and leaves of Croton caudatus, trivially named crotusins A-C (1-3). The structures of compounds 1-3 were elucidated on the basis of extensive spectral methods. These new compounds were highly oxygenated and heavily substituted. Cytotoxic activity against five human tumor cell lines was assessed for compounds 1-3 of which compound 3 showed significant inhibitory activity with IC50 values ranging from 0.49 to 4.19 µM against these cells, while crotusins A and B exhibited moderate activity.

  8. Cytotoxic guanidine alkaloids from Pterogyne nitens.

    PubMed

    Regasini, Luis Octávio; Castro-Gamboa, Ian; Silva, Dulce Helena Siqueira; Furlan, Maysa; Barreiro, Eliezer Jesus; Ferreira, Paulo Michel Pinheiro; Pessoa, Cláudia; Lotufo, Letícia Veras Costa; de Moraes, Manoel Odorico; Young, Maria Claudia Marx; Bolzani, Vanderlan da Silva

    2009-03-27

    As part of a bioprospecting program aimed at the discovery of potential anticancer drugs, two new guanidine-type alkaloids, nitensidines D and E (1, 2), and the known pterogynine (3), pterogynidine (4), and galegine (5), were isolated from the leaves of Pterogyne nitens. The structures of 1 and 2 were established on the basis of spectroscopic data interpretation. These compounds were tested against a small panel of human cancer cell lines. Compound 2 exhibited cytotoxicity for HL-60 (human myeloblastic leukemia) and SF-245 (human glioblastoma) cells.

  9. Mitigation of Quantum Dot Cytotoxicity by Microencapsulation

    PubMed Central

    Romoser, Amelia; Ritter, Dustin; Majitha, Ravish; Meissner, Kenith E.; McShane, Michael; Sayes, Christie M.

    2011-01-01

    When CdSe/ZnS-polyethyleneimine (PEI) quantum dots (QDs) are microencapsulated in polymeric microcapsules, human fibroblasts are protected from acute cytotoxic effects. Differences in cellular morphology, uptake, and viability were assessed after treatment with either microencapsulated or unencapsulated dots. Specifically, QDs contained in microcapsules terminated with polyethylene glycol (PEG) mitigate contact with and uptake by cells, thus providing a tool to retain particle luminescence for applications such as extracellular sensing and imaging. The microcapsule serves as the “first line of defense” for containing the QDs. This enables the individual QD coating to be designed primarily to enhance the function of the biosensor. PMID:21814567

  10. Cytotoxic phenylpropanoid glycosides from Cirsium japonicum.

    PubMed

    Shang, Dong-Li; Ma, Qin-Ge; Wei, Rong-Rui

    2016-12-01

    Three new phenylpropanoid glycosides 1-3, along with nine known phenylpropanoid glycosides 4-12, were isolated from the aerial parts of Cirsium japonicum. The structures of isolated compounds were elucidated by chemical and spectroscopic methods. Compounds 1, 3, 6, 8, and 11 showed moderate cytotoxicities against MCF-7, U87, HCT116, and A549 cell lines with IC50 values in the range of 1.35-11.32 μM. The known compounds 4-12 were obtained from this plant for the first time.

  11. Cytotoxic Homoisoflavonoids from Ophiopogon japonicus Tubers.

    PubMed

    Dang, Nguyen Hai; Chung, Nguyen Dinh; Tuan, Ha Manh; Hiep, Nguyen Tuan; Dat, Nguyen Tien

    2017-02-01

    A phytochemical fractionation of a methanol extract of Ophiopogon japonicus tubers led to the isolation of a new homoisoflavanone, homoisopogon A (1), and three new homoisoflavanes, homoisopogon B-D (2-4). Their chemical structures were elucidated by mass, NMR, and circular dichroism (CD) spectroscopic methods. Homoisopogon A (1) exhibited potent cytotoxicity against human lung adenocarcinoma LU-1, human epidermoid carcinoma KB, and human melanoma SK-Mel-2 cancer cells with IC50 values ranging from 0.51 to 0.66 µM.

  12. Flavonoids of Calligonum polygonoides and their cytotoxicity.

    PubMed

    Ahmed, Hayam; Moawad, Abeer; Owis, Asmaa; AbouZid, Sameh; Ahmed, Osama

    2016-10-01

    Context Calligonum polygonoides L. subsp. comosum L' Hér. (Polygonaceae), locally known as "arta", is a slow-growing small leafless desert shrub. Objective Isolation, structure elucidation and evaluation of cytotoxic activity of flavonoids from C. polygonoides aerial parts. Materials and methods Flavonoids in the hydroalcoholic extract of the of C. polygonoides were isolated and purified using column chromatography and preparative HPLC. The structures of the isolated flavonoids were elucidated on the basis of spectroscopic data including 2D NMR techniques. The cytotoxic activity of the isolated flavonoids (6.25, 25, 50 and 100 μg/mL) was evaluated against liver HepG2 and breast MCF-7 cancer cell lines using sulphorhodamine-B assay. Results A new flavonoid, kaempferol-3-O-β-D-(6″-n-butyl glucuronide) (1), and 13 known flavonoids, quercetin 3-O-β-D-(6″-n-butyl glucuronide) (2), kaempferol-3-O-β-D-(6″-methyl glucuronide) (3), quercetin-3-O-β-D-(6″-methyl glucuronide) (4), quercetin-3-O-glucuronide (5), kaempferol-3-O-glucuronide (6), quercetin-3-O-α-rhamnopyranoside (7), astragalin (8), quercetin-3-O-glucopyranoside (9), taxifolin (10), (+)-catechin (11), dehydrodicatechin A (12), quercetin (13), and kaempferol (14), were isolated from the aerial parts of C. polygonoides. Quercetin showed significant cytotoxic activity against HepG2 and MCF-7 cell lines with IC50 values of 4.88 and 0.87 μg/mL, respectively. Structure-activity relationships were analyzed by comparing IC50 values of several pairs of flavonoids differing in one structural element. Discussion and conclusion The activity against breast cancer cell lines decreased by glycosylation at C-3. The presence of 2,3-double bond in ring C, carbonyl group at C-4 and 3',4'-dihydroxy substituents in ring B are essential structural requirements for the cytotoxic activity against breast cancer cells.

  13. CALOTROPIN, A CYTOTOXIC PRINCIPLE ISOLATED FROM ASCLEPIAS CURASSAVICA L.

    PubMed

    KUPCHAN, S M; KNOX, J R; KELSEY, J E; SAENZRENAULD, J A

    1964-12-25

    An alcoholic extract of Asclepias curassavica L., a plant widely used in folk medicine for treating cancer and warts, shows cytotoxic activity when tested in vitro against cells derived from human carcinoma of the nasopharynx. Systematic fractionation of the extract has led to isolation and characterization of calotropin as a cytotoxic principle. Calotropin is similar in structure to two cardiac glycosides recently shown to be responsible for the cytotoxicity of Apocynum cannabinum L.

  14. In vitro cytotoxicity of the protoberberine-type alkaloids.

    PubMed

    Iwasa, K; Moriyasu, M; Yamori, T; Turuo, T; Lee, D U; Wiegrebe, W

    2001-07-01

    In vitro cytotoxic activities of 24 quaternary protoberberine alkaloids related to berberine have been evaluated using a human cancer cell line panel coupled with a drug sensitivity database. Extending the alkyl chain at position 8 or 13 strongly influenced the cytotoxic activity, that is, relative lipophilicity as well as the size of the substituent affects cytotoxicity. The highest level of activity was observed in 8- or 13-hexyl-substituted derivatives of berberine. Structure-activity relationships are described.

  15. Variant antigenic peptide promotes cytotoxic T lymphocyte adhesion to target cells without cytotoxicity

    PubMed Central

    Shotton, David M.; Attaran, Amir

    1998-01-01

    Timelapse video microscopy has been used to record the motility and dynamic interactions between an H-2Db-restricted murine cytotoxic T lymphocyte clone (F5) and Db-transfected L929 mouse fibroblasts (LDb) presenting normal or variant antigenic peptides from human influenza nucleoprotein. F5 cells will kill LDb target cells presenting specific antigen (peptide NP68: ASNENMDAM) after “browsing” their surfaces for between 8 min and many hours. Cell death is characterized by abrupt cellular rounding followed by zeiosis (vigorous “boiling” of the cytoplasm and blebbing of the plasma membrane) for 10–20 min, with subsequent cessation of all activity. Departure of cytotoxic T lymphocytes from unkilled target cells is rare, whereas serial killing is sometimes observed. In the absence of antigenic peptide, cytotoxic T lymphocytes browse target cells for much shorter periods, and readily leave to encounter other targets, while never causing target cell death. Two variant antigenic peptides, differing in nonamer position 7 or 8, also act as antigens, albeit with lower efficiency. A third variant peptide NP34 (ASNENMETM), which differs from NP68 in both positions and yet still binds Db, does not stimulate F5 cytotoxicity. Nevertheless, timelapse video analysis shows that NP34 leads to a significant modification of cell behavior, by up-regulating F5–LDb adhesive interactions. These data extend recent studies showing that partial agonists may elicit a subset of the T cell responses associated with full antigen stimulation, by demonstrating that TCR interaction with variant peptide antigens can trigger target cell adhesion and surface exploration without activating the signaling pathway that results in cytotoxicity. PMID:9861010

  16. Fibril Fragmentation Enhances Amyloid Cytotoxicity*♦

    PubMed Central

    Xue, Wei-Feng; Hellewell, Andrew L.; Gosal, Walraj S.; Homans, Steve W.; Hewitt, Eric W.; Radford, Sheena E.

    2009-01-01

    Fibrils associated with amyloid disease are molecular assemblies of key biological importance, yet how cells respond to the presence of amyloid remains unclear. Cellular responses may not only depend on the chemical composition or molecular properties of the amyloid fibrils, but their physical attributes such as length, width, or surface area may also play important roles. Here, we report a systematic investigation of the effect of fragmentation on the structural and biological properties of amyloid fibrils. In addition to the expected relationship between fragmentation and the ability to seed, we show a striking finding that fibril length correlates with the ability to disrupt membranes and to reduce cell viability. Thus, despite otherwise unchanged molecular architecture, shorter fibrillar samples show enhanced cytotoxic potential than their longer counterparts. The results highlight the importance of fibril length in amyloid disease, with fragmentation not only providing a mechanism by which fibril load can be rapidly increased but also creating fibrillar species of different dimensions that can endow new or enhanced biological properties such as amyloid cytotoxicity. PMID:19808677

  17. Cytotoxic activity of lignans from Justicia procumbens.

    PubMed

    Jin, Hong; Yin, Hai-Long; Liu, Shi-Jun; Chen, Li; Tian, Ying; Li, Bin; Wang, Qiong; Dong, Jun-Xing

    2014-04-01

    Three new lignans, Pronaphthalide A (1), Procumbiene (2), and Procumbenoside J (3), along with a novel natural product Juspurpudin (4), and twelve other known lignans were isolated from Justicia procumbens. The structures of the new compounds were elucidated by extensive spectroscopic analyses and the data of 3 provided insight into the conformational equilibria existing in it. All compounds were evaluated for their in vitro cytotoxic activity against Human LoVo and BGC-823 cell lines except for compound 2, and eight of them were found to possess potent cytotoxicity. The structure-activity relationship (SAR) analysis revealed that (i) the parent structure of 2-carbonyl arylnaphthalide lactone attached with 6 and 7-OMe was the essential element; (ii) the polarity of substituents on C-4 might significantly affect the activity; (iii) a proper cyclic lipophilic group at the C-3″ and C-5″ of apiofuranose on C-4 might enhance the activity, which could optimize the application of 3 similar to VP-16. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Cytotoxic isoferulic acidamide from Myricaria germanica (Tamaricaceae)

    PubMed Central

    Nawwar, Mahmoud A.; Swilam, Noha F.; Hashim, Amani N.; Al-Abd, Ahmed M.; Abdel-Naim, Ashraf B.; Lindequist, Ulrike

    2013-01-01

    Tamgermanitin, a unique N-trans-Isoferuloyltyramine, together with the hitherto unknown polyphenolics, 2,4-di-O-galloyl-(α/β)-glucopyranose and kaempferide 3,7-disulphate have been isolated from the leaf aqueous ethanol extract of the false tamarisk, Myricaria germanica DESV. In addition, 18 known phenolics were also separated and characterized. All structures were elucidated on the basis of detailed analysis of 1D- 1H and 13C NMR, COSY, HSQC, HMBC and HRFTESIMS spectral data. The extract, its chromatographic column fractions and the isolated isoferuloyltyramine, tamgermanetin demonstrated potential cytotoxic effect against three different tumor cell lines, namely liver (Huh-7), breast (MCF-7) and prostate (PC-3). The IC50''s were found to be substantially low with low-resistance possibility. DNA flow-cytometic analysis indicated that column fractions and tamgermanetin enhanced pre-G apoptotic fraction. Both materials showed inhibiting activity against PARP enzyme activity. In conclusion, we report the isolation and identification of a novel compound, tamgermanitin, from the aqueous ethanol extract of Myricaria germanica leaves. Further, different fractions of the extract and tamgermanitin exhibit potent cytotoxic activities which warrant further investigations. PMID:23123452

  19. Cytotoxicity and genotoxicity of butyl cyclohexyl phthalate.

    PubMed

    Köksal, Çinel; Nalbantsoy, Ayse; Karabay Yavaşoğlu, N Ülkü

    2016-03-01

    Butyl cyclohexyl phthalate (BCP) is frequently used in personal care products, medical and household applications. The aim of this study is therefore to evaluate possible cytotoxicity and genotoxicity of BCP using in vitro and in vivo assays. The in vitro cytotoxic effect of BCP was investigated on mouse fibroblastic cell line (L929 cells) by MTT assay. The result showed that BCP inhibits cell proliferation in a concentration-dependent manner (IC50 value = 0.29 µg/mL). For genotoxicity assessment, tested concentrations of BCP demonstrated mutagenic activity in the presence of S9 mix with the Salmonella strain TA100 in the Ames test. Results showed that BCP is a secondary mutagenic substance even in low concentrations. The data obtained from 28-days repeated toxicity tests on mice revealed that BCP caused abnormalities of chromosome number, in a dose-dependent manner. Additionally, DNA damage, particularly DNA strand breaks, was assessed by Comet assay. The test result shows that BCP seemed to have genotoxic potential at a high level of exposure.

  20. Cytotoxicity of occupationally and environmentally relevant mycotoxins.

    PubMed

    Bünger, Jürgen; Westphal, Götz; Mönnich, Angelika; Hinnendahl, Britta; Hallier, Ernst; Müller, Michael

    2004-10-01

    Mycotoxins can cause various toxic effects in humans. Acute and chronic respiratory diseases were reported after inhalation of organic dust containing toxigenic moulds and mycotoxins, respectively. To gain first insights into health effects from airborne exposure to these compounds, five toxigenic airborne moulds of the genera Aspergillus and Penicillium collected at composting plants and eight reference mycotoxins were tested for cytotoxicity in four established cell lines as a surrogate of tissues known or suspected to be targets of toxic effects of mycotoxins. The known mycotoxins sterigmatocystin, fumagillin, verruculogen, penitrem A, and roquefortine C were detected in extracts of the moulds. All five extracts caused serious toxic effects in the cell lines. Sterigmatocystin caused a 80-fold higher toxicity in the A-549 lung cell line compared to Hep-G2 liver cells indicating a specific susceptibility of A-549 to this agent. Since only a minor part of the toxic effects of the extracts in A-549 cells and--to a lesser extent--in the other cell lines could be explained by contents of the identified mycotoxins, the presence of additional mycotoxins or other toxic principles is assumed in the mould extracts. However, the detected mycotoxins in the mould extracts and their distinctive cytotoxicity support the hypothesis that mycotoxins may be involved in the aetiology of lung diseases due to the inhalation of organic dust.

  1. Cytotoxic isoferulic acidamide from Myricaria germanica (Tamaricaceae).

    PubMed

    Nawwar, Mahmoud A; Swilam, Noha F; Hashim, Amani N; Al-Abd, Ahmed M; Abdel-Naim, Ashraf B; Lindequist, Ulrike

    2013-01-01

    Tamgermanitin, a unique N-trans-Isoferuloyltyramine, together with the hitherto unknown polyphenolics, 2,4-di-O-galloyl-(α/β)-glucopyranose and kaempferide 3,7-disulphate have been isolated from the leaf aqueous ethanol extract of the false tamarisk, Myricaria germanica DESV. In addition, 18 known phenolics were also separated and characterized. All structures were elucidated on the basis of detailed analysis of 1D- (1)H and (13)C NMR, COSY, HSQC, HMBC and HRFTESIMS spectral data. The extract, its chromatographic column fractions and the isolated isoferuloyltyramine, tamgermanetin demonstrated potential cytotoxic effect against three different tumor cell lines, namely liver (Huh-7), breast (MCF-7) and prostate (PC-3). The IC 50''s were found to be substantially low with low-resistance possibility. DNA flow-cytometic analysis indicated that column fractions and tamgermanetin enhanced pre-G apoptotic fraction. Both materials showed inhibiting activity against PARP enzyme activity. In conclusion, we report the isolation and identification of a novel compound, tamgermanitin, from the aqueous ethanol extract of Myricaria germanica leaves. Further, different fractions of the extract and tamgermanitin exhibit potent cytotoxic activities which warrant further investigations.

  2. Quercetin-induced cardioprotection against doxorubicin cytotoxicity

    PubMed Central

    2013-01-01

    Background Cancer has continually been the leading cause of death worldwide for decades. Thus, scientists have actively devoted themselves to studying cancer therapeutics. Doxorubicin is an efficient drug used in cancer therapy, but also produces reactive oxygen species (ROS) that induce severe cytotoxicity against heart cells. Quercetin, a plant-derived flavonoid, has been proven to contain potent antioxidant and anti-inflammatory properties. Thus, this in vitro study investigated whether quercetin can decrease doxorubicin-induced cytotoxicity and promote cell repair systems in cardiomyocyte H9C2 cells. Results Proteomic analysis and a cell biology assay were performed to investigate the quercetin-induced responses. Our data demonstrated that quercetin treatment protects the cardiomyocytes in a doxorubicin-induced heart damage model. Quercetin significantly facilitated cell survival by inhibiting cell apoptosis and maintaining cell morphology by rearranging the cytoskeleton. Additionally, 2D-DIGE combined with MALDI-TOF MS analysis indicated that quercetin might stimulate cardiomyocytes to repair damage after treating doxorubicin by modulating metabolic activation, protein folding and cytoskeleton rearrangement. Conclusion Based on a review of the literature, this study is the first to report detailed protective mechanisms for the action of quercetin against doxorubicin-induced cardiomyocyte toxicity based on in-depth cell biology and proteomic analysis. PMID:24359494

  3. Cytotoxicity and genotoxicity of biogenic silver nanoparticles

    NASA Astrophysics Data System (ADS)

    Lima, R.; Feitosa, L. O.; Ballottin, D.; Marcato, P. D.; Tasic, L.; Durán, N.

    2013-04-01

    Biogenic silver nanoparticles with 40.3 ± 3.5 nm size and negative surface charge (- 40 mV) were prepared with Fusarium oxysporum. The cytotoxicity of 3T3 cell and human lymphocyte were studied by a TaliTM image-based cytometer and the genotoxicity through Allium cepa and comet assay. The results of BioAg-w (washed) and BioAg-nw (unwashed) biogenic silver nanoparticles showed cytotoxicity exceeding 50 μg/mL with no significant differences of response in 5 and 10 μg/mL regarding viability. Results of genotoxicity at concentrations 5.0 and 10.0 ug/mL show some response, but at concentrations 0.5 and 1.0 μg/mL the washed and unwashed silver nanoparticles did not present any effect. This in an important result since in tests with different bacteria species and strains, including resistant, MIC (minimal inhibitory concentration) had good answers at concentrations less than 1.9 μg/mL. This work concludes that biogenic silver nanoparticles may be a promising option for antimicrobial use in the range where no cyto or genotoxic effect were observed. Furthermore, human cells were found to have a greater resistance to the toxic effects of silver nanoparticles in comparison with other cells.

  4. [Fibers glass induced cytotoxicity and genotoxicity].

    PubMed

    Proietti, L; Giallongo, A; Zakrzewska, A M; Ammoscato, I; Lombardo, L; Frasca, G; Cardile, V

    2007-01-01

    Man-made vitrous fibers, have been widely used as a substitute for asbestos, as an insulation material. However the fibrous morphology of MMVFs raises concern about potential health hazard. The aim of our study was to assess cytotoxic and genotoxic effects induced on a human alveolar cell line A549 by exposure to glass wool fibers (GW). Cells were exposed for 72 h to 5, 50, 100 microg/ml of glass wool, after incubation the cell viability was determined by a MTT reduction assay. The genotoxic effect was studies by Comet test. An undamaged cell appeared as a nucleoid and a cell with damaged DNA as a comet. Measurement of Comet parameters: % DNA in the tail, tail length and tail momente (the product of relative tail intensity and lenght, that provides a parameter of DNA damage) were obtained from the analysis. A MTT assay indicated that glass wool caused a decrease in cell viability and this decrease was concentration-dependent. The results of the Comet test for DNA damage detection indicated in cell exposed to glass wool fibers a significant increase of mean TM value. All these results provide that the glass wool fibers can induce cytotoxicity and genotoxicity

  5. Study of Cytotoxic Effects of Benzonitrile Pesticides.

    PubMed

    Lovecka, Petra; Thimova, Marketa; Grznarova, Petra; Lipov, Jan; Knejzlik, Zdenek; Stiborova, Hana; Nindhia, Tjokorda Gde Tirta; Demnerova, Katerina; Ruml, Tomas

    2015-01-01

    The benzonitrile herbicides bromoxynil, chloroxynil, dichlobenil, and ioxynil have been used actively worldwide to control weeds in agriculture since 1970s. Even though dichlobenil is prohibited in EU since 2008, studies addressing the fate of benzonitrile herbicides in the environment show that some metabolites of these herbicides are very persistent. We tested the cytotoxic effects of benzonitrile herbicides and their microbial metabolites using two human cell lines, Hep G2 and HEK293T, representing liver and kidneys as potential target organs in humans. The cell viability and proliferation were determined by MTT test and RTCA DP Analyzer system, respectively. The latter allows real-time monitoring of the effect of added substances. As the cytotoxic compounds could compromise cell membrane integrity, the lactate dehydrogenase test was performed as well. We observed high toxic effects of bromoxynil, chloroxynil, and ioxynil on both tested cell lines. In contrast, we determined only low inhibition of cell growth in presence of dichlobenil and microbial metabolites originating from the tested herbicides.

  6. Cytotoxic benzophenone and triterpene from Garcinia hombroniana.

    PubMed

    Jamila, Nargis; Khairuddean, Melati; Yaacob, Nik Soriani; Kamal, Nik Nur Syazni Nik Mohamed; Osman, Hasnah; Khan, Sadiq Noor; Khan, Naeem

    2014-06-01

    Garcinia hombroniana (seashore mangosteen) in Malaysia is used to treat itching and as a protective medicine after child birth. This study was aimed to investigate the bioactive chemical constituents of the bark of G. hombroniana. Ethyl acetate and dichloromethane extracts of G. hombroniana yielded two new (1, 9) and thirteen known compounds which were characterized by the spectral techniques of NMR, UV, IR and EI/ESI-MS, and identified as; 2,3',4,5'-tetrahydroxy-6-methoxybenzophenone(1), 2,3',4,4'-tetrahydroxy-6-methoxybenzophenone (2), 2,3',4,6-tetrahydroxybenzophenone (3), 1,3,6,7-tetrahydroxyxanthone (4), 3,3',4',5,7-pentahydroxyflavone (5),3,3',5,5',7-pentahydroxyflavanone (6), 3,3',4',5,5',7-hexahydroxyflavone (7), 4',5,7-trihydroxyflavanone-7-rutinoside (8), 18(13→17)-abeo-3β-acetoxy-9α,13β-lanost-24E-en-26-oic acid (9), garcihombronane B (10), garcihombronane D (11), friedelan-3-one (12), lupeol (13), stigmasterol (14) and stigmasterol glucoside (15). In the in vitro cytotoxicity against MCF-7, DBTRG, U2OS and PC-3 cell lines, compounds 1 and 9 displayed good cytotoxic effects against DBTRG cancer cell lines. Compounds 1-8 were also found to possess significant antioxidant activities. Owing to these properties, this study can be further extended to explore more significant bioactive components of this plant.

  7. Triterpenes from Euphorbia hirta and their cytotoxicity.

    PubMed

    Ragasa, Consolacion Y; Cornelio, Kimberly B

    2013-09-01

    To investigate the chemical constituents of the stems, leaves and roots of Euphorbia hirta, and to test for the cytotoxic and antimicrobial potentials of the major constituents of the plant. The compounds were isolated by silica gel chromatography and their structures were elucidated by NMR spectroscopy. The cytotoxicity tests were conducted using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, while the antimicrobial tests employed the agar well method. The air-dried stems of E. hirta afforded taraxerone 1, a mixture of 25-hydroperoxycycloart-23-en-3β-ol (2a) and 24-hydroperoxycycloart-25-en-3β-ol (2b) (sample 2) in a 2 : 1 ratio, and another mixture of cycloartenol (3a), lupeol (3b), α-amyrin (3c) and β-amyrin (3d) (sample 3) in a 0.5 : 4 : 1 : 1 ratio. The air-dried leaves of E. hirta yielded sample 2 in a 3 : 2 ratio, sample 3 in a 2 : 3 : 1 : 1 ratio, phytol and phytyl fatty acid ester, while the roots afforded sample 2 in a 2 : 1 ratio, sample 3 in a 2 : 1 : 1 : 1 ratio, a mixture of cycloartenyl fatty acid ester 4a, lupeol fatty acid ester 4b, α-amyrin fatty acid ester 4c and β-amyrin fatty acid ester 4d (sample 4) in a 3 : 2 : 1 : 1 ratio, linoleic acid, β-sitosterol and squalene. Compound 1 from the stems, sample 2 from the leaves, and sample 3 from the stems were assessed for cytotoxicity against a human cancer cell line, colon carcinoma (HCT 116). Sample 2 showed good activity with an IC50 value of 4.8 μg·mL(-1), while 1 and sample 3 were inactive against HCT 116. Sample 2 was further tested for cytotoxicity against non-small cell lung adenocarcinoma (A549). It showed good activity against this cell line with an IC50 value of 4.5 μg·mL(-1). Antimicrobial assays were conducted on 1 and sample 2. Results of the study indicated that 1 was active against the bacteria: Pseudomonas aeruginosa and Staphylococcus aureus, but was inactive against Escherichia coli and Bacillus subtilis. Sample 2 was active against the

  8. Cytotoxic Killing and Immune Evasion by Repair

    NASA Astrophysics Data System (ADS)

    Chan, Cliburn; George, Andrew J. T.; Stark, Jaroslav

    2007-07-01

    The interaction between the immune system and pathogens is a complex one, with pathogens constantly developing new ways of evading destruction by the immune system. The immune system's task is made even harder when the pathogen in question is an intra-cellular one (such as a virus or certain bacteria) and it is necessary to kill the infected host cell in order to eliminate the pathogen. This causes damage to the host, and such killing therefore needs to be carefully controlled, particularly in tissues with poor regenerative potential, or those involved in the immune response itself. Host cells therefore possess repair mechanisms which can counteract killing by immune cells. These in turn can be subverted by pathogens which up-regulate the resistance of infected cells to killing. In this paper, we explore the hypothesis that this repair process plays an important role in determining the efficacy of evasion and escape from immune control. We model a situation where cytotoxic T lymphocytes (CTL) and natural killer (NK) cells kill pathogen-infected and tumour cells by directed secretion of preformed granules containing perforin and granzymes. Resistance to such killing can be conferred by the expression of serine protease inhibitors (serpins). These are utilized by several virally infected and tumour cells, as well as playing a role in the protection of host bystander, immune and immuneprivileged cells. We build a simple stochastic model of cytotoxic killing, where serpins can neutralize granzymes stoichiometrically by forming an irreversible complex, and the survival of the cell is determined by the balance between serpin depletion and replenishment, which in its simplest form is equivalent to the well known shot noise process. We use existing analytical results for this process, and additional simulations to analyse the effects of repair on cytotoxic killing. We then extend the model to the case of a replicating target cell population, which gives a branching process

  9. Hydrogen sulfide mediates the anti-survival effect of sulforaphane on human prostate cancer cells

    SciTech Connect

    Pei, Yanxi; Wu, Bo; Cao, Qiuhui; Wu, Lingyun; Yang, Guangdong

    2011-12-15

    Hydrogen sulfide (H{sub 2}S) is a novel gasotransmitter that regulates cell proliferation and other cellular functions. Sulforaphane (SFN) is a sulfur-containing compound that exhibits anticancer properties, and young sprouts of broccoli are particularly rich in SFN. There is consistent epidemiological evidence that the consumption of sulfur-containing vegetables, such as garlic and cruciferous vegetables, may help reduce the occurrence of prostate cancer. Here we found that a large amount of H{sub 2}S is released when SFN is added into cell culture medium or mixed with mouse liver homogenates, respectively. Both SFN and NaHS (a H{sub 2}S donor) decreased the viability of PC-3 cells (a human prostate cancer cell line) in a dose-dependent manner, and supplement of methemoglobin or oxidized glutathione (two H{sub 2}S scavengers) reversed SFN-reduced cell viability. We further found both cystathionine gamma-lyase (CSE) and cystathionine beta-synthase are expressed in PC-3 cells and mouse prostate tissues. H{sub 2}S production in prostate tissues from CSE knockout mice was only 20% of that from wild-type mice, suggesting CSE is a major H{sub 2}S-producing enzyme in prostate. CSE overexpression enhanced H{sub 2}S production and inhibited cell viability in PC-3 cells. In addition, both SFN and NaHS activated p38 mitogen-activated protein kinases (MAPK) and c-Jun N-terminal kinase (JNK). Pre-treatment of PC-3 cells with methemoglobin decreased SFN-stimulated MAPK activities. Suppression of both p38 MAPK and JNK reversed H{sub 2}S- or SFN-reduced viability of PC-3 cells. Our results demonstrated that H{sub 2}S mediates the inhibitory effect of SFN on the proliferation of PC-3 cells, which suggests that H{sub 2}S-releasing diet or drug might be beneficial in the treatment of prostate cancer. Highlights: Black-Right-Pointing-Pointer A large amount of H{sub 2}S is released from sulforaphane. Black-Right-Pointing-Pointer H{sub 2}S mediates the anti-survival effect of sulforaphane on human prostate cancer cells. Black-Right-Pointing-Pointer Cystathionine gamma-lyase is a major H{sub 2}S-producing enzyme in prostate tissues. Black-Right-Pointing-Pointer p38 MAPK and JNK contribute to H{sub 2}S and sulforaphane-reduced viability in prostate cancer cells.

  10. Hydrogen sulfide mediates hypoxia-induced relaxation of trout urinary bladder smooth muscle.

    PubMed

    Dombkowski, Ryan A; Doellman, Meredith M; Head, Sally K; Olson, Kenneth R

    2006-08-01

    Hydrogen sulfide (H2S) is a recently identified gasotransmitter that may mediate hypoxic responses in vascular smooth muscle. H2S also appears to be a signaling molecule in mammalian non-vascular smooth muscle, but its existence and function in non-mammalian non-vascular smooth muscle have not been examined. In the present study we examined H2S production and its physiological effects in urinary bladder from steelhead and rainbow trout (Oncorhynchus mykiss) and evaluated the relationship between H2S and hypoxia. H2S was produced by trout bladders, and its production was sensitive to inhibitors of cystathionine beta-synthase and cystathionine gamma-lyase. H2S produced a dose-dependent relaxation in unstimulated and carbachol pre-contracted bladders and inhibited spontaneous contractions. Bladders pre-contracted with 80 mmol l(-1) KCl were less sensitive to H2S than bladders contracted with either 80 mmol l(-1) KC2H3O2 (KAc) or carbachol, suggesting that some of the H2S effects are mediated through an ion channel. However, H2S relaxation of bladders was not affected by the potassium channel inhibitors, apamin, charybdotoxin, 4-aminopyridine, and glybenclamide, or by chloride channel/exchange inhibitors 4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt, tamoxifen and glybenclamide, or by the presence or absence of extracellular HCO3-. Inhibitors of neuronal mechanisms, tetrodotoxin, strychnine and N-vanillylnonanamide were likewise ineffective. Hypoxia (aeration with N2) also relaxed bladders, was competitive with H2S for relaxation, and it was equally sensitive to KCl, and unaffected by neuronal blockade or the presence of extracellular HCO3-. Inhibitors of H2S synthesis also inhibited hypoxic relaxation. These experiments suggest that H2S is a phylogenetically ancient gasotransmitter in non-mammalian non-vascular smooth muscle and that it serves as an oxygen sensor/transducer, mediating the effects of hypoxia.

  11. Hydrogen sulfide mediates the protection of dietary restriction against renal senescence in aged F344 rats

    PubMed Central

    Wang, Wen-juan; Cai, Guang-yan; Ning, Yi-chun; Cui, Jing; Hong, Quan; Bai, Xue-yuan; Xu, Xiao-meng; Bu, Ru; Sun, Xue-feng; Chen, Xiang-mei

    2016-01-01

    Renal aging is always accompanied by increased oxidative stress. Hydrogen sulfide (H2S) can be up-regulated by 50% dietary restriction (DR) for 7-day and can block mitochondrial oxidative stress. H2S production exerts a critical role in yeast, worm, and fruit fly models of DR-mediated longevity. In this study, we found that renal aging could be attenuated by 30% DR for 6-month (DR-6M) and life-long (DR-LL), but not for 6-week (DR-6W). The expressions of cystathionine-γ-lyase (CGL) and cystathionine-β- synthase (CBS) were improved by DR-6M and DR-LL. Endogenous H2S production shared the same trend with CBS and CGL, while glutathione (GSH) didn’t. When comparing efficiencies of DR for different durations, more evident production of H2S was found in DR-6M and DR-LL than in DR-6W. Finally the level of oxidative stress was improved by DR-6M and DR-LL rather than by DR-6W. It concluded that aged rats had the ability to produce enough H2S on 30% DR interventions protecting against renal aging, and the effect of DR for long-term were more significant than that of DR for short-term. PMID:27456368

  12. Hydrogen-sulfide-mediated vasodilatory effect of nucleoside 5'-monophosphorothioates in perivascular adipose tissue.

    PubMed

    Bełtowski, Jerzy; Guranowski, Andrzej; Jamroz-Wiśniewska, Anna; Wolski, Andrzej; Hałas, Krzysztof

    2015-07-01

    Hydrogen sulfide (H2S) is synthesized in perivascular adipose tissue (PVAT) and induces vasorelaxation. We examined whether the sulfur-containing AMP and GMP analogs AMPS and GMPS can serve as the H2S donors in PVAT. H2S production by isolated rat periaortic adipose tissue (PAT) was measured with a polarographic sensor. In addition, phenylephrine-induced contractility of aortic rings with (+) or without (-) PAT was examined. Isolated PAT produced H2S from AMPS or GMPS in the presence of the P2X7 receptor agonist BzATP. Phenylephrine-induced contractility of PAT(+) rings was lower than of PAT(-) rings. AMPS or GMPS had no effect on the contractility of PAT(-) rings, but used together with BzATP reduced the contractility of PAT(+) rings when endogenous H2S production was inhibited with propargylglycine. A high-fat diet reduced endogenous H2S production by PAT. Interestingly, AMPS and GMPS were converted to H2S by PAT of obese rats, and reduced contractility of PAT(+) aortic rings isolated from these animals even in the absence of BzATP. We conclude that (i) AMPS and GMPS can be hydrolyzed to H2S by PAT when P2X7 receptors are activated, (ii) a high-fat diet impairs endogenous H2S production by PAT, (iii) AMPS and GMPS restore the anticontractile effects of PAT in obese animals without P2X7 stimulation.

  13. Impaired Hydrogen Sulfide-Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults.

    PubMed

    Greaney, Jody L; Kutz, Jessica L; Shank, Sean W; Jandu, Sandeep; Santhanam, Lakshmi; Alexander, Lacy M

    2017-05-01

    Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2S in contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2S-dependent vasodilation, and vascular responsiveness to exogenous H2S (sodium sulfide) would be attenuated in HTN compared to normotensive adults. Fifteen normotensive (51±2 years; blood pressure, 116±3/76±3 mm Hg) and 14 HTN adults (57±2 years; blood pressure 140±3/89±2 mm Hg) participated. H2S biosynthetic enzyme expression (Western blot) and substrate-dependent H2S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10(-6)-10(-1) mol/L) and sodium sulfide (10(-5)-10(1) mol/L) using intradermal microdialysis; the functional role of H2S was determined using pharmacological inhibition with aminooxyacetic acid (0.5 mmol/L). H2S biosynthetic enzyme expression and substrate-dependent H2S production were reduced in HTN adults (all P<0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN adults (P=0.012). Aminooxyacetic acid attenuated ACh-induced vasodilation in normotensive adults (ACh, 1.31±0.13 versus ACh+aminooxyacetic acid, 1.07±0.09 flux/mm Hg; P=0.025) but had no effect on vasodilation in HTN adults (ACh, 1.16±0.10 versus ACh+aminooxyacetic acid, 1.37±0.11 flux/mm Hg; P=0.47). Sodium sulfide-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2S, reductions in endogenous synthesis and H2S-dependent vasodilation contribute to endothelial dysfunction in human hypertension. © 2017 American Heart Association, Inc.

  14. Hydrogen sulfide mediates nicotine biosynthesis in tobacco (Nicotiana tabacum) under high temperature conditions.

    PubMed

    Chen, Xiaodong; Chen, Qian; Zhang, Xiaoming; Li, Ruijing; Jia, Yujie; Ef, Abd Allah; Jia, Aiqun; Hu, Liwei; Hu, Xiangyang

    2016-07-01

    Hydrogen sulfide (H2S) acts as a signal to induce many physiological processes in plants, but its role in controlling the biosynthesis of secondary metabolites is not well established. In this study, we found that high temperature (HT) treatment induced nicotine biosynthesis in tobacco (Nicotiana tabacum) and promoted the rapid accumulation of H2S. Furthermore, HT triggered the biosynthesis of jasmonic acid (JA), a plant hormone that promotes nicotine biosynthesis. Suppression of the H2S signal using chemical inhibitors or via RNAi suppression of l-cysteine desulphydrase (L-CD) in transgenic plants, compromised JA production and nicotine biosynthesis under HT treatments, and these inhibitory effects could be reversed by applying exogenous H2S. Based on these data, we propose that H2S is an important trigger of nicotine biosynthesis in tobacco under HT conditions, and that H2S acts upstream of JA signaling by modulating the transcription of genes associated with JA biosynthesis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. In Vitro Cytotoxic Potential of Afghanistan Sand Extract

    DTIC Science & Technology

    2013-02-05

    arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress -regulated signaling pathway. Arch Toxicol 85: 565-75. 72. Zhang L, Li L...cytotoxicity through an oxidative stress mechanism. Moreover, the toxicity was associated with mitochondrial dysfunction followed by release of...impairing mitochondrial function. 15. SUBJECT TERMS Sand, Particulate Matter, Neurons, Cytotoxicity, Oxidative Stress 16. SECURITY CLASSIFICATION OF

  16. Stereochemistry-dependent cytotoxicity of some artemisinin derivatives.

    PubMed

    Beekman, A C; Barentsen, A R; Woerdenbag, H J; Van Uden, W; Pras, N; Konings, A W; el-Feraly, F S; Galal, A M; Wikström, H V

    1997-04-01

    We determined the cytotoxicity of some artemisinin derivatives against EN2 tumor cells using the MTT assay. Artemisinin (1) was clearly more cytotoxic than deoxyartemisinin (2), which lacks the endoperoxide bridge. Ether-linked dimers of dihydroartemisinin with defined stereochemistry were found to differ in the extent of cytotoxic effect on EN2 cells. The nonsymmetrical dimer (3) was more cytotoxic than the symmetrical dimer (4). The nonsymmetrical dimer of dihydrodeoxyartemisinin (5) lacking the endoperoxide bridges was also effective in the MTT assay, although less cytotoxic than 3 and 4. Similarly, the symmetrical dimer (6) was less effective than 5. Epoxides of artemisitene also showed that stereochemistry was an important factor for cytotoxicity. The results suggested that the endoperoxide bridge was not crucial for cytotoxicity to the tumor cells, but contributed to the cytotoxic effect apparently exerted by the ether linkage of the dimers. Flow cytometry data indicated that the dimers 3 and 4 caused an accumulation of the cells in the G1-phase of the cell cycle. In contrast, artemisinin (1) caused a slight increase of S-phase cells.

  17. New cytotoxic steroids from the soft coral Clavularia viridis.

    PubMed

    Duh, Chang-Yih; Lo, I-Wen; Wang, Shang-Kwei; Dai, Chang-Feng

    2007-06-01

    Ten new cytotoxic steroids, stoloniferones H-Q (1-10) were isolated from the methylene chloride solubles of the soft coral Clavularia viridis. The structures of the metabolites were elucidated on the basis of spectroscopic (IR, MS, and 1D and 2D NMR) analysis and their cytotoxicity against selected cancer cells was measured in vitro.

  18. Cytotoxicity of diterpenes from Premna schimperi and Premna oligotricha.

    PubMed

    Habtemariam, S

    1995-08-01

    The cytotoxicity of two diterpenes from Premna schimperi and Premna oligotricha (Verbenaceae) was studied using the MTT assay. Their cytotoxic activity against three human (HeLa, SK.N.SH, and ECV 304) and two murine (L929 and RAW 264.7) carcinoma cell lines varied between 1.5 to 35 micrograms/ml and was comparable with azauridine and chlorambucil.

  19. Cell signaling and cytotoxicity by peroxynitrite.

    PubMed Central

    Cantoni, Orazio; Palomba, Letizia; Guidarelli, Andrea; Tommasini, Ilaria; Cerioni, Liana; Sestili, Piero

    2002-01-01

    Reactive nitrogen species are now considered to play an important role in various pathologies. Although the pathological significance of these molecules, peroxynitrite in particular, has long been attributed to their abilities to react with any component of the cells, including lipids, proteins, and DNA, a paradigm shift has recently been occurring whereby reactive nitrogen species are appreciated as signaling molecules. The question therefore arises as to whether nitrosative stress is indeed the result of a random (stochastic) process of cell damage, as it has traditionally been viewed, or rather is a consequence of the specific activation of a cascade of signaling events. The above considerations have provided the bases for the research work performed in our laboratory, and the results obtained are illustrated in the present article. In particular, our results indicate that some effects of peroxynitrite are not directly mediated by the oxidant; rather, it appears that peroxynitrite triggers a signaling pathway that finally leads to cytotoxicity. PMID:12426139

  20. Cytotoxic Withanolide Constituents of Physalis longifolia

    PubMed Central

    Zhang, Huaping; Samadi, Abbas K.; Gallagher, Robert J.; Araya, Juan J.; Tong, Xiaoqin; Day, Victor W.; Cohen, Mark S.; Kindscher, Kelly; Gollapudi, Rao; Timmermann, Barbara N.

    2011-01-01

    Fourteen new withanolides 1-14, named withalongolides A-N, respectively, were isolated from the aerial parts of Physalis longifolia together with eight known compounds (15-22). The structures of compounds 1-14 were elucidated through spectroscopic techniques and chemical methods. In addition, the structures of withanolides 1, 2, 3, and 6 were confirmed by X-ray crystallographic analysis. Using a MTS viability assays, eight withanolides (1, 2, 3, 7, 8, 15, 16, and 19) and four acetylated derivatives (1a, 1b, 2a, and 2b) showed potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal fibroblast (MRC-5) cells with IC50 values in the range between 0.067 and 9.3 μM. PMID:22098611

  1. Cytotoxic activities of some Greek Labiatae herbs.

    PubMed

    Badisa, R B; Tzakou, O; Couladis, M; Pilarinou, E

    2003-05-01

    Nineteen methanolic crude plant extracts of Labiatae family, collected in Greece from different locations, were evaluated for cytotoxic activity against brine shrimps and three human cancer cell lines along with a normal mouse cells as a control cell line. In the brine shrimp lethality test, Mentha pulegium was the only sample found to be active with an LC(50) value 347.3 micro g/ml, while all remaining samples had LC(50) values greater than 1000 micro g/ml. In case of Caco-2 and HepG2 cell lines, only one sample, namely Thymus parnassicus Halacsy, was active with LC(50) values 44.6 and 50.3 micro g/ml respectively, while against MCF-7 cell line, two samples, namely, Clinopodium vulgare L. (LC(50): 60.4 micro g/ml), and Thymus parnassicus Halacsy (LC(50): 54.7 micro g/ml), were found active. Copyright 2003 John Wiley & Sons, Ltd.

  2. Size dependent cytotoxicity of fly ash particles

    SciTech Connect

    Liu, W.K.; Tam, J.S.K.; Wong, M.H.

    1988-01-01

    Fly ash samples were collected from the electrostatic precipitator of a coal-fired power plant in Hong Kong. The particles of the respirable range (smaller than 10 {mu}m) were divided into 4 groups according to their particle size (mass median aerodynamic diameters). The surface morphology and the metal contents (Fe, Mn, Al and Zn) of fly ash particles were examined by a scanning electron microscopy and an inductively coupled plasma spectrophotometer, respectively. The particles were very heterogeneous in size and shape as well as the concentration of metals. The cytotoxicity of these four groups of fly ash particles were evaluated using an in vitro rat alveolar macrophages culture assay. The viability of alveolar macrophages was lower when incubated with smaller size particles. This relationship was also reflected by the damage of the surface morphology of the cells and the release of cytoplasmic (lactate dehydrogenase) and lysosomal (acid phosphatase and {beta}-glucuronidase) marker enzymes into the culture media.

  3. Cytotoxic withanolides from Physalis angulata L.

    PubMed

    He, Qing-Ping; Ma, Lei; Luo, Jie-Ying; He, Fu-Yuan; Lou, Li-Guang; Hu, Li-Hong

    2007-03-01

    Four new withanolides, physagulins L-O (1-4), were isolated from the MeOH extract of the aerial parts of Physalis angulata L. (Solanaceae), together with seven known withanolides, compounds 5-11. Their structures were determined by spectroscopic techniques, including 1H-, 13C-NMR (DEPT), and 2D-NMR (HMBC, HMQC, 1H,1H-COSY, NOESY) experiments, as well as by HR-MS. All eleven compounds were tested for their antiproliferative activities towards human colorectal-carcinoma (HCT-116) and human non-small-cell lung-cancer (NCI-H460) cells. Compound 5 exhibited the highest anticancer activity against the HCT-116 cell line, with an IC50 value of 1.64+/-0.06 microM. Compound 9 exhibited the highest cytotoxicity towards the NCI-H460 cell line, with an IC50 value of 0.43+/-0.02 microM.

  4. Cytotoxic withanolide constituents of Physalis longifolia.

    PubMed

    Zhang, Huaping; Samadi, Abbas K; Gallagher, Robert J; Araya, Juan J; Tong, Xiaoqin; Day, Victor W; Cohen, Mark S; Kindscher, Kelly; Gollapudi, Rao; Timmermann, Barbara N

    2011-12-27

    Fourteen new withanolides, 1-14, named withalongolides A-N, respectively, were isolated from the aerial parts of Physalis longifolia together with eight known compounds (15-22). The structures of compounds 1-14 were elucidated through spectroscopic techniques and chemical methods. In addition, the structures of withanolides 1, 2, 3, and 6 were confirmed by X-ray crystallographic analysis. Using a MTS viability assay, eight withanolides (1, 2, 3, 7, 8, 15, 16, and 19) and four acetylated derivatives (1a, 1b, 2a, and 2b) showed potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal fibroblast (MRC-5) cells with IC₅₀ values in the range between 0.067 and 9.3 μM.

  5. Cytotoxic neolignans and butanolides from Machilus obovatifolia.

    PubMed

    Tsai, I L; Chen, J H; Duh, C Y; Chen, I S

    2001-08-01

    From the chloroform-soluble portion of the stem wood of Machilus obovatifolia, one new neolignan, perseal F (1), four known neolignans, perseal G (2), licarin A, licarin B, acuminatin, two butanolides, linderanolide E and isolinderanolide E, two steroids, beta-sitosterol, beta-sitosterol-beta-D-glucoside, and syringaldehyde were isolated. Perseal F (1) and G (2) are neolignans that have a C-1' formyl side chain instead of a propenyl group. Compound 2 was isolated in a mixture with acuminatin. The structure of 2 was identified by comparison with the product formed by the Lemieux-von Rudloff oxidation of licarin B. Two minor oxidative by-products, 2a and 2b, were also obtained. Linderanolide E showed cytotoxicities against P-388, KB16, A549 and HT-29, 1 against P-388, KB16 and HT-29, and isolinderanolide E against P-388, cancer cell lines, respectively. All structures were identified by means of spectroscopic analyses.

  6. Cytotoxicity of Exfoliated Layered Vanadium Dichalcogenides.

    PubMed

    Latiff, Naziah Mohamad; Sofer, Zdeněk; Fisher, Adrian C; Pumera, Martin

    2017-01-12

    Transition-metal Group 5 vanadium dichalcogenides have shown promising properties for many applications, such as batteries, capacitors, electrocatalysts for hydrogen production and many more. However, their toxicological effects have not yet been well understood. Here, we studied the cytotoxicity of exfoliated VS2 , VSe2 and VTe2 by incubating various concentrations of the materials with human lung carcinoma (A549) cells for 24 h and measuring the remaining cell viabilities after the treatment. We found that these vanadium dichalcogenides are relatively more toxic compared to Group 6 transition-metal dichalcogenides (TMDs), namely MoS2 , WS2 and WSe2 . This study is important for a better understanding of the toxicity of TMDs in preparation for their actual commercialisation in the future.

  7. Cytotoxic Action of Carboxyborane Heterocyclic Amine Adducts

    PubMed Central

    Miller, Merrill C.; Sood, Anup; Spielvogel, Bernard F.; Bastow, Ken

    1997-01-01

    The heterocyclic carboxyborane amines were found to be potent cytotoxic agents in the murine L1210 lymphoid leukemia and human HeLa suspended carcinoma cells. These agents were observed to inhibit HeLa DNA topoisomerase II activity ~ 200 μM and L1210 topoisomerase II activity ≥ 100 μM. These agents did not cause DNA protein linked breaks themselves, but upon incubation for 14-24 hr did enhance the ability of VP-16 to cause cleavable complexes. The heterocyclic amineboranes inhibited DNA synthesis and caused DNA strand scission. They were additive with VP-16 in affording these results as well as inhibiting colony growth of L1210 cells after co-incubation for 1 hr. The agents inhibited in vitro PKC phosphorylation of both L1210 lymphoid leukemia and human topoisomerase II enzyme. PMID:18475792

  8. Cytotoxic and antimicrobial coumarins from Mammea africana.

    PubMed

    Ouahouo, B M W; Azebaze, A G B; Meyer, M; Bodo, B; Fomum, Z T; Nkengfack, A E

    2004-10-01

    Six coumarin derivatives [three 4-phenylcoumarins (Mammea A/AA, Mammea A/BA and MAB 3), two 4-n-propylcoumarins (Mammea B/BB and Mammea B/BA) and one 4-n-pentylcoumarin (Mammea C/OB)], 1,5-dihydroxyxanthone and 1-methoxy-5-hydroxyxanthone have been isolated from the stem bark of Mammea africana Sabine collected in Cameroon. Although known, the structures of the coumarin derivatives were confirmed by spectral analysis, including two-dimensional nuclear magnetic resonance. All the coumarin compounds showed noteworthy cytotoxicity against the human 9-KB cell line. Both of the 4-n-propylcoumarins were also found to exhibit significant activity against Staphylococcus aureus.

  9. Cytotoxicity of Two Bioactive Root Canal Sealers

    PubMed Central

    Pezelj-Ribaric, Sonja; Roguljić, Marija; Miletic, Ivana

    2016-01-01

    Objective The aim of this study was to investigate the cytotoxicity of two different bioactive root canal sealers: one based on mineral trioxide aggregate, MTA Fillapex (Angelus, Solucoes Odontologicas, Londrina, PR, Brazil), and the other based on bioceramics, Endosequence BC Sealer (Brasseler, Savannah, Georgia, USA), in culture of mouse L929 fibroblasts. Materials and methods Mouse fibroblasts (L929), obtained from subcutaneous connective tissue of mouse line C3Hf, were cultivated in plastic culture flasks in an incubator at 37şC, with 5% CO2 and 90% humidity. Freshly mixed Endosequence BC Sealer and MTA Fillapex (0.1 g each) were placed on sterile teflon discs, 6 mm in diameter. Teflon discs with the materials as well as empty discs serving as control were placed in wells of 12-well plate. After incubation times of 1, 6, 20 and 24 hours, the teflon discs were removed from the wells and the number of viable cells was determined using trypan blue in Neubauer chamber. Results In comparison to the control group, MTA Fillapex had significantly less viable cells for all incubation periods (p≤0.05), while Endosequence BC sealer had significantly less viable cells after 6, 20, and 24 hours of incubation (p≤0.05). MTA Fillapex comprised significantly less viable cells in comparison to Endosequence BC sealer after the first hour and after 20 hours of incubation (p≤0.05), while for the other incubation periods there were no significant differences (p≥0.05). Conclusion MTA Fillapex and Endosequence BC sealer were both cytotoxic in cultures of mouse L929 fibroblasts. PMID:27688421

  10. Antitumor Activity of Cytotoxic Cyclooxygenase-2 Inhibitors

    PubMed Central

    Uddin, Md. Jashim; Crews, Brenda C.; Xu, Shu; Ghebreselasie, Kebreab; Daniel, Cristina K.; Kingsley, Philip J.; Banerjee, Surajit; Marnett, Lawrence J.

    2017-01-01

    Targeted delivery of chemotherapeutic agents to tumors has been explored as a means to increase the selectivity and potency of cytotoxicity. Most efforts in this area have exploited the molecular recognition of proteins highly expressed on the surface of cancer cells followed by internalization. A related approach that has received less attention is the targeting of intracellular proteins by ligands conjugated to anti-cancer drugs. An attractive target for this approach is the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in a range of malignant tumors. Herein, we describe the synthesis and evaluation of a series of chemotherapeutic agents targeted to COX-2 by conjugation to indomethacin. Detailed characterization of compound 12, a conjugate of indomethacin with podophyllotoxin, revealed highly potent and selective COX-2 inhibition in vitro and in intact cells. Kinetics and X-ray crystallographic studies demonstrated that compound 12 is a slow, tight-binding inhibitor that likely binds to COX-2’s allosteric site with its indomethacin moiety in a conformation similar to that of indomethacin. Compound 12 exhibited cytotoxicity in cell culture similar to that of podophyllotoxin with no evidence of COX-2-dependent selectivity. However, in vivo, compound 12 accumulated selectively in and more effectively inhibited the growth of a COX-2-expressing xenograft compared to a xenograft that did not express COX-2. Compound 12, which we have named chemocoxib A, provides proof-of-concept for the in vivo targeting of chemotherapeutic agents to COX-2, but suggests that COX-2-dependent selectivity may not be evident in cell culture-based assays. PMID:27588346

  11. Cytotoxicity of Two Bioactive Root Canal Sealers.

    PubMed

    Baraba, Anja; Pezelj-Ribaric, Sonja; Roguljić, Marija; Miletic, Ivana

    2016-03-01

    The aim of this study was to investigate the cytotoxicity of two different bioactive root canal sealers: one based on mineral trioxide aggregate, MTA Fillapex (Angelus, Solucoes Odontologicas, Londrina, PR, Brazil), and the other based on bioceramics, Endosequence BC Sealer (Brasseler, Savannah, Georgia, USA), in culture of mouse L929 fibroblasts. Mouse fibroblasts (L929), obtained from subcutaneous connective tissue of mouse line C3Hf, were cultivated in plastic culture flasks in an incubator at 37şC, with 5% CO2 and 90% humidity. Freshly mixed Endosequence BC Sealer and MTA Fillapex (0.1 g each) were placed on sterile teflon discs, 6 mm in diameter. Teflon discs with the materials as well as empty discs serving as control were placed in wells of 12-well plate. After incubation times of 1, 6, 20 and 24 hours, the teflon discs were removed from the wells and the number of viable cells was determined using trypan blue in Neubauer chamber. In comparison to the control group, MTA Fillapex had significantly less viable cells for all incubation periods (p≤0.05), while Endosequence BC sealer had significantly less viable cells after 6, 20, and 24 hours of incubation (p≤0.05). MTA Fillapex comprised significantly less viable cells in comparison to Endosequence BC sealer after the first hour and after 20 hours of incubation (p≤0.05), while for the other incubation periods there were no significant differences (p≥0.05). MTA Fillapex and Endosequence BC sealer were both cytotoxic in cultures of mouse L929 fibroblasts.

  12. Cytotoxic steroidal saponins from Panicum turgidum Forssk.

    PubMed

    Zaki, Ahmed A; Ali, Zulfiqar; Wang, Yan-Hong; El-Amier, Yasser A; Khan, Shabana I; Khan, Ikhlas A

    2017-09-01

    Three new bidesmosidic cholestane-type steroidal glycosides, 16-O-β-d-glucopyranosyl-cholest-5-en-3β,16β-diol-22-one-3-O-α-l-rhamnopyranosyl-(1→2)-O-[(β-d-glucopyranosyl(1→4)]-O-β-d-glucopyranoside (1), 16-O-β-d-glucopyranosylcholest-5-en-3β,16β-diol-22-one-3-O-α-l-rhamnopyranosyl-(1→2)-O-β-d-glucopyranoside (2), and 16-O-β-d-glucopyranosylcholestan-3β,16β-diol-6,22-dione-3-O-α-l-rhamnopyranosyl-(1→2)-O-β-d-glucopyranoside (3) were isolated from a methanolic extract of Panicum turgidum. In addition four known compounds, pennogenin 3β-O-α-l-rhamnopyranosyl-(1→2)-O-[α-l-rhamnopyranosyl-(1→4)-O-α-l-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside (4), yamogenin 3β-O-α-l-rhamnopyranosyl-(1→2)-O-[α-l-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside (5), yamogenin 3β-O-α-l-rhamnopyranosyl-(1→2)-O-[α-l-rhamnopyranosyl-(1→4)-O-α-l-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside (6), and pennogenin 3β-O-α-l-rhamnopyranosyl-(1→2)-O-[α-l-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside (7) were also isolated and characterized. Their structures were established using extensive spectroscopic methods including 1D and 2D NMR and HRESIMS. The isolated compounds were screened for cytotoxicity towards a panel of mammalian cell lines and 4-7 were found to be cytotoxic. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Study of the in vitro cytotoxicity testing of medical devices.

    PubMed

    Li, Weijia; Zhou, Jing; Xu, Yuyin

    2015-09-01

    The cytotoxicity test is one of the biological evaluation and screening tests that use tissue cells in vitro to observe the cell growth, reproduction and morphological effects by medical devices. Cytotoxicity is preferred as a pilot project test and an important indicator for toxicity evaluation of medical devices as it is simple, fast, has a high sensitivity and can save animals from toxicity. Three types of cytotoxicity test are stated in the International Organization for Standardization 109993-5: Extract, direct contact and indirect contact tests. The xCELLigence real-time cell analysis system shows a significant potential in regards to cytotoxicity in recent years. The present review provides a brief insight into the in vitro cytotoxicity testing of medical devices.

  14. Study of the in vitro cytotoxicity testing of medical devices

    PubMed Central

    LI, WEIJIA; ZHOU, JING; XU, YUYIN

    2015-01-01

    The cytotoxicity test is one of the biological evaluation and screening tests that use tissue cells in vitro to observe the cell growth, reproduction and morphological effects by medical devices. Cytotoxicity is preferred as a pilot project test and an important indicator for toxicity evaluation of medical devices as it is simple, fast, has a high sensitivity and can save animals from toxicity. Three types of cytotoxicity test are stated in the International Organization for Standardization 109993-5: Extract, direct contact and indirect contact tests. The xCELLigence real-time cell analysis system shows a significant potential in regards to cytotoxicity in recent years. The present review provides a brief insight into the in vitro cytotoxicity testing of medical devices. PMID:26405534

  15. Immunohistochemical identification of cytotoxic lymphocytes using human perforin monoclonal antibody.

    PubMed Central

    Hameed, A.; Olsen, K. J.; Cheng, L.; Fox, W. M.; Hruban, R. H.; Podack, E. R.

    1992-01-01

    Perforin is a potent cytolytic pore-forming protein expressed in cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells. A new monoclonal antibody raised against human perforin was used to detect both in vitro and in vivo perforin expression in cytotoxic cells. Immunohistochemical analysis of human peripheral blood mononuclear cells cultured in recombinant interleukin-2 (rIL-2) showed strong granular cytoplasmic staining of the IL-2 activated cytotoxic cells. Fresh-frozen tissue sections from patients with heart allograft rejection were also stained. Strong granular cytoplasmic staining of the mononuclear inflammatory infiltrate characteristic for perforin in cardiac allograft rejection was observed. The detection and quantitative analysis of perforin-associated cytotoxic cells by the human anti-perforin monoclonal antibody will help to evaluate the significance of these functionally distinct cytotoxic cells in human tissue. Images Figure 1 PMID:1374586

  16. Cytotoxicity screening of endemic plants from Guayana highlands.

    PubMed

    Guil-Guerrero, José Luis; Campra, Pablo

    2009-08-01

    A chemical-ecology approach has been used to screen plants growing in Guyana Highlands as an indicator of production of biologically active secondary metabolites. Extracts of leaves from 19 species, most of them endemic in this area, and collected at the top of Roraima Tepui (2,723 m) were screened in vitro at different concentrations for their potential cytotoxic activity against three tumour cell lines: HT29 (colon), A549 (lung) and MDA-MB-231 (breast). MTT (tetrazolium blue) colorimetric assay was employed as cytotoxicity test. Extracts of nine species caused less than 30% growth in at least one cell line. From these species, high cytotoxic activity was detected in Casearia sylvestris var. lingua and Ledotamnus sessiliflorus extracts; medium activity was found in Cyathea sp. Two other species, Cyrilla racemiflora and Heliamphora minor showed lower but significant cytotoxicity. Further cytotoxicity-directed fractionation of these extracts would be advisable to isolate and identify the active principles of these plants.

  17. Resistance of cytotoxic T lymphocytes to lysis by a clone of cytotoxic T lymphocytes

    SciTech Connect

    Kranz, D.M.; Eisen, H.N.

    1987-05-01

    To investigate how cytotoxic T lymphocytes (CTL) avoid killing themselves when they destroy target cells, the authors compared 20 different cell lines as target cells, including several CTL cell lines, for their susceptibility to lysis by CTL, measured by a standard /sup 51/Cr-release assay. Variations in recognition of this diverse set of target cells was circumvented by attaching to all of them a monoclonal antibody to the antigen-specific receptor of a cloned CTL cell line (clone 2C) and using the 2C cell line as the standard aggressor or effector cell. All of the nine tumor cell lines and the four noncytolytic T-helper cell lines tested as targets were highly susceptible to lysis by the aggressor CTL, but seven cytotoxic T-cell lines (six CTL and one T-helper cell line with cytotoxic activity) were largely resistant. These results, and the use of the lectin Con A as an alternative means for triggering CTL activity, point clearly to a level of resistance that could enable CTL to avoid their own destruction when they lyse target cells. The resistance of the cytolytic T cells did not appear to be accompanied by a similar resistance to complement-mediated lysis, indicating that mechanisms of CTL-mediated and complement-mediated lysis are not identical.

  18. Acrylic Resin Cytotoxicity for Denture Base--Literature Review.

    PubMed

    Goiato, Marcelo C; Freitas, Emily; dos Santos, Daniela; de Medeiros, Rodrigo; Sonego, Mariana

    2015-01-01

    Acrylic resin is a widely used material in clinical practice, and a satisfactory biocompatibility is essential. When the resin polymerization reaction is incomplete, residual monomers are released into the oral cavity. The aim of this study was to evaluate, through a literature review, the cytotoxicity caused by the denture base acrylic resin used, and its components. The selection of published studies was performed on the Pubmed database from January 2008 to July 2013. The keywords used were: "cytotoxicity and acrylic resins", "cytotoxicity and denture base resins" and "cytotoxicity and oral prosthesis". Inclusion criteria were: in vitro studies and literature reviews published in English that evaluated the acrylic resin cytotoxicity for denture base and its components. Studies with no reference to the search strategy were excluded. A total of 182 articles were found. Among these, only 13 were included for writing this review. The MTT test is the most common test used to evaluate acrylic resin cytotoxicity. Auto-polymerized resin is more cytotoxic than heat-polymerized resin because of its higher quantity of residual monomers which cause cell and tissue changes in the oral mucosa. However, more studies are necessary for the development of biocompatible materials.

  19. The cytotoxic mechanism of glyoxal involves oxidative stress.

    PubMed

    Shangari, Nandita; O'Brien, Peter J

    2004-10-01

    Glyoxal is a reactive alpha-oxoaldehyde that is a physiological metabolite formed by lipid peroxidation, ascorbate autoxidation, oxidative degradation of glucose and degradation of glycated proteins. Glyoxal is capable of inducing cellular damage, like methylglyoxal (MG), but may also accelerate the rate of glycation leading to the formation of advanced glycation end-products (AGEs). However, the mechanism of glyoxal cytotoxicity has not been precisely defined. In this study we have focused on the cytotoxic effects of glyoxal and its ability to overcome cellular resistance to oxidative stress. Isolated rat hepatocytes were incubated with different concentrations of glyoxal. Glyoxal by itself was cytotoxic at 5mM, depleted GSH, formed reactive oxygen species (ROS) and collapsed the mitochondrial membrane potential. Glyoxal also induced lipid peroxidation and formaldehyde formation. Glycolytic substrates, e.g. fructose, sorbitol and xylitol inhibited glyoxal-induced cytotoxicity and prevented the decrease in mitochondrial membrane potential suggesting that mitochondrial toxicity contributed to the cytotoxic mechanism. Glyoxal cytotoxicity was prevented by the glyoxal traps d-penicillamine or aminoguanidine or ROS scavengers were also cytoprotective even when added some time after glyoxal suggesting that oxidative stress contributed to the glyoxal cytotoxic mechanism.

  20. Cytotoxic effects of catechol to neuroblastoma N2a cells.

    PubMed

    Lima, Rute M F; Alvarez, Lisandro D G; Costa, Maria F D; Costa, Silvia L; Clarêncio, Jorge; El-Bachá, Ramon S

    2008-12-01

    The mechanisms of catechol-induced cytotoxicity were studied in cultures of neuroblastoma N2a cells. The minimal cytotoxic concentration after 72 h was 20 micromol x l(-1). The EC50 after 72 h was 38 micromol x l(-1). There was not a correlation between the cytotoxicity and the formation of quinones in the medium. Catechol-induced cytotoxicity was increased significantly when superoxide dismutase (SOD) was added. The addition of catalase did not protect cells, but this enzyme reverted the deleterious effect of SOD. The experimental studies showed a detrimental effect of deferoxamine on catechol-induced cytotoxicity suggesting that cells need iron to maintain its metabolism. NF-kappaB inhibitors increased the cytotoxicity, suggesting that this factor is also important for cell viability. L-cysteine and N-acetyl-L-cysteine protected cells significantly in a dose-dependent manner. The use of monochlorobimane showed that catechol induced reduced glutathione (GSH) depletion after 24 h, prior to cell death. The mode of cell death was studied by flow cytometry after double staining with annexin V and propidium iodide. Catechol induced apoptosis after 72 h. Furthermore, catechol also induced nuclear fragmentation. These data showed that catechol-induced cytotoxicity to N2a cell was not directly a consequence of reactive oxygen species production. Rather, it was due to GSH depletion followed by the induction of apoptosis.

  1. Natural killer cell mediated cytotoxic responses in the Tasmanian devil.

    PubMed

    Brown, Gabriella K; Kreiss, Alexandre; Lyons, A Bruce; Woods, Gregory M

    2011-01-01

    The Tasmanian devil (Sarcophilus harrisii), the world's largest marsupial carnivore, is under threat of extinction following the emergence of an infectious cancer. Devil facial tumour disease (DFTD) is spread between Tasmanian devils during biting. The disease is consistently fatal and devils succumb without developing a protective immune response. The aim of this study was to determine if Tasmanian devils were capable of forming cytotoxic antitumour responses and develop antibodies against DFTD cells and foreign tumour cells. The two Tasmanian devils immunised with irradiated DFTD cells did not form cytotoxic or humoral responses against DFTD cells, even after multiple immunisations. However, following immunisation with xenogenic K562 cells, devils did produce cytotoxic responses and antibodies against this foreign tumour cell line. The cytotoxicity appeared to occur through the activity of natural killer (NK) cells in an antibody dependent manner. Classical NK cell responses, such as innate killing of DFTD and foreign cancer cells, were not observed. Cells with an NK-like phenotype comprised approximately 4 percent of peripheral blood mononuclear cells. The results of this study suggest that Tasmanian devils have NK cells with functional cytotoxic pathways. Although devil NK cells do not directly recognise DFTD cancer cells, the development of antibody dependent cell-mediated cytotoxicity presents a potential pathway to induce cytotoxic responses against the disease. These findings have positive implications for future DFTD vaccine research.

  2. Natural Killer Cell Mediated Cytotoxic Responses in the Tasmanian Devil

    PubMed Central

    Brown, Gabriella K.; Kreiss, Alexandre; Lyons, A. Bruce; Woods, Gregory M.

    2011-01-01

    The Tasmanian devil (Sarcophilus harrisii), the world's largest marsupial carnivore, is under threat of extinction following the emergence of an infectious cancer. Devil facial tumour disease (DFTD) is spread between Tasmanian devils during biting. The disease is consistently fatal and devils succumb without developing a protective immune response. The aim of this study was to determine if Tasmanian devils were capable of forming cytotoxic antitumour responses and develop antibodies against DFTD cells and foreign tumour cells. The two Tasmanian devils immunised with irradiated DFTD cells did not form cytotoxic or humoral responses against DFTD cells, even after multiple immunisations. However, following immunisation with xenogenic K562 cells, devils did produce cytotoxic responses and antibodies against this foreign tumour cell line. The cytotoxicity appeared to occur through the activity of natural killer (NK) cells in an antibody dependent manner. Classical NK cell responses, such as innate killing of DFTD and foreign cancer cells, were not observed. Cells with an NK-like phenotype comprised approximately 4 percent of peripheral blood mononuclear cells. The results of this study suggest that Tasmanian devils have NK cells with functional cytotoxic pathways. Although devil NK cells do not directly recognise DFTD cancer cells, the development of antibody dependent cell-mediated cytotoxicity presents a potential pathway to induce cytotoxic responses against the disease. These findings have positive implications for future DFTD vaccine research. PMID:21957452

  3. Evaluation of the In Vitro Cytotoxicity of Crosslinked Biomaterials

    PubMed Central

    Wang, Martha O.; Etheridge, Julie M.; Thompson, Joshua A.; Vorwald, Charlotte E.; Dean, David; Fisher, John P.

    2013-01-01

    This study evaluated the in vitro cytotoxicity of poly(propylene fumarate) (PPF). PPF is an aliphatic biodegradable polymer that has been well characterized for use in bone tissue engineering scaffolds. Four different cell types, human mesenchymal stem cells (hMSC), fibroblasts (L929), pre-osteoblasts (MC3T3), and canine mesenchymal stem cells (cMSC), were used to evaluate the cytotoxicity of PPF. These cell types represent the tissues that PPF would interact with in vivo as a bone tissue scaffold. The sol fraction of the PPF films was measured and then utilized to estimate crosslinking density. Cytotoxicity was evaluated using XTT assay and fluorescence imaging. Results showed that PPF supported similar cell metabolic activities of hMSC, L929, MC3T3 and cMSC compared to the non-cytotoxic control, high density polyethylene (HDPE) and were statistically different than those cultured with the cytotoxic control, a polyurethane film containing 0.1% zinc diethyldithiocarbamate (ZCF). Results showed differing cellular responses to ZCF, the cytotoxic control. The L929 cells had the lowest cell metabolic activity levels after exposure to ZCF compared to the cell metabolic activity levels of the MC3T3, hMSC or cMSC cells. Qualitative verification of the results using fluorescence imaging demonstrated no change in cell morphology, vacuolization, or detachment when cultured with PPF compared to HDPE or blank media cultures. Overall the cytotoxicity response of the cells to PPF was demonstrated to be similar to the cytotoxic response of cells to known non-cytotoxic materials (HDPE). PMID:23627804

  4. Interleukin-2 activation of cytotoxic cells in postmastectomy seroma.

    PubMed

    Gercel-Taylor, C; Hoffman, J P; Taylor, D D; Owens, K J; Eisenberg, B L

    1996-02-15

    Lymphocytes were isolated from breast seroma fluids and used to study the mechanism of activation of cytotoxic lymphocytes and possible role of immunological potentiation following surgery in breast cancer patients. Single or serial samples were obtained from patients who had undergone mastectomy or lumpectomy with axillary node dissection. Lymphocytes were activated with rIL-2 (interleukin-2) and their cytotoxic activity was studied against Daudi and K562 cells and against a breast tumor line (SKBr-3). All of the patients (21/21) responded to IL-2 stimulation by significant activation of cytotoxic activity. The unstimulated cytotoxic activity of these cells against NK targets was low with less than 10% specific release in cytotoxicity assays. In simultaneous experiments, autologous seroma fluid was included during activation of lymphocytes to study possible regulatory molecules that may be present. In 17/21 patients, the presence of their seroma fluid, during the activation period, enhanced or did not effect the cytotoxic potential of their lymphocytes; inhibition was observed when seroma fluids from 4/21 patients were included. Analysis of the cytotoxic population derived from combined IL-2 and seroma treatments indicates the presence of cells with increased expression of CD56, and CD2, as well as in some cases CD16 expression. Cytotoxic lymphocytes derived from IL-2 and seroma treatments appeared to be more effective killers. Modulation of CD2 expression with seroma alone appeared to result in the generation of this highly cytotoxic population. This study demonstrates the role of CD2 expression in the effectiveness of LAK cell killing and also potential benefit of an immunotherapeutic approach to the postoperative treatment of carcinoma of the breast.

  5. Stability and cytotoxicity of crystallin amyloid nanofibrils

    NASA Astrophysics Data System (ADS)

    Kaur, Manmeet; Healy, Jackie; Vasudevamurthy, Madhusudan; Lassé, Moritz; Puskar, Ljiljana; Tobin, Mark J.; Valery, Celine; Gerrard, Juliet A.; Sasso, Luigi

    2014-10-01

    Previous work has identified crystallin proteins extracted from fish eye lenses as a cheap and readily available source for the self-assembly of amyloid nanofibrils. However, before exploring potential applications, the biophysical aspects and safety of this bionanomaterial need to be assessed so as to ensure that it can be effectively and safely used. In this study, crude crystallin amyloid fibrils are shown to be stable across a wide pH range, in a number of industrially relevant solvents, at both low and high temperatures, and in the presence of proteases. Crystallin nanofibrils were compared to well characterised insulin and whey protein fibrils using Thioflavin T assays and TEM imaging. Cell cytotoxicity assays suggest no adverse impact of both mature and fragmented crystallin fibrils on cell viability of Hec-1a endometrial cells. An IR microspectroscopy study supports long-term structural integrity of crystallin nanofibrils.Previous work has identified crystallin proteins extracted from fish eye lenses as a cheap and readily available source for the self-assembly of amyloid nanofibrils. However, before exploring potential applications, the biophysical aspects and safety of this bionanomaterial need to be assessed so as to ensure that it can be effectively and safely used. In this study, crude crystallin amyloid fibrils are shown to be stable across a wide pH range, in a number of industrially relevant solvents, at both low and high temperatures, and in the presence of proteases. Crystallin nanofibrils were compared to well characterised insulin and whey protein fibrils using Thioflavin T assays and TEM imaging. Cell cytotoxicity assays suggest no adverse impact of both mature and fragmented crystallin fibrils on cell viability of Hec-1a endometrial cells. An IR microspectroscopy study supports long-term structural integrity of crystallin nanofibrils. Electronic supplementary information (ESI) available: ThT fluorescence graphs of buffers and solvents used for

  6. Antileishmanial activity and cytotoxicity of Brazilian plants.

    PubMed

    Ribeiro, Tatiana G; Chávez-Fumagalli, Miguel A; Valadares, Diogo G; Franca, Juçara R; Lage, Paula S; Duarte, Mariana C; Andrade, Pedro H R; Martins, Vivian T; Costa, Lourena E; Arruda, Ana L A; Faraco, André A G; Coelho, Eduardo A F; Castilho, Rachel O

    2014-08-01

    Leishmaniasis is a major public health problem, and the alarming spread of parasite resistance has increased the importance of discovering new therapeutic products. The present study aimed to investigate the in vitro leishmanicidal activity from 16 different Brazilian medicinal plants. Stationary-phase promastigotes of Leishmania amazonensis and murine macrophages were exposed to 44 plant extracts or fractions for 48 h at 37°C, in order to evaluate their antileishmanial activity and cytotoxicity, respectively. The most potent extracts against L. amazonensis were the hexanic extract of Dipteryx alata (IC50 of 0.08 μg/mL), the hexanic extract of Syzygium cumini (IC50 of 31.64 μg/mL), the ethanolic and hexanic extracts of leaves of Hymenaea courbaril (IC50 of 44.10 μg/mL and 35.84 μg/mL, respectively), the ethanolic extract of H. stignocarpa (IC50 of 4.69 μg/mL), the ethanolic extract of Jacaranda caroba (IC50 of 13.22 μg/mL), and the ethanolic extract of J. cuspidifolia leaves (IC50 of 10.96 μg/mL). Extracts of D. alata and J. cuspidifolia presented higher selectivity index, with high leishmanicidal activity and low cytotoxicity in the mammalian cells. The capacity in treated infected macrophages using the extracts and/or fractions of D. alata and J. cuspidifolia was also analyzed, and reductions of 95.80%, 98.31%, and 97.16%, respectively, in the parasite burden, were observed. No nitric oxide (NO) production could be observed in the treated macrophages, after stimulation with the extracts and/or fractions of D. alata and J. cuspidifolia, suggesting that the biological activity could be due to mechanisms other than macrophage activation mediated by NO production. Based on phytochemistry studies, the classes of compounds that could contribute to the observed activities are also discussed. In conclusion, the data presented in this study indicated that traditional medicinal plant extracts present effective antileishmanial activity. Future studies could focus on

  7. Synthesis and In Vitro Cytotoxic Activity of Chromenopyridones

    PubMed Central

    Singh, Balwinder; Sharma, Vishal; Singh, Gagandeep; Kumar, Rakesh; Arora, Saroj; Ishar, Mohan Paul Singh

    2013-01-01

    Novel substituted chromenopyridones (3a–j and 6a–d) were synthesized and evaluated in vitro for the cytotoxic activity against various human cancer cell lines such as prostate (PC-3), breast (MCF-7), CNS (IMR-32), cervix (Hela), and liver (Hep-G2). preliminary cytotoxic screening showed that all the compounds possess a good to moderate inhibitory activity against various cancer cell lines. Particularly, compound 6b bearing allyl moiety displayed a significant cytotoxic potential in comparison to standard drugs. PMID:25379292

  8. Safe handling of cytotoxic agents: a team approach.

    PubMed

    Willemsen-McBride, Tara; Willemson-McBride, Tara L; Gehan, Karen

    2009-11-01

    The use of cytotoxic medications has become increasingly prevalent in the OR for the treatment of bladder tumors. Perioperative nursing staff members in the day surgery unit, OR, and postanesthesia care unit at St Mary's General Hospital, Kitchener, Ontario, Canada, expressed concern about their lack of knowledge in the safe handling of cytotoxic medications and contaminated wastes. Facility educators recognized this as an area of risk for the hospital and a learning need for staff members. As a result, they formed a committee with members representing nursing, pharmacy, infection control, occupational health, and environmental safety to develop a policy and protocol for the safe use of cytotoxic medications.

  9. CYTOTOXICITY AND BIOCOMPATIBILITY OF DIRECT AND INDIRECT PULP CAPPING MATERIALS

    PubMed Central

    Modena, Karin Cristina da Silva; Casas-Apayco, Leslie Caroll; Atta, Maria Teresa; Costa, Carlos Alberto de Souza; Hebling, Josimeri; Sipert, Carla Renata; Navarro, Maria Fidela de Lima; Santos, Carlos Ferreira

    2009-01-01

    There are several studies about the cytotoxic effects of dental materials in contact with the pulp tissue, such as calcium hydroxide (CH), adhesive systems, resin composite and glass ionomer cements. The aim of this review article was to summarize and discuss the cytotoxicity and biocompatibility of materials used for protection of the dentin-pulp complex, some components of resin composites and adhesive systems when placed in direct or indirect contact with the pulp tissue. A large number of dental materials present cytotoxic effects when applied close or directly to the pulp, and the only material that seems to stimulate early pulp repair and dentin hard tissue barrier formation is CH. PMID:20027424

  10. Cytotoxic lanostanes from fruits of Garcinia wallichii Choisy (Guttiferae).

    PubMed

    Hongthong, Sakchai; Meesin, Jatuporn; Pailee, Phanruethai; Soorukram, Darunee; Kongsaeree, Palangpon; Prabpai, Samran; Piyachaturawat, Pawinee; Jariyawat, Surawat; Suksen, Kanoknetr; Jaipetch, Thaworn; Nuntasaen, Narong; Reutrakul, Vichai; Kuhakarn, Chutima

    2016-12-01

    Five new lanostanes, wallichinanes A-E (1-5) together with a known lanostane derivative 6 were isolated from the cytotoxic hexanes extract of fruits of Garcinia wallichii Choisy (Guttiferae). The structures of the isolated compounds were established by analysis of spectroscopic data, X-ray diffraction technique as well as comparison with the literature data. The cytotoxicity of all isolated compounds against a panel of cultured cancer cell lines was evaluated. Compound 4 exhibited good cytotoxicity with ED50 values ranging from 3.91 to 7.63μM. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Cytotoxic activities of some benzothiazole-piperazine derivatives.

    PubMed

    Gurdal, Enise Ece; Durmaz, Irem; Cetin-Atalay, Rengul; Yarim, Mine

    2015-01-01

    Synthesis, characterization and cytotoxic activities of ten benzothiazole-piperazine derivatives were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. Based on the GI50 values of the compounds, most of the benzothiazole-piperazine derivatives are active against HUH-7, MCF-7 and HCT-116 cancer cell lines. Compound 1d is highly cytotoxic against all tested cancer cell lines. Further investigation of compound 1d by Hoechst Staining and Fluorescence-Activated Cell Sorting Analysis (FACS) revealed that this compound causes apoptosis by cell cycle arrest at subG1 phase.

  12. The effect of cytotoxic chemotherapy on female fertility.

    PubMed

    Chasle, Sharon; How, Christine C

    2003-06-01

    Nurses are now primarily responsible for the provision of patient information, and the administration of an escalating number of cytotoxic agents. This paper aims to provide nurses with key information concerning the adverse effects of cytotoxic chemotherapy on the reproductive system of women of childbearing age. The provision of information on gonadal function and fertility is vital, particularly with the increase in the survival of women treated for cancer, and the trend towards women starting a family later in life. Gonadal toxicity of the various cytotoxic agents, disruption of the menstrual cycle, premature menopause, avoidance of pregnancy, chemotherapy in pregnancy, and fertility prospects post-chemotherapy are addressed in this paper.

  13. Cytotoxic effects of the root extracts of Eurycoma longifolia Jack.

    PubMed

    Nurhanan, M Y; Azimahtol Hawariah, L P; Mohd Ilham, A; Mohd Shukri, M A

    2005-11-01

    The methanol, n-butanol, chloroform and water extracts obtained from the root of Eurycoma longifolia Jack were assayed using methylene blue assay to evaluate its cytotoxic effect against KB, DU-145, RD, MCF-7, CaOV-3, MDBK cell lines. The results showed that all the root extracts except the water extract of E. longifolia produced significant cytotoxic effect on these cell lines. However, no significant cytotoxic effect was detected on MDBK (kidney) normal cell line. 9-methoxycanthin-6-one, an alkaloid, was detected in each extract with different intensities by reversed-phase high performance liquid chromatography.

  14. "False" cytotoxicity of ions-adsorbing hydroxyapatite - Corrected method of cytotoxicity evaluation for ceramics of high specific surface area.

    PubMed

    Klimek, Katarzyna; Belcarz, Anna; Pazik, Robert; Sobierajska, Paulina; Han, Tomasz; Wiglusz, Rafal J; Ginalska, Grazyna

    2016-08-01

    An assessment of biomaterial cytotoxicity is a prerequisite for evaluation of its clinical potential. A material is considered toxic while the cell viability decreases under 70% of the control. However, extracts of certain materials are likely to reduce the cell viability due to the intense ions adsorption from culture medium (e.g. highly bioactive ceramics of high surface area). Thus, the standard ISO 10993-5 procedure is inappropriate for cytotoxicity evaluation of ceramics of high specific surface area because biomaterial extract obtained in this method (ions-depleted medium) is not optimal for cell cultures per se. Therefore, a simple test was designed as an alternative to ISO 10993-5 standard for cytotoxicity evaluation of the biomaterials of high surface area and high ions absorption capacity. The method, presented in this paper, included the evaluation of ceramics extract prepared according to corrected procedure. The corrected extract was found not cytotoxic (cell viability above 70%), suggesting that modified method for cytotoxicity evaluation of ions-adsorbing ceramics is more appropriate than ISO 10993-5 standard. For such biomaterials, the term "false" cytotoxicity is more suitable. Moreover, it was noted that NRU assay and microscopic observations should be recommended for cytotoxicity evaluation of ceramics of high surface area. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Experimental considerations on the cytotoxicity of nanoparticles

    PubMed Central

    Kong, Bokyung; Seog, Ji Hyun; Graham, Lauren M; Lee, Sang Bok

    2011-01-01

    Engineered nanoparticles are one of the leading nanomaterials currently under investigation due to their applicability in various fields, including drug and gene delivery, biosensors, cancer treatment and diagnostic tools. Moreover, the number of commercial products containing nanoparticles released on the market is rapidly increasing. Nanoparticles are already widely distributed in air, cosmetics, medicines and even in food. Therefore, the unintended adverse effect of nanoparticle exposure is a growing concern both academically and socially. In this context, the toxicity of nanoparticles has been extensively studied; however, several challenges are encountered due to the lack of standardized protocols. In order to improve the experimental conditions of nanoparticle toxicity studies, serious consideration is critical to obtain reliable and realistic data. The cell type must be selected considering the introduction route and target organ of the nanoparticle. In addition, the nanoparticle dose must reflect the realistic concentration of nanoparticles and must be loaded as a well-dispersed form to observe the accurate size- and shape-dependent effect. In deciding the cytotoxicity assay method, it is important to choose the appropriate method that could measure the toxicity of interest without the false-negative or -positive misinterpretation of the toxicity result. PMID:21793681

  16. New and Cytotoxic Components from Antrodia camphorata.

    PubMed

    Lee, Tzong-Huei; Chen, Chien-Chih; Chen, Jih-Jung; Liao, Hui-Fen; Chang, Hsun-Shuo; Sung, Ping-Jyun; Tseng, Mei-Hwei; Wang, Sheng-Yang; Ko, Horng-Huey; Kuo, Yueh-Hsiung

    2014-12-19

    The solid-state cultured products of Antrodia camphorata as health foods has been blooming for the past few decades in Taiwan. In continuing our studies on the chemical constituents of the solid-state cultured products of this fungus, 6-methoxy-4-methyl-2,3-(methylenedioxy)phenol (1) and 4,4'-(ethane-1,2-diyl)bis(2,3,6-trimethoxyphenol)(2) together with 2,3,6-trimethoxy-4-methylphenol (3), 1(10→6)abeo-ergosta-5,7,9,22-tetraen-3α-ol (4), citreoanthrasteroid B (5) and dankasterones A (6) and B (7) were purified by a series of column chromatography. Their structures were elucidated by spectral data analysis. For bioactivity assay, compounds 4-7 showed significant cytotoxicity toward murine colorectal CT26 and human leukemia K562 cancer cell lines with IC50 values ranging from 6.7 to 15.3 µM and from 12.5 to 23.1 µM, respectively.

  17. Tamoxifen Induces Cytotoxic Autophagy in Glioblastoma.

    PubMed

    Graham, Christopher D; Kaza, Niroop; Klocke, Barbara J; Gillespie, G Yancey; Shevde, Lalita A; Carroll, Steven L; Roth, Kevin A

    2016-10-01

    Glioblastomas (GBMs) are the most common and aggressive primary human malignant brain tumors. 4-Hydroxy tamoxifen (OHT) is an active metabolite of the tamoxifen (TMX) prodrug and a well-established estrogen receptor (ER) and estrogen-related receptor antagonist. A recent study from our laboratory demonstrated that OHT induced ER-independent malignant peripheral nerve sheath tumor (MPNST) cell death by autophagic degradation of the prosurvival protein Kirsten rat sarcoma viral oncogene homolog. Because both MPNST and GBM are glial in cell origin, we hypothesized that OHT could mediate similar effects in GBM. OHT induced a concentration-dependent reduction in cell viability that was largely independent of caspase activation in a human GBM cell line and 2 patient-derived xenolines. Further, OHT induced both cytotoxic autophagy and a concentration-dependent decrease in epidermal growth factor receptor (EGFR) protein levels. A GBM cell line expressing EGFR variant III (EGFRvIII) was relatively resistant to OHT-induced death and EGFRvIII was refractory to OHT-induced degradation. Thus, OHT induces GBM cell death through a caspase-independent, autophagy-related mechanism and should be considered as a potential therapeutic agent in patients with GBM whose tumors express wild-type EGFR.

  18. In vitro cytotoxic effects of orthodontic appliances.

    PubMed

    Locci, P; Lilli, C; Marinucci, L; Calvitti, M; Belcastro, S; Bellocchio, S; Staffolani, N; Guerra, M; Becchetti, E

    2000-09-01

    The objective of this study was to evaluate the effects of an orthodontic appliance and of its components (brackets, bands, and arch wires) on some cell functions. Fibroblasts were cultured either in the presence of one unwashed orthodontic appliance, or one orthodontic appliance immersed in MEM for 28 days before use (washed appliance), or in the presence of MEM in which the appliances had been immersed. At the end of in vitro maintenance, morphological studies were carried out with SEM and TEM. Cell proliferation and GAG synthesis and secretion by radio-labeled precursors were assessed. The data indicated that unwashed appliances were more cytotoxic than washed ones. Moreover, the arch wire was the most biocompatible component of the orthodontic appliance, and the bracket was the least biocompatible. A comparative study into the effects on cell proliferation of the most common metal ions released by the appliances was also carried out. At the concentration released by one orthodontic appliance immersed for 28 days, the highest reduction in DNA synthesis was observed in the presence of Cu(++).

  19. Genotoxic Monitoring of Nurses Handling Cytotoxic Drugs

    PubMed Central

    Tompa, Anna; Biró, Anna; Jakab, Mátyás

    2016-01-01

    Objective: Several biomarkers may be used to detect harmful exposure and individual susceptibility to cancer. Monitoring of biomarkers related to exposure may have a significant effect on early detection of cell transformation, thereby aiding the primary prevention of various chronic and malignant diseases. Nurses who handle cytotoxic drugs are exposed to carcinogenic agents, which have the potential to interrupt the cell cycle and to induce chromosomal aberrations. The presence of high chromosomal aberrations indicates the need for intervention even when exposure to these carcinogens is low. Methods: Nationally representative samples of 552 nurses were investigated by a follow-up monitoring system. The measured biomarkers were clinical laboratory routine tests, completed with genotoxicological (chromosome aberrations [CAs] and sister chromatid exchanges [SCEs]) and immunotoxicological monitoring (ratio of lymphocyte subpopulations and lymphocyte activation markers) measured on peripheral blood lymphocytes. Results were compared to the data of 140 healthy, age-matched controls. Results: In nurses exposed to cytostatics, we observed a significantly increased frequency of CAs and SCEs compared with those in the controls. Cytostatic drug exposure also manifested itself in an increased frequency of helper T lymphocytes. Genotoxicological and immunotoxicological changes, as well as negative health effects (i.e., iron deficiency, anemia, and thyroid diseases), increased among cytostatic exposed subjects. Conclusions: These results raised concerns about the protection of nursing staff from chemical carcinogens in the working environment. PMID:28083554

  20. Biosynthetically Distinct Cytotoxic Polyketides from Setophoma terrestris

    PubMed Central

    El-Elimat, Tamam; Figueroa, Mario; Raja, Huzefa A.; Graf, Tyler N.; Swanson, Steven M.; Falkinham, Joseph O.; Wani, Mansukh C.; Pearce, Cedric J.

    2014-01-01

    Sixteen polyketides belonging to diverse structural classes, including monomeric/dimeric tetrahydroxanthones and resorcylic acid lactones, were isolated from an organic extract of a fungal culture Setophoma terrestris (MSX45109) using bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Of these, six were new: penicillixanthone B (5), blennolide H (6), 11-deoxy blennolide D (7), blennolide I (9), blennolide J (10), and pyrenomycin (16). The known compounds were: secalonic acid A (1), secalonic acid E (2), secalonic acid G (3), penicillixanthone A (4), paecilin B (8), aigialomycin A (11), hypothemycin (12), dihydrohypothemycin (13), pyrenochaetic acid C (14), and nidulalin B (15). The structures were elucidated using a set of spectroscopic and spectrometric techniques; the absolute configurations of compounds 1–10 were determined using ECD spectroscopy combined with time-dependent density functional theory (TDDFT) calculations, while a modified Mosher’s ester method was used for compound 16. The cytotoxic activities of compounds (1–15) were evaluated using the MDA-MB-435 (melanoma) and SW-620 (colon) cancer cell lines. Compounds 1, 4, and 12 were the most potent with IC50 values ranging from 0.16 to 2.14 μM. When tested against a panel of bacteria and fungi, compounds 3 and 5 showed promising activity against the Gram-positive bacterium Micrococcus luteus with MIC values of 5 and 15 μg/mL, respectively. PMID:25574154

  1. Oleandrin: A cardiac glycosides with potent cytotoxicity

    PubMed Central

    Kumar, Arvind; De, Tanmoy; Mishra, Amrita; Mishra, Arun K.

    2013-01-01

    Cardiac glycosides are used in the treatment of congestive heart failure and arrhythmia. Current trend shows use of some cardiac glycosides in the treatment of proliferative diseases, which includes cancer. Nerium oleander L. is an important Chinese folk medicine having well proven cardio protective and cytotoxic effect. Oleandrin (a toxic cardiac glycoside of N. oleander L.) inhibits the activity of nuclear factor kappa-light-chain-enhancer of activated B chain (NF-κB) in various cultured cell lines (U937, CaOV3, human epithelial cells and T cells) as well as it induces programmed cell death in PC3 cell line culture. The mechanism of action includes improved cellular export of fibroblast growth factor-2, induction of apoptosis through Fas gene expression in tumor cells, formation of superoxide radicals that cause tumor cell injury through mitochondrial disruption, inhibition of interleukin-8 that mediates tumorigenesis and induction of tumor cell autophagy. The present review focuses the applicability of oleandrin in cancer treatment and concerned future perspective in the area. PMID:24347921

  2. The Cytotoxicity of Layered Black Phosphorus.

    PubMed

    Latiff, Naziah Mohamad; Teo, Wei Zhe; Sofer, Zdenek; Fisher, Adrian C; Pumera, Martin

    2015-09-28

    Black phosphorus (BP), the latest addition to the family of 2D layered materials, has attracted much interest owing to potential optoelectronics, nanoelectronics, and biomedicine applications. Little is known about its toxicity, such as whether it could be as toxic as white phosphorus. In response to the possibility of BP employment into commercial products and biomedical devices, its cytotoxicity to human lung carcinoma epithelial cells (A549) was investigated. Following a 24 h exposure of the cells with different BP concentrations, cell viability assessments were conducted using water-soluble tetrazolium salt (WST-8) and methylthiazolyldiphenyltetrazolium bromide (MTT) assays. The toxicological effects were found to be dose-dependent, with BP reducing cell viabilities to 48% (WST-8) and 34% (MTT) at 50 μg mL(-1) exposure. This toxicity was observed to be generally intermediate between that of graphene oxides and exfoliated transition-metal dichalcogenides (MoS2, WS2, WSe2). The relatively low toxicity paves the way to utilization of black phosphorus.

  3. Cytotoxic activity of quassinoids from Eurycoma longifolia.

    PubMed

    Miyake, Katsunori; Li, Feng; Tezuka, Yasuhiro; Awale, Suresh; Kadota, Shigetoshi

    2010-07-01

    Twenty-four quassinoids isolated from Eurycoma longifolia Jack were investigated for their cytotoxicity against a panel of four different cancer cell lines, which includes three murine cell lines [colon 26-L5 carcinoma (colon 26-L5), B16-BL6 melanoma (B16-BL6), Lewis lung carcinoma (LLC)] and a human lung A549 adenocarcinoma (A549) cell line. Among the tested compounds, eurycomalactone (9) displayed the most potent activity against all the tested cell lines; colon 26-L5 (IC50 = 0.70 microM), B16-BL6 (IC50 = 0.59 microM), LLC (IC50 = 0.78 microM), and A549 (IC50 = 0.73 microM). These activities were comparable to clinically used anticancer agent doxorubicin (colon 26-L5, IC50 = 0.76 microM; B16-BL6, IC50 = 0.86 microM; LLC, IC50 = 0.80 microM; A549, IC50 = 0.66 microM).

  4. Copper Nanoparticle Induced Cytotoxicity to Nitrifying Bacteria ...

    EPA Pesticide Factsheets

    With the inclusion of engineered nanomaterials in industrial processes and consumer products, wastewater treatments plants (WWTPs) will serve as a major sink for these emerging contaminants. Previous research has demonstrated that nanomaterials are potentially toxic to microbial communities utilized in biological wastewater treatment (BWT). Copper-based nanoparticles (CuNPs) are of particular interest based on their increasing use in wood treatment, paints, household products, coatings, and byproducts of semiconductor manufacturing. A critical step in BWT is nutrient removal via denitrification. This study examined the potential toxicity of bare and polyvinylpyrrolidone (PVP) coated CuO, and Cu2O nanoparticles, as well as Cu ions to microbial communities responsible for nitrogen removal in BWT. Inhibition was inferred from changes to the specific oxygen uptake rate (sOUR) in the absence and presence of Cu ions and CuNPs. X-ray absorption fine structure spectroscopy, with Linear Combination Fitting (LCF), was utilized to track changes to Cu speciation throughout exposure. Results indicate that the dissolution of Cu ions from CuNPs drive microbial inhibition. The presence of a PVP coating on CuNPs has little effect on inhibition. LCF fitting of the biomass combined with metal partitioning analysis supports the current hypothesis that Cu-induced cytotoxicity is primarily caused by reactive oxygen species formed from ionic Cu in solution via catalytic reaction inter

  5. Cytotoxicity of gamma-ray in rat immature hippocampal neurons

    PubMed Central

    Yang, Miyoung; Song, Myoung-Sub; Kim, Sung-Ho; Kim, Jong-Choon; Kim, Joong-Sun; Shin, Taekyun

    2011-01-01

    This in vitro study evaluated the detrimental effect of acute gamma (γ)-irradiation on rat immature hippocampal neurons. Rat immature hippocampal neurons (0.5 day in vitro) were irradiated with 0~4 Gy γ-rays. Cytotoxicity was analyzed using a lactate dehydrogenase release assay at 24 h after γ-irradiation. Radiation-induced cytotoxicity in immature hippocampal neurons increased in a dose-dependent manner. Pre-treatments of pro-apoptotic caspase inhibitors and anti-oxidative substances significantly blocked γ-irradiation-induced cytotoxicity in immature hippocampal neurons. The results suggest that the caspase-dependent cytotoxicity of γ-rays in immature hippocampal cultured neurons may be caused by oxidative stress. PMID:21897091

  6. IN VITRO CYTOTOXICITY OF BTEX METABOLITES IN HELA CELL LINES

    EPA Science Inventory

    Fuel leakage from underground storage tanks is a major source of groundwater contamination. Although the toxicity of regulated compounds such as benzene, toluene, ethylbenzene, and xylene (BTEX) are well recognized, the cytotoxicity of their metabolites has not been studied exte...

  7. Safe handling of parenteral cytotoxics: recommendations for ontario.

    PubMed

    Green, Esther; Johnston, Mary; Trudeau, Maureen; Schwartz, Lisa; Poirier, Susan; Macartney, Gail; Milliken, Deborah

    2009-09-01

    In caring for patients with cancer, health care workers may be exposed to cytotoxic agents. Recommendations are needed to mitigate potential risks for cancer and adverse reproductive outcomes associated with exposure.

  8. Toxicity of nanoparticle surface coating agents: Structure-cytotoxicity relationship.

    PubMed

    Zhang, Ying; Li, Xiaoping; Yu, Hongtao

    2016-07-02

    Surface coating agents for metal nanoparticles, cationic alkyl ammonium bromides, and anionic alkyl sulfates were tested against human skin keratinocytes (HaCaT) and blood T lymphocytes (TIB-152). The surfactants of short chain (C8) are not cytotoxic, but as chain length increases, their cytotoxicity increases and levels off at C12 for cationic surfactants against both cell lines and for anionic surfactants against the TIB-152, but C14 for anionic surfactants against HaCaT. The cationic surfactants are more toxic than the anionic surfactants for HaCaT; while with similar cytotoxicity for TIB-152 cells. di- and tetra-Alkyl ammonium salts are more cytotoxic than the mono-substituted.

  9. IN VITRO CYTOTOXICITY OF BTEX METABOLITES IN HELA CELL LINES

    EPA Science Inventory

    Fuel leakage from underground storage tanks is a major source of groundwater contamination. Although the toxicity of regulated compounds such as benzene, toluene, ethylbenzene, and xylene (BTEX) are well recognized, the cytotoxicity of their metabolites has not been studied exte...

  10. Prenatal exposure to cypermethrin modulates rat NK cell cytotoxic functions.

    PubMed

    Santoni, G; Cantalamessa, F; Mazzucca, L; Romagnoli, S; Piccoli, M

    1997-07-11

    The synthetic pyrethroid insecticide, cypermethrin, was given during gestation to pregnant rats by gavage in corn oil. Peripheral blood and spleen cytotoxic activity of dams and their offspring were then evaluated at different times (30, 60, 90, 120 days) after birth. Pups showed a significant increase in peripheral blood natural killer (NK) and antibody-dependent (ADCC) cytotoxic activity paralleled with a similar increase in the percentage of NK-RP1+ cells and decreased activity in the spleen. Pregnant cypermethrin-exposed dams showed no changes in peripheral blood or spleen cytotoxic function during the postnatal period. Overall, these results suggest that immunomodulation of cytotoxic activity observed in the offspring is likely attributable to a specific effect of cypermethrin administered during the prenatal period.

  11. [Cytotoxic and genotoxic activity of certain preservative agents in cosmetics].

    PubMed

    Jantová, S; Hojerová, J; Hanusová, B; Mikulásová, M

    2001-09-01

    Cytotoxic effects of the preservative compounds for cosmetics JMAC TD, Bronopol, CA 24, and Euxyl K100 were studied. Bronopol demonstrated the highest cytotoxic effect on the proliferation of V79 and VH10 fibroblast cell lines--the IC100 values being 10 mg/l during the whole experiment. The preservatives CA 24 and Euxyl K100 showed 4-times and 5-times smaller cytotoxic activity than Bronopol IC100 = 42 or 50.3 mg/l). The preservative compounds on silver chloride ions JMAC TD manifested the lowest cytotoxicity of the preservatives tested (IC100 = 150 mg/l); 15-times smaller than Bronopol, 3.5-times smaller than CA 24 and 3-times smaller than Euxyl K100. The biocide JMAC TD did not exhibit mutagenic effects on the bacteria Salmonella typhimurium TA 98 and TA 100.

  12. Synthesis of 13-amino telekin derivatives and their cytotoxic activity.

    PubMed

    Wang, Xiujie; Zhang, Xiumei; Zheng, Beibei; Hu, Nan; Xie, Weidong; Row, Kyungho

    2015-01-01

    Telekin is a eudesmane sesquiterpene-lactone naturally occurring in many medicinal plants with antitumour and anti-inflammatory activity. In this study, a series of 13-amino derivatives of telekin have been synthesised through Michael addition reaction, and their relative configurations were exemplified by the single crystal X-ray diffraction of the dimethylamine adduct. The in vitro cytotoxicity against three tumour cell lines of these amine derivatives was evaluated. The piperidine and 4-hydroxypiperidine adducts displayed stronger cytotoxic activity than telekin.

  13. Icogenin, a new cytotoxic steroidal saponin isolated from Dracaena draco.

    PubMed

    Hernández, Juan C; León, Francisco; Quintana, José; Estévez, Francisco; Bermejo, Jaime

    2004-08-15

    This paper reports on the cytotoxic effect induced by a new natural steroidal saponin, icogenin, on the myeloid leukemia cell line HL-60. Icogenin was found to be a cytotoxic compound IC(50) 2.6+/-0.9microM at 72h, with growth inhibition caused by the induction of apoptosis, as determined by microscopy of nuclear changes and the fragmentation of poly(ADP-ribose) polymerase-1.

  14. Fatigue in cancer patients treated with cytotoxic drugs.

    PubMed

    Hartvig, Per; Aulin, Johan; Hugerth, Matilda; Wallenberg, Sofia; Wagenius, Gunnar

    2006-09-01

    Cancer-related fatigue is a significant and distressing problem for the cancer patient, affecting their physical and psychosocial function negatively, and reducing their quality of life. The aims of this study were to assess frequency, severity, and the consequence of fatigue in cancer outpatients receiving cytotoxic drugs, using an existing international fatigue scale applied for Swedish use. The study used a non-randomized, prospective design to evaluate fatigue and its impact on quality of life in outpatients receiving cytotoxic drugs. Once a week, 147 cancer patients, in an outpatient ward for cytotoxic drug administration, filled out questionnaires containing 13 items from the Fatigue Symptom Inventory (FSI), and five additional questions. Prevalence of fatigue was 92% in the week after all patients had received cytotoxic drugs, and patients were statistically significantly more fatigued during than before treatment. The degree of fatigue was highest the week after treatment, and declined over the following week. Other symptoms, especially depressed mood, showed a strong correlation with cancer and cytotoxic-induced fatigue. Lung and breast cancer patients experienced the highest degree of fatigue. Some cytotoxic drug regimens were, apart from the underlying disease, associated with high fatigue scores, eg, those with cyclophosphamide or gemcitabine. Patients not receiving first line treatment scored significantly higher fatigue with more influence on daily living. The study verified that fatigue is a common side effect, and affects quality of life negatively, even for outpatients receiving cytotoxic drugs. The clinical oncology pharmacist must inform patients that a severe tiredness, fatigue, may follow cytotoxic drug administration.

  15. Propofol Enhances Hemoglobin-Induced Cytotoxicity in Neurons

    PubMed Central

    Yuan, Jing; Cui, Guiyun; Li, Wenlu; Zhang, Xiaoli; Wang, Xiaoying; Zheng, Hui; Zhang, Jian; Xiang, Shuanglin; Xie, Zhongcong

    2016-01-01

    BACKGROUND It has been increasingly suggested that propofol protects against hypoxic-/ischemic-induced neuronal injury. As evidenced by hemorrhage-induced stroke, hemorrhage into the brain may also cause brain damage. Whether propofol protects against hemorrhage-induced brain damage remains unknown. Therefore, in this study, we investigated the effects of propofol on hemoglobin-induced cytotoxicity in cultured mouse cortical neurons. METHODS Neurons were prepared from the cortex of embryonic 15-day-old mice. Hemoglobin was used to induce cytotoxicity in the neurons. The neurons were then treated with propofol for 4 hours. Cytotoxicity was determined by lactate dehydrogenase release assay. Caspase-3 activation was examined by Western blot analysis. Finally, the free radical scavenger U83836E was used to examine the potential involvement of oxidative stress in propofol’s effects on hemoglobin-induced cytotoxicity. RESULTS We found that treatment with hemoglobin induced cytotoxicity in the neurons. Propofol enhanced hemoglobin-induced cytotoxicity. Specifically, there was a significant difference in the amount of lactate dehydrogenase release between hemoglobin plus saline (19.84% ± 5.38%) and hemoglobin plus propofol (35.79% ± 4.41%) in mouse cortical neurons (P = 0.00058, Wilcoxon Mann-Whitney U test, n = 8 in the control group or the treatment group). U83836E did not attenuate the enhancing effects of propofol on hemoglobin-induced cytotoxicity in the neurons, and propofol did not significantly affect caspase-3 activation induced by hemoglobin. These data suggested that caspase-3 activation and oxidative stress might not be the underlying mechanisms by which propofol enhanced hemoglobin-induced cytotoxicity. Moreover, these data suggested that the neuroprotective effects of propofol would be dependent on the condition of the brain injury, which will need to be confirmed in future studies. CONCLUSIONS These results from our current proof-of-concept study should

  16. Mild Hypothermia Attenuates the Anesthetic Isoflurane-Induced Cytotoxicity

    PubMed Central

    Li, Cheng; Dong, Yuanlin; Chen, Dan; Xie, Zhongcong; Zhang, Yiying

    2017-01-01

    The commonly used inhalation anesthetic isoflurane has been reported to induce DNA damage and cytotoxicity. However, the methods to attenuate these effects remain largely to be determined. Mild hypothermia has neuroprotective effects. We therefore set out to assess whether mild hypothermia could protect the isoflurane-induced DNA damage and cytotoxicity. Moreover, we investigated the underlying mechanisms by assessing the effects of mild hypothermia on the isoflurane-induced changes in ATP levels. H4 human neuroglioma cells were treated with 2% isoflurane for 3 or 6 h with and without mild hypothermia (35°C). We assessed the cell viability by using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and lactate dehydrogenase (LDH) assay. We determined DNA damage by measuring levels of phosphorylation of the histone protein H2A variant X at Ser139 (γH2A.X), the marker of DNA damage. We also measured ATP levels in the cells. Here we showed that the treatment with 2% isoflurane for 6 h induced cytotoxicity and DNA damage in the cells. Moreover, the treatment with 2% isoflurane for 3 h decreased ATP levels without inducing cytotoxicity. Mild hypothermia attenuated the isoflurane-induced cytotoxicity, DNA damage, and ATP reduction in the cells. Taken together, these data suggest that the isoflurane-induced reduction in ATP levels occurred before the isoflurane-induced cytotoxicity. Isoflurane may induce DNA damage and cause cytotoxicity through reducing ATP levels. Mild hypothermia would ameliorate isoflurane-induced DNA damage and cytotoxicity by attenuating the isoflurane-induced reduction in ATP levels. These pilot studies have established a system and will promote the future investigations of anesthesia neurotoxicity. PMID:28228717

  17. Comparing the cytotoxicity of electronic cigarette fluids, aerosols and solvents.

    PubMed

    Behar, Rachel Z; Wang, Yuhuan; Talbot, Prue

    2017-06-08

    As thousands of electronic cigarette (e-cigarette) refill fluids continue to be formulated and distributed, there is a growing need to understand the cytotoxicity of the flavouring chemicals and solvents used in these products to ensure they are safe. The purpose of this study was to compare the cytotoxicity of e-cigarette refill fluids/solvents and their corresponding aerosols using in vitro cultured cells. E-cigarette refill fluids and do-it-yourself products were screened in liquid and aerosol form for cytotoxicity using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The sensitivity of human pulmonary fibroblasts, lung epithelial cells (A549) and human embryonic stem cells to liquids and aerosols was compared. Aerosols were produced using Johnson Creek's Vea cartomizer style e-cigarette. A hierarchy of potency was established for the aerosolised products. Our data show that (1) e-cigarette aerosols can produce cytotoxic effects in cultured cells, (2) four patterns of cytotoxicity were found when comparing refill fluids and their corresponding aerosols, (3) fluids accurately predicted aerosol cytotoxicity 74% of the time, (4) stem cells were often more sensitive to aerosols than differentiated cells and (5) 91% of the aerosols made from refill fluids containing only glycerin were cytotoxic, even when produced at a low voltage. Our data show that various flavours/brands of e-cigarette refill fluids and their aerosols are cytotoxic and demonstrate the need for further evaluation of e-cigarette products to better understand their potential health effects. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  18. Semisynthesis and cytotoxicity of styryl-lactone derivatives.

    PubMed

    Bermejo, A; Léonce, S; Cabedo, N; Andreu, I; Caignard, D H; Atassi, G; Cortes, D

    1999-08-01

    The cytotoxicity and the cell-cycle action of altholactone (1), goniofufurone (2), and eight altholactone derivatives (5-12), were determined in vitro on L-1210 cells. Semisyntheses and structure-activity relationships of these compounds are described. The results of this study suggest that the cytotoxicity of altholactone (1), 11-nitro-altholactone (8), and 7-chloro-6,7-dihydroaltholactone (10) is due to the accumulation of the cells in the G2 + M phase of the cell cycle.

  19. A novel cytotoxic flavonoid glycoside from Physalis angulata.

    PubMed

    Ismail, N; Alam, M

    2001-08-01

    A new flavonol glycoside, myricetin 3-O-neohesperidoside (1) was isolated from a cytotoxic MeOH extract of the leaves of Physalis angulata. Compound 1 showed remarkable cytotoxicity in vitro against murine leukemia cell line P-388, epidermoid carcinoma of the nasopharynx KB-16 cells, and lung adenocarcinoma A-549 with ED(50) values of 0.048, 0.50 and 0.55 microg ml(-1), respectively.

  20. Mild Hypothermia Attenuates the Anesthetic Isoflurane-Induced Cytotoxicity.

    PubMed

    Li, Cheng; Dong, Yuanlin; Chen, Dan; Xie, Zhongcong; Zhang, Yiying

    2017-01-01

    The commonly used inhalation anesthetic isoflurane has been reported to induce DNA damage and cytotoxicity. However, the methods to attenuate these effects remain largely to be determined. Mild hypothermia has neuroprotective effects. We therefore set out to assess whether mild hypothermia could protect the isoflurane-induced DNA damage and cytotoxicity. Moreover, we investigated the underlying mechanisms by assessing the effects of mild hypothermia on the isoflurane-induced changes in ATP levels. H4 human neuroglioma cells were treated with 2% isoflurane for 3 or 6 h with and without mild hypothermia (35°C). We assessed the cell viability by using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and lactate dehydrogenase (LDH) assay. We determined DNA damage by measuring levels of phosphorylation of the histone protein H2A variant X at Ser139 (γH2A.X), the marker of DNA damage. We also measured ATP levels in the cells. Here we showed that the treatment with 2% isoflurane for 6 h induced cytotoxicity and DNA damage in the cells. Moreover, the treatment with 2% isoflurane for 3 h decreased ATP levels without inducing cytotoxicity. Mild hypothermia attenuated the isoflurane-induced cytotoxicity, DNA damage, and ATP reduction in the cells. Taken together, these data suggest that the isoflurane-induced reduction in ATP levels occurred before the isoflurane-induced cytotoxicity. Isoflurane may induce DNA damage and cause cytotoxicity through reducing ATP levels. Mild hypothermia would ameliorate isoflurane-induced DNA damage and cytotoxicity by attenuating the isoflurane-induced reduction in ATP levels. These pilot studies have established a system and will promote the future investigations of anesthesia neurotoxicity.

  1. Cytotoxicity of commonly used luting cements -An in vitro study.

    PubMed

    Trumpaite-Vanagiene, Rita; Bukelskiene, Virginija; Aleksejuniene, Jolanta; Puriene, Alina; Baltriukiene, Daiva; Rutkunas, Vygandas

    2015-01-01

    The study aimed to 1) evaluate the cytotoxicity of luting cements: Hoffmann's Zinc Phosphate (Hoffmann's ZP), GC Fuji Plus Resin Modified Glass Ionomer (Fuji Plus RMGI) and 3M ESPE RelyX Unicem Resin Cement (RelyX Unicem RC) and 2) test if pre-washing reduces the cements' cytotoxicity. In vitro human gingival fibroblast (HGF) culture model was chosen. The cytotoxicity was evaluated by MTT test, the cell viability -by staining the cells with AO/EB dye mixture. The means±SD of Cell Survival Ratio (CSR%) were compared among different cement types under two testing conditions, with or without cement pre-washing. The CSR%s were compared by ANOVA and linear multiple regression (LMR). Hoffmann's ZPC was less cytotoxic, while Fuji Plus RMGIC and RelyX Unicem RC were more cytotoxic (ANOVA, p<0.001). The type of cement and cement pre-washing jointly explained 90% of cell survival (LMR, p<0.001, adjusted squared R=0.889). The commonly used luting cements such as Hoffmann's ZP, Fuji Plus RMGI and RelyX Unicem RC may have a cytotoxic potential.

  2. Cytotoxicity and Antimicrobial Activity of Oral Rinses In Vitro

    PubMed Central

    Müller, Heinz-Dieter; Moritz, Andreas; Lussi, Adrian

    2017-01-01

    While oral rinses used for cosmetic purposes only do not necessarily have to be antiseptic, antimicrobial activity is required for medical indications, including oral and periodontal surgery. So the question arises—is the antimicrobial activity of oral rinses associated with any destructive changes in cell viability in vitro? To answer this question, we examined twelve oral rinses with respect to their antimicrobial and cytotoxic activity. Antimicrobial activity was screened against five bacterial strains using disc diffusion. Cytotoxicity was determined by mitochondrial reductase activity with primary gingival fibroblasts, L929 cells, and HSC-2 epithelial cells. Phase contrast microscopy and trypan blue staining were then performed to reveal cell morphology. Cells remained vital after exposure to oral rinses that were only used for cosmetic purposes. Moderate cytotoxic effects were observed for oral rinses containing 0.05% chlorhexidine, ethanol, or pegylated hydrogenated castor oil and sodium dodecyl sulfate. Other oral rinses containing 0.2% chlorhexidine and cocamidopropyl betaine exhibited strong cytotoxic and antimicrobial activity. Strong cytotoxic but moderate antimicrobial activity was observed in oral rinses containing cetylpyridinium chloride. The in vitro data show that oral rinses are heterogeneous with respect to their cytotoxic and antimicrobial effects. Based on their respective properties, oral rinses can be selected either to reduce the microbial load or for cosmetic purposes. PMID:28401154

  3. Cytotoxicity and Antimicrobial Activity of Oral Rinses In Vitro.

    PubMed

    Müller, Heinz-Dieter; Eick, Sigrun; Moritz, Andreas; Lussi, Adrian; Gruber, Reinhard

    2017-01-01

    While oral rinses used for cosmetic purposes only do not necessarily have to be antiseptic, antimicrobial activity is required for medical indications, including oral and periodontal surgery. So the question arises-is the antimicrobial activity of oral rinses associated with any destructive changes in cell viability in vitro? To answer this question, we examined twelve oral rinses with respect to their antimicrobial and cytotoxic activity. Antimicrobial activity was screened against five bacterial strains using disc diffusion. Cytotoxicity was determined by mitochondrial reductase activity with primary gingival fibroblasts, L929 cells, and HSC-2 epithelial cells. Phase contrast microscopy and trypan blue staining were then performed to reveal cell morphology. Cells remained vital after exposure to oral rinses that were only used for cosmetic purposes. Moderate cytotoxic effects were observed for oral rinses containing 0.05% chlorhexidine, ethanol, or pegylated hydrogenated castor oil and sodium dodecyl sulfate. Other oral rinses containing 0.2% chlorhexidine and cocamidopropyl betaine exhibited strong cytotoxic and antimicrobial activity. Strong cytotoxic but moderate antimicrobial activity was observed in oral rinses containing cetylpyridinium chloride. The in vitro data show that oral rinses are heterogeneous with respect to their cytotoxic and antimicrobial effects. Based on their respective properties, oral rinses can be selected either to reduce the microbial load or for cosmetic purposes.

  4. Cytotoxic constituents of Pachyrhizus tuberosus from Peruvian amazon.

    PubMed

    Leuner, Olga; Havlik, Jaroslav; Budesinsky, Milos; Vrkoslav, Vladimir; Chu, Jessica; Bradshaw, Tracey D; Hummelova, Jana; Miksatkova, Petra; Lapcik, Oldrich; Valterova, Irena; Kokoska, Ladislav

    2013-10-01

    Investigations into the chemical constituents of the seeds of the neglected tuber crop Pachyrhizus tuberosus (Leguminosae) resulted in the isolation of seven components: five rotenoids [12a-hydroxyerosone (1), 12a-hydroxydolineone (2), erosone (3), 12a-hydroxyrotenone (4) and rotenone (6)], a phenylfuranocoumarin [pachyrrhizine (5)] and an isoflavanone [neotenone (7)]. The compounds were isolated using several chromatography techniques and characterized and verified by NMR and HPLC/MS. The MTT assay was used to examine the selective cytotoxic effects of the methanolic P. tuberosus extract and isolated compounds in two human cancer cell lines [breast (MCF-7) and colorectal (HCT-116)] and in non-transformed human fibroblasts (MRC-5); IC50 values were calculated. The methanolic P. tuberosus extract displayed respectable cytotoxic effects against HCT-116 and MCF-7 cells with IC50 values of 7.3 and 6.3 microg/mL, respectively. Of the compounds, 6 exacted greatest cytotoxicity and selectivity towards the cancer cell lines tested, yielding IC50 values of 0.3 microg/mL against both MCF-7 and HCT-116 cells, and a 6-fold reduced activity against MRC-5 fibroblasts. Compound 4 also demonstrated cytotoxicity against MCF-7 and HCT-116 (1.1 and 1.8 microg/mL, respectively), and reduced cytotoxicity towards MRC-5 cells (7.5 mirog/mL). The results revealed from the in vitro cytotoxic MTT assay are worthy of further antitumor investigation.

  5. Molecular cytotoxic mechanisms of chlorpromazine in isolated rat hepatocytes.

    PubMed

    MacAllister, Stephanie L; Young, Cheryl; Guzdek, Anna; Zhidkov, Nickholas; O'Brien, Peter J

    2013-01-01

    Chlorpromazine (CPZ), a member of the largest class of first-generation antipsychotic agents, is known to cause hepatotoxicity in the form of cholestasis and hepatocellular necrosis in some patients. The mechanism of CPZ hepatotoxicity is unclear, but is thought to result from reactive metabolite formation. The goal of this research was to assess potential cytotoxic mechanisms of CPZ using the accelerated cytotoxicity mechanism screening (ACMS) technique with freshly isolated rat hepatocytes. This study identified CPZ cytotoxicity and inhibition of mitochondrial membrane potential (MMP) to be concentration-dependent. Furthermore, inhibition of cytochrome P450s (CYPs), including CYP2D1 and 1A2, delayed CPZ cytotoxicity, suggesting a role for CYP activation of CPZ to a toxic metabolite(s) in this model. Metabolism studies also demonstrated glucuronide and glutathione (GSH) requirement for CPZ detoxification in hepatocytes. Inactivating the 2-electron reduction pathway, NAD(P)H quinone oxidoreductase (NQO1), caused a significant increase in hepatocyte susceptibility to CPZ, indicating quinoneimine contribution to CPZ cytotoxicity. Nontoxic concentrations of peroxidase/H(2)O(2) (inflammatory model) increased cytotoxicity in CPZ-treated hepatocytes and caused additional mitochondrial toxicity. Inflammation further depleted GSH and increased oxidized glutathione (GSSG) levels. Results suggest activation of CPZ to reactive metabolites by 2 pathways in hepatocytes: (i) a CYP-catalyzed quinoneimine pathway, and (ii) a peroxidase-catalyzed oxidation of CPZ to CPZ radicals.

  6. Tumour-expressed tissue factor inhibits cellular cytotoxicity.

    PubMed

    Li, Chao; Colman, Lucy M; Collier, Mary E W; Dyer, Charlotte E; Greenman, John; Ettelaie, Camille

    2006-11-01

    The association between tissue factor (TF) expression and increased rate of tumour metastasis is well established. In this study, we have examined the hypothesis that the expression of TF by disseminated tumour cells confers protection against immune recognition and cytotoxicity. A hybrid EGFP-TF protein was expressed in HT29 colon carcinoma and K562 lymphoblast cell lines. To assess the cytotoxic activity against tumour cells over-expressing TF, a novel method was used, based on the direct measurement of fluorescently labelled HT29 or K562 target cells. Upon challenge with peripheral blood mononuclear cells (PBMC), tumour cells expressing TF partially evaded cellular cytotoxicity (Delta=15-40% reduction in cytotoxicity). Moreover, the influence of TF was not primarily dependent on its procoagulant function, although the inclusion of 20% (v/v) plasma did lower the rate of cytotoxicity against untransfected cells. However, expression of a truncated form of TF, devoid of the cytoplasmic domain, did not mediate any degree of inhibition of cytotoxicity, suggesting that the protective function of TF is principally due to this domain. We conclude that TF can promote immune evasion in tumour cells expressing this protein leading to increased survival and therefore metastatic rate in such cells.

  7. Evaluation of cytotoxicity of different tobacco product preparations.

    PubMed

    Arimilli, Subhashini; Damratoski, Brad E; Bombick, Betsy; Borgerding, Michael F; Prasad, G L

    2012-12-01

    Acute exposure to cigarette smoke or its components triggers diverse cellular effects, including cytotoxicity. However, available data regarding the potential cytotoxic effects of smokeless tobacco (ST) extracts lack consensus. Here, we investigated the relative biological effects of 2S3 reference ST, and whether ST elicits differential cellular/molecular responses compared to combustible tobacco product preparations (TPPs) prepared from 3R4F cigarettes. Total particulate matter (TPM) and whole smoke conditioned medium (WS-CM) were employed as combustible TPPs, while the ST extract was used as non-combustible TPP. HL60, THP1 cells and human PBMCs were used to examine the effects of TPPs in short-term cell culture. Corresponding EC(50) values, normalized for nicotine content of the TPPs, suggest that combustible TPPs induced higher cytotoxicity as follows: WS-CM TPM ≥ ≫ST extract>nicotine. While all three TPPs induced detectable levels of DNA damage and IL8 secretion, the combustible TPPs were significantly more potent than the ST preparation. The major PBMC subsets showed differential cytotoxicity to combustible TPPs as follows: CD4>CD8>monocytes>NK cells. These findings suggest that, relative cytotoxic and other cell biological effects of TPPs are dose-dependent, and that ST extract is the least cytotoxic TPP tested in this study.

  8. Properties of cytotoxic peptide-formed ion channels.

    PubMed

    Kourie, J I; Shorthouse, A A

    2000-06-01

    Cytotoxic peptides are relatively small cationic molecules such as those found 1) in venoms, e.g., melittin in bee, scorpion toxins in scorpion, pilosulin 1 in jumper ant, and lycotoxin I and II in wolf spider; 2) in skin secretions (e.g., magainin I and II from Xenopus laevis, dermaseptin from frog, antimicrobials from carp) and cells of the immune system (e.g., insect, scorpion, and mammalian defensins and cryptdins); 3) as autocytotoxicity peptides, e.g., amylin cytotoxic to pancreatic beta-cells, prion peptide fragment 106-126 [PrP-(106-126)], and amyloid beta-protein (AbetaP) cytotoxic to neurons; and 4) as designed synthetic peptides based on the sequences and properties of naturally occurring cytotoxic peptides. The small cytotoxic peptides are composed of beta-sheets, e.g., mammalian defensins, AbetaP, amylin, and PrP-(106-126), whereas the larger cytotoxic peptides have several domains composed of both alpha-helices and beta-sheets stabilized by cysteine bonds, e.g., scorpion toxins, scorpion, and insect defensins. Electrophysiological and molecular biology techniques indicate that these structures modify cell membranes via 1) interaction with intrinsic ion transport proteins and/or 2) formation of ion channels. These two nonexclusive mechanisms of action lead to changes in second messenger systems that further augment the abnormal electrical activity and distortion of the signal transduction causing cell death.

  9. In vitro evaluation of cytotoxicity of permanent prosthetic materials.

    PubMed

    Sabaliauskas, Vaidotas; Juciute, Rima; Bukelskiene, Virginija; Rutkunas, Vygandas; Trumpaite-Vanagiene, Rita; Puriene, Alina

    2011-01-01

    To assess qualitative and quantitative cytotoxicity effect on permanent prosthetic materials to human gingival fibroblasts. Human gingival tissues were collected (with informed consent) from patients undergoing periodontal surgical procedures and fibroblasts were cultured in vitro. Cell type was determined by performing proteomic analysis. Selected prosthetic materials including titanium, feldspathic ceramic, gold and chrome-cobalt alloy specimens (5×2 mm) were fabricated. The toxicity of prepared specimens was tested by exposing them to cell culture medium for 48, 72, 96 and 120 hours at 37°C under sterile conditions. Cell viability was estimated using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. The data concerning cell viability were statistically analyzed using two-way ANOVA test and Tukey multiple comparison test. Results obtained after 48 hours showed no toxic effect of titanium compared to control group. Cytotoxic effect was observed in gold alloy and feldspathic ceramic, however, it was not significant compared to control group. Chrome-cobalt alloy significantly reduced cell viability compared to control group (p≤0.001). Cytotoxicity diminished with increasing incubation time of specimens. After 120 hours of incubation all tested materials, except chrome-cobalt alloy, had no cytotoxicity. Titanium proved to be non-toxic. Gold alloy and feldspathic ceramic had short-term cytotoxic effect. Chrome-cobalt alloy had highest cytotoxic effect on fibroblast cells.

  10. Long-term cytotoxic effects of contemporary root canal sealers

    PubMed Central

    da SILVA, Emmanuel João Nogueira Leal; SANTOS, Carolina Carvalho; ZAIA, Alexandre Augusto

    2013-01-01

    Objectives: The aim of the present study was to investigate the effects of root canal sealers on the cytotoxicity of 3T3 fibroblasts during a period of 5 weeks. Material and Methods: Fibroblasts (3T3, 1x105 cells per well) were incubated with elutes of fresh specimens from eight root canal sealers (AH Plus, Epiphany, Endomethasone N, EndoReZ, MTA Fillapex, Pulp Canal Sealer EWT, RoekoSeal and Sealapex) and with elutes of the same specimens for 5 succeeding weeks after immersing in simulated body fluid. The cytotoxicity of all root canal sealers was determined using the MTT assay. Data were analyzed using ANOVA and Tukey's test. Results: RoekoSeal was the only sealer that did not show any cytotoxic effects (p<0.05). All the other tested sealers exhibited severe toxicity initially (week 0). MTA Fillapex remained moderately cytotoxic after the end of experimental period. Toxicity of the other tested sealers decreased gradually over time. The evaluated root canal sealers presented varying degrees of cytotoxicity, mainly in fresh mode. Conclusions: RoekoSeal had no cytotoxic effect both freshly mixed and in the other tested time points. MTA Fillapex was associated with significantly less cell viability when compared to the other tested root canal sealers. PMID:23559111

  11. Cytotoxicity of titanium and silicon dioxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Wagner, Stefanie; Münzer, Simon; Behrens, Peter; Scheper, Thomas; Bahnemann, Detlef; Kasper, Cornelia

    2009-05-01

    Different TiO2 and SiO2 nanoparticles have been tested concerning their toxicity on selected mammalian cell lines. Various powders and suspensions, all of which consist of titanium or silicon dioxide nanoparticles have been examined. These particles differ in the crystal structure, the size and the BET-surface area. There was also a classification in fixed particles and in particles easily accessible in solution. With focus on the possible adsorption of the nanoparticles into the human organism, via skin and via respiratory tract, the effects on fibroblasts (NIH-3T3) and on a human lung adenocarcinoma epithelial cell line were examined. Additionally, the particles were tested with HEP-G2 cells, which are often used as model cell line for biocompatibility tests, and PC-12 cells, a rat adrenal pheochromocytoma cell line. The viability of the cells was examined by the MTT-test. The viability results were found to partly depend on the type of cells used. The experimental results show that the adhesion of the cells on the different powders strongly depends on the type of cell lines as well as on the type of powder. It was found that the lower viability of some cells on the powder coatings is not only caused by a cytotoxicity effect of the powders, but is also due to a lower adhesion of the cells on the particle surfaces. Furthermore, it could be shown that the physical properties of the powders cannot be easily correlated to any observed biological effect. While some powders show a significant suppression of the cell growth, others with similar physical properties indicate no toxic effect.

  12. Gastroprotective effect and cytotoxicity of labdenamides.

    PubMed

    Izquierdo, Rafael; Astudillo, Luis; Rodríguez, Jaime A; Theoduloz, Cristina; Palenzuela, José A; Schmeda-Hirschmann, Guillermo

    2007-04-01

    Some 18 aromatic amides from the labdane diterpenes 15-acetoxyimbricatolic acid and 15-acetoxylabd-8(9)-en-19-oic acid were prepared and assessed for their gastroprotective effect in the HCl/EtOH-induced gastric lesion model in mice. The analysis of the gastroprotective activity of the benzylamides belonging to the series 8(9)- and 8(17)-ene was undertaken at doses of 12.5, 25 and 50 mg/kg in the HCl/EtOH-induced gastric lesion model in mice. A statistically significant gastroprotective effect was observed for 15-acetoxylabd-8(9)-en-19-oic acid benzylamide starting at 12.5 mg/kg, reducing the gastric lesions by 50%, while 15-acetoxylabd-8(17)-en-19-oic acid benzylamide reduced lesions by 66% at 25 mg/kg. The 25 mg/kg dose was used for the comparison of the different amides. At 25 mg/kg, the highest gastroprotective effect was observed for the benzyl- and 3-bromophenylamides from 15-acetoxyimbricatolic acid as well as for the benzyl- and P-toluidylamides of 15-acetoxylabd-8(9)-en-19-oic acid, being as active as lansoprazole at 20 mg/kg. Most compounds displayed low toxicity against epithelial gastric (AGS) and human lung fibroblasts cells, with IC50 values>1000 microM. The highest cytotoxicity towards AGS cells was observed for the 2-bromophenyl- and 2-hydroxy-5-chlorophenylamides in both diterpene series, with IC50 values in the range of 14-34 microM towards AGS cells and 10-37 microM towards fibroblasts, respectively.

  13. Antifeedant and cytotoxic activity of longipinane derivatives.

    PubMed

    Cerda-García-Rojas, Carlos M; Burgueño-Tapia, Eleuterio; Román-Marín, Luisa U; Hernández-Hernández, Juan D; Agulló-Ortuño, Teresa; González-Coloma, Azucena; Joseph-Nathan, Pedro

    2010-02-01

    The polyoxygenated longipinane derivatives 1- 8 were tested as antifeedant compounds against the herbivorous insects Spodoptera littoralis, Rhopalosiphum padi, and Myzus persicae. Compounds 1-3 and 8 exhibited significant antifeedant activity against S. littoralis and M. persicae. The antifeedant activity against S. littoralis increased moderately after the C-8 hydroxy group in 3 was removed to afford 1 and increased strongly after the remaining two hydroxy groups were acetylated to afford 2. Compound 1 was active on M. persicae. Compounds 1, 3, and 4, with an unsaturated six-membered ring, exhibited an increase in post-ingestive effects on S. littoralis ranging from antifeedant in the case of 1 to toxic for compounds 3 and 4. These compounds did not have any phytotoxic effect on Lactuca sativa. When tested on a panel of tumoral cells, compounds 2 and 6 exhibited moderate selective cytotoxic effects on the p53 null lung carcinoma cells H1299, which were not affected by the drug paclitaxel. In addition, vibrational circular dichroism (VCD) was applied to the representative longipinene derivative 2 to verify its absolute configuration, and the sensitivity of the VCD methodology was evaluated by comparing spectra of the three diastereoisomers (4 R,5 S,7 R,9 R,10 R,11 R)-7,9-diacetyloxylongipin-2-en-1-one (2), (4 R,5 S,7 S,9 R,10 R,11 R)-7,9-diacetyloxylongipin-2-en-1-one, and (4 R,5 S,7 R,9 S,10 R,11 R)-7,9-diacetyloxylongipin-2-en-1-one. Georg Thieme Verlag KG Stuttgart-New York.

  14. Genotoxicity and cytotoxicity of 2-hydroxyethyl methacrylate.

    PubMed

    Pawlowska, Elzbieta; Poplawski, Tomasz; Ksiazek, Dominika; Szczepanska, Joanna; Blasiak, Janusz

    2010-02-01

    Resin-based methacrylate materials are widely used in restorative dentistry. They are viscous substances that are converted into solid material via polymerization. This process, however, may be incomplete, leading to the release of monomers into the oral cavity and the pulp, which can be reached through the dentin micro-channels. This opens the opportunity for the monomers to reach the bloodstream. Monomers can reach concentrations in the millimolar range, high enough to cause cellular damage, so it is justified to study their potential toxic effects. In the present work we investigated the cytotoxicity and genotoxicity of 2-hydroxyethyl methacrylate (HEMA) in human peripheral blood lymphocytes and A549 lung-tumour cells. HEMA at concentrations up to 10mM neither affected the viability of the cells nor interacted with isolated plasmid DNA during a 1h exposure. However, HEMA induced concentration-dependent DNA damage in lymphocytes, as assessed by alkaline and pH 12.1 versions of the comet assay. HEMA did not cause double-strand breaks, as assessed by the neutral version of the comet assay and pulsed-field gel electrophoresis. The use of DNA repair enzymes, spin traps and vitamin C produced results suggesting that HEMA induced oxidative modifications to DNA bases. DNA damage caused by HEMA at 10mM was removed within 120min. HEMA induced apoptosis in a concentration-dependent manner and caused cell-cycle delay at the G0/G1-checkpoint. Methylglycol chitosan displayed a protective effect against the DNA-damaging action of HEMA. The results obtained in this study suggest that HEMA induces adverse biological effects, mainly via reactive oxygen species, which can lead to DNA damage, apoptosis and cell-cycle delay. Chitosan and its derivatives can be considered as additional components of dental restoration to decrease the harmful potency of HEMA.

  15. alpha-Mangostin enhances betulinic acid cytotoxicity and inhibits cisplatin cytotoxicity on HCT 116 colorectal carcinoma cells.

    PubMed

    Aisha, Abdalrahim F A; Abu-Salah, Khalid M; Ismail, Zhari; Majid, Amin Malik Shah Abdul

    2012-03-08

    Despite the progress in colon cancer treatment, relapse is still a major obstacle. Hence, new drugs or drug combinations are required in the battle against colon cancer. α-Mangostin and betulinic acid (BA) are cytotoxic compounds that work by inducing the mitochondrial apoptosis pathway, and cisplatin is one of the most potent broad spectrum anti-tumor agents. This study aims to investigate the enhancement of BA cytotoxicity by α-mangostin, and the cytoprotection effect of α-mangostin and BA on cisplatin-induced cytotoxicity on HCT 116 human colorectal carcinoma cells. Cytotoxicity was investigated by the XTT cell proliferation test, and the apoptotic effects were investigated on early and late markers including caspases-3/7, mitochondrial membrane potential, cytoplasmic shrinkage, and chromatin condensation. The effect of α-mangostin on four signalling pathways was also investigated by the luciferase assay. α-Mangostin and BA were more cytotoxic to the colon cancer cells than to the normal colonic cells, and both compounds showed a cytoprotective effect against cisplatin-induced cytotoxicity. On the other hand, α-mangostin enhanced the cytotoxic and apoptotic effects of BA. Combination therapy hits multiple targets, which may improve the overall response to the treatment, and may reduce the likelihood of developing drug resistance by the tumor cells. Therefore, α-mangostin and BA may provide a novel combination for the treatment of colorectal carcinoma. The cytoprotective effect of the compounds against cisplatin-induced cytotoxicity may find applications as chemopreventive agents against carcinogens, irradiation and oxidative stress, or to neutralize cisplatin side effects.

  16. Gastroprotective and cytotoxic effect of semisynthetic ferruginol derivatives.

    PubMed

    Areche, Carlos; Rodríguez, Jaime A; Razmilic, Iván; Yáñez, Tania; Theoduloz, Cristina; Schmeda-Hirschmann, Guillermo

    2007-02-01

    The gastroprotective abietane diterpene ferruginol has been shown to present high cytotoxicity. In order to obtain active compounds with less cytotoxicity, 18 semisynthetic ferruginol derivatives and totarol were assessed for their gastroprotective effects in the HCl/ethanol-induced gastric lesion model in mice, as well as for cytotoxicity in human gastric epithelial cells (AGS) and human lung fibroblasts (MRC-5). At 20 mg kg(-1), the greatest gastroprotective effects were provided by abieta-8,11,13-triene (1), abieta-8,11,13-trien-12-yl-2-chloropropanoate (8), abieta-8,11,13-trien-12-yl propenoate (9), 12-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-abieta-8,11,13-triene (17) and 12-(beta-D-galactopyranosyloxy)-abieta-8,11,13-triene (18), all of which were as active as the reference drug lansoprazole at 20 mg kg(-1), reducing gastric lesions by 69, 76, 67, 72 and 61%, respectively. No relation was observed between lipophilicity and the gastroprotective effect. Compounds that showed the greatest cytotoxicity towards AGS cells were ferruginol (2), the corresponding formate (5), acetate (6), propionate (7), 8, 9, 12-(beta-D-glucopyranosyloxy)-abieta-8,11,13-triene (16), 18 and totarol (20) (IC50 18-44 microM). Ferruginol and compounds 5-9, 16, 18 and 20 were the most toxic compounds against fibroblasts (IC50 19-56 microM), with a correlation to AGS cells. The derivative 19 was much more active against AGS cells than towards fibroblasts. The best activity/cytotoxicity ratio was found for compound 17, with a lesion index comparable with lansoprazole at 20 mg kg(-1) and cytotoxicity >1000 microM towards MRC-5 and AGS cells, respectively. In conclusion, some derivatives showed a better gastroprotective effect/cytotoxicity ratio than the parent compound ferruginol. A total of 13 new compounds are reported here for the first time.

  17. Intracellular concentrations determine the cytotoxicity of adefovir, cidofovir and tenofovir.

    PubMed

    Zhang, Xun; Wang, Ruduan; Piotrowski, Mary; Zhang, Hui; Leach, Karen L

    2015-02-01

    Lack of in vitro to in vivo translation is a major challenge in safety prediction during early drug discovery.One of the most common in vitro assays to evaluate the probability of a compound to cause adverse effects is a cytotoxicity assay. Cytotoxicity of a compound is often measured by dose–response curves assuming the administered doses and intracellular exposures are equal at the time of measurement.However, this may not be true for compounds with low membrane permeability or those which are substrates for drug transporters as intracellular concentrations are determined both by passive permeability and active uptake through drug transporters. We show here that three antiviral drugs, adefovir, cidofovir and tenofovir exhibit significantly increased cytotoxicity in HEK293 cells transfected with organic anion transporter (OAT) 1 and 3 compared to a lack of cytotoxicity in HEK293 wildtype cells. A further look at the media and intracellular drug concentrations showed that 24 h after dosing, all three drugs had higher intracellular drug concentrations than that of media in the HEK-OAT1 cells whereas the intracellular drug concentrations in the wildtype cells were much lower than the administered doses. Comparing cytotoxicity IC(50) values of adefovir, cidofovir and tenofovir based on administered doses and measured intracellular concentrations in HEK-OAT1 cells revealed that intracellular drug concentrations have significant impact on calculated IC(50) values. Tenofovir showed much less intrinsic cytotoxicity than adefovir and cidofovir using intracellular concentrations rather than media concentration. Our data suggest that for low permeable drugs or drugs that are substrates for drug transporters, the choice of cellular model is critical for providing an accurate determination of cytotoxicity.

  18. Human sinonasal explant system for testing cytotoxicity of intranasal agents

    PubMed Central

    Lim, Jae H.; Davis, Greg E.; Rue, Tessa C.; Storm, Daniel R.

    2011-01-01

    BACKGROUND Intranasal agents play a critical role in the management of sinonasal disorders. There are ongoing efforts to develop new intranasal medications to combat sinonasal disease. Some intranasal agents, however, can have cytotoxic effects on human sinonasal tissue. In order to facilitate safe drug discovery, we developed a simple and reliable in vitro screening assay using human sinonasal explants to measure the cytotoxic profiles of intranasal agents. METHODS We obtained sinonasal tissues from several regions of the nasal cavity from 12 patients undergoing endoscopic sinonasal surgery. These tissues were cultured on polytetrafluoroethane membrane in serum free growth medium. We determined the biochemical properties of these explants by measuring extracellular lactate dehydrogenase (LDH) levels and performing histological analyses over a period of 1–2 weeks. We then examined the cytotoxic profiles of 13 intranasal agents by measuring extracellular LDH levels using the human sinonasal explant system. RESULTS Sinonasal explants exhibited a rapid reduction in extracellular LDH levels indicating stabilization in the culture environment within 2 days. Histological analysis showed maintenance of good cellular architecture for up to 2 weeks. The explants displayed intact epithelium and expressed βIII-tubulin and Ki-67. Of the 13 tested intranasal agents, 1% zinc sulfate, 5% zinc sulfate and Zicam application were cytotoxic. CONCLUSIONS Based on the unique biochemical properties of the human nasal explant culture system, we developed a simple and reliable in vitro screening assay to determine the cytotoxic profiles of various intranasal agents by examining extracellular LDH levels and histopathology. PMID:22170775

  19. Arsenic Induction of Metallothionein and Metallothionein Induction Against Arsenic Cytotoxicity.

    PubMed

    Rahman, Mohammad Tariqur; De Ley, Marc

    Human exposure to arsenic (As) can lead to oxidative stress that can become evident in organs such as the skin, liver, kidneys and lungs. Several intracellular antioxidant defense mechanisms including glutathione (GSH) and metallothionein (MT) have been shown to minimize As cytotoxicity. The current review summarizes the involvement of MT as an intracellular defense mechanism against As cytotoxicity, mostly in blood. Zinc (Zn) and selenium (Se) supplements are also proposed as a possible remediation of As cytotoxicity. In vivo and in vitro studies on As toxicity were reviewed to summarize cytotoxic mechanisms of As. Intracellular antioxidant defense mechanisms of MT are linked in relation to As cytotoxicity. Arsenic uses a different route, compared to major metal MT inducers such as Zn, to enter/exit blood cells. A number of in vivo and in vitro studies showed that upregulated MT biosynthesis in blood components are related to toxic levels of As. Despite the cysteine residues in MT that aid to bind As, MT is not the preferred binding protein for As. Nonetheless, intracellular oxidative stress due to As toxicity can be minimized, if not eliminated, by MT. Thus MT induction by essential metals such as Zn and Se supplementation could be beneficial to fight against As toxicity.

  20. Cytotoxic sesquiterpene lactones from the root of Saussurea lappa.

    PubMed

    Sun, Chang-Ming; Syu, Wan-Jr; Don, Ming-Jaw; Lu, Jang-Jih; Lee, Gum-Hee

    2003-09-01

    Bioassay-directed fractionation of Saussurea lappa led to the isolation of a novel lappadilactone (1) and seven sesquiterpene lactones (2-8) as cytotoxic principles against selected human cancer cell lines. Lappadilactone (1), dehydrocostuslactone (2), and costunolide (5) exhibited the most potent cytotoxicity with CD50 values in the range 1.6-3.5 microg/mL in dose- and time-dependent manners. The cytotoxicities were not specific and showed similar activities against HepG2, OVCAR-3 and HeLa cell lines. The structure-activity relationship showed that the alpha-methylene-gamma-lactone moiety is necessary for cytotoxicity, and activity is reduced with the presence of a hydroxyl group. In addition, seven noncytotoxic compounds (9-15) were also isolated, including two novel sesquiterpenes, a guaianolide-type with a C17 skeleton, lappalone (13), and 1beta,6alpha-dihydroxycostic acid ethyl ester (14). The structures of the new compounds were elucidated from spectroscopic and/or X-ray data interpretations. Some representative compounds were also tested for antibacterial activity; however, only marginal activities were observed. Therefore, compounds 1-8 are potential cytotoxic agents but without significant antibacterial effect.

  1. Functional differentiation of cytotoxic cancer drugs and targeted cancer therapeutics.

    PubMed

    Winkler, Gian C; Barle, Ester Lovsin; Galati, Giuseppe; Kluwe, William M

    2014-10-01

    There is no nationally or internationally binding definition of the term "cytotoxic drug" although this term is used in a variety of regulations for pharmaceutical development and manufacturing of drugs as well as in regulations for protecting medical personnel from occupational exposure in pharmacy, hospital, and other healthcare settings. The term "cytotoxic drug" is frequently used as a synonym for any and all oncology or antineoplastic drugs. Pharmaceutical companies generate and receive requests for assessments of the potential hazards of drugs regularly - including cytotoxicity. This publication is intended to provide functional definitions that help to differentiate between generically-cytotoxic cancer drugs of significant risk to normal human tissues, and targeted cancer therapeutics that pose much lesser risks. Together with specific assessments, it provides comprehensible guidance on how to assess the relevant properties of cancer drugs, and how targeted therapeutics discriminate between cancer and normal cells. The position of several regulatory agencies in the long-term is clearly to regulate all drugs regardless of classification, according to scientific risk based data. Despite ongoing discussions on how to replace the term "cytotoxic drugs" in current regulations, it is expected that its use will continue for the near future. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Cytotoxic activity in children with insulin-dependent diabetes mellitus.

    PubMed

    Lorini, R; Moretta, A; Valtorta, A; d'Annunzio, G; Cortona, L; Vitali, L; Bozzola, M; Severi, F

    1994-02-01

    We determined the percentage of circulating natural killer (NK) cells, using the monoclonal antibodies anti-CD57 and anti-CD16, NK cytotoxic activity (lytic units/10(6)) and lymphokine-activated killer (LAK) activity in 25 IDDM patients aged 3-23 years, 12 with disease for < 1 year (Group I) and 13 with disease for > 3 years (Group II). Nine age-matched healthy subjects served as controls. The percentage of CD57+ cells was similar in IDDM patients and controls, while the percentage of CD16+ cells was lower in IDDM patients (P < 0.05) than in controls. NK cell cytotoxic activity was lower in IDDM patients than in controls (P < 0.01), in Group I and II compared with controls (P < 0.005). LAK activity was similar in IDDM patients and in controls. No correlation was found between NK cytotoxic activity and metabolic control, HLA typing, while a negative correlation was found between NK cytotoxic activity and insulin requirement (P < 0.05). The decreased NK cytotoxic activity observed in our patients, in particular in long-standing diabetics, with normal NK cell number, could be due to a qualitative defect of the NK cells, or to a deficient IL-2 and/or TNF-alpha production, or to a immunomodulatory or immunosuppressing effect of insulin.

  3. Novel Aldehyde-Terminated Dendrimers; Synthesis and Cytotoxicity Assay

    PubMed Central

    Hamidi, Aliasghar; Sharifi, Simin; Davaran, Soodabeh; Ghasemi, Saeed; Omidi, Yadollah; Rashidi, Mohammad-Reza

    2012-01-01

    Introduction Polyamidoamine (PAMAM) dendrimers are a unique family of dendritic polymers with numerous pharmaceutical and biomedical applications. One major problem with these polymers is their cytotoxicity. The purpose of this study was to synthesize novel dendrimers with aldehyde terminal groups and compare their cytotoxicity with that of dendri¬mers containing amine-terminated groups. Methods G1(first generation) and G2 (second generation) dendrimers with amine-terminated groups were synthesized by divergent method and then the amine-terminated groups were converted to the aldehyde groups using surface modification of the functional group inversion (FGI) method. The cytotoxicity of the novel G1 and G2 polyamidoaldehyde (PAMAL) dendrimers together with that of G1 and G2 PAMAM-NH2 dendrimers was investigated by MTT assay using MCF-7 cell line. Results The results showed that cytotoxicity of dendrimers with aldehyde-terminated groups is much lower than that of G1 and G2 PAMAM-NH2 dendri¬mers. Conclusion Dendrimers with aldehyde-terminated groups could be used as novel and convenient carriers for drug delivery with low cytotoxic effect compared with the amine-terminated dendrimers. The results revealed that the same generations of the dendri¬mers with aldehyde-terminated groups are far less toxic than the corresponding amine-terminated dendrimers. PMID:23678447

  4. Carbon nanotubes enhance cytotoxicity mediated by human lymphocytes in vitro.

    PubMed

    Sun, Zhao; Liu, Zhe; Meng, Jie; Meng, Jie; Duan, Jinhong; Xie, Sishen; Lu, Xin; Zhu, Zhaohui; Wang, Chen; Chen, Shuchang; Xu, Haiyan; Yang, Xian-Da

    2011-01-01

    With the expansion of the potential applications of carbon nanotubes (CNT) in biomedical fields, the toxicity and biocompatibility of CNT have become issues of growing concern. Since the immune system often mediates tissue damage during pathogenesis, it is important to explore whether CNT can trigger cytotoxicity through affecting the immune functions. In the current study, we evaluated the influence of CNT on the cytotoxicity mediated by human lymphocytes in vitro. The results showed that while CNT at low concentrations (0.001 to 0.1 µg/ml) did not cause obvious cell death or apoptosis directly, it enhanced lymphocyte-mediated cytotoxicity against multiple human cell lines. In addition, CNT increased the secretion of IFN-γ and TNF-α by the lymphocytes. CNT also upregulated the NF-κB expression in lymphocytes, and the blockage of the NF-κB pathway reduced the lymphocyte-mediated cytotoxicity triggered by CNT. These results suggest that CNT at lower concentrations may prospectively initiate an indirect cytotoxicity through affecting the function of lymphocytes.

  5. Signaling lymphocytic activation molecule (SLAM) regulates T cellular cytotoxicity.

    PubMed

    Henning, G; Kraft, M S; Derfuss, T; Pirzer, R; de Saint-Basile, G; Aversa, G; Fleckenstein, B; Meinl, E

    2001-09-01

    Signaling lymphocytic activation molecule (SLAM) is a CD2-related surface receptor expressed by activated T cells and B cells. SLAM is a self ligand and enhances T cellular proliferation and IFN-gamma production. A defective SLAM associated protein (SAP) causes X-linked lymphoproliferative syndrome (XLP), a frequently lethal mononucleosis based on the inability to control EBV. We report that SLAM augments TCR-mediated cytotoxicity. In normal CD4(+) and CD8(+) T cells, SLAM enhanced TCR-mediated cytotoxicity. In CD4(+) and CD8(+) Herpesvirus saimiri (H.saimiri) infected T cells, SLAM engagement alone triggered cytotoxicity. Using H.saimiri-transformed T cells as a model system we found that SLAM-engagement promotes the release of lytic granules and a CD95-independent killing that requires extracellular Ca(2+), cytoskeletal rearrangements, and signaling mediated by mitogen-activated protein kinase kinases MEK1/2. SLAM-enhanced cytotoxicity implies an immunoregulatory function by facilitating the elimination of APC and a role in overcoming infections with pathogens requiring a cytotoxic immune response.

  6. Cytotoxicity assessment of residual high-level disinfectants.

    PubMed

    Ryu, Mizuyuki; Kobayashi, Toshihiro; Kawamukai, Emiko; Quan, Glenlelyn; Furuta, Taro

    2013-01-01

    Some studies show the uptake of disinfectants on medical devices but no studies on their cytotoxicity have been reported. This study aimed to assess that cytotoxicity in a 3-dimensional culture system using HeLa cells grown in matrices composed of collagen. Plastic materials were soaked in the use solutions of the widely used high-level disinfectants, glutaraldehyde (GA), ortho-phthalaldehyde (OPA) and peracetic acid (PAA). After being rinsed, they were allowed to dry and were embedded into the cell medium to investigate the cytotoxicity of the residual disinfectants. Cytotoxicity was observed with the polyvinyl chloride, polyurethane and silicon tubes soaked in GA and OPA, indicating that both disinfectants were absorbed in the test pieces, whereas for PAA, none was observed. As for the polytetrafluoroethylene (PTFE) tubes, no disinfectant displayed cytotoxicity. GA and OPA are primary irritants, having a potential to cause anaphylaxis and other forms of allergic reactions. There should be consideration not only about the toxicity of the residual disinfectant from poor rinsing, but also about the toxicity that would result from the disinfectants that were absorbed and consequently released from the medical devices or materials.

  7. Profiling flavonoid cytotoxicity in human breast cancer cell lines: determination of structure-function relationships.

    PubMed

    Yadegarynia, Sina; Pham, Anh; Ng, Alex; Nguyen, Duong; Lialiutska, Tetiana; Bortolazzo, Anthony; Sivryuk, Valentin; Bremer, Martina; White, J Brandon

    2014-05-01

    Flavonoids have been shown to be cytotoxic to cancer cells. However, the mechanism of cytotoxicity has not been clearly defined. It has previously been reported that HER2/ERBB2, the estrogen receptor, progesterone receptor, and p53 were required for flavonoid induced cytotoxicity in breast cancer cell lines. We have used a panel of breast cancer cell lines, known to contain as well as be deficient in these signaling pathways, to screen fourteen different flavonoids. Comparing the cytotoxicity for all flavonoids allows us to determine if a structure-functional relationship exists between cytotoxicity and flavonoid, and if a particular signaling pathway is required for cytotoxicity. We show that several flavonoids are cytotoxic to all cell lines including primary mammary epithelial cells tested. The cytotoxic flavonoids are also able to inhibit Mitochondrial Outer Membrane Permeability while at the same time stimulate ATP levels whereas the non-cytotoxic flavonoids are not able to do this. We also show that both cytotoxic and non-cytotoxic flavonoids can transverse the cell membrane to enter MDA-MB-231 cells at different levels. Finally, all flavonoids regardless of their cytotoxicity were able to induce some form of cell cycle arrest. We conclude that for flavonoids to be strongly cytotoxic, they must possess the 2,3-double bond in the C-ring and we believe the cytotoxicity occurs through mitochondrial poisoning in both cancer and normal cells.

  8. Profiling flavonoid cytotoxicity in human breast cancer cell lines: determination of structure-function relationships.

    PubMed

    Yadegarynia, Sina; Pham, Anh; Ng, Alex; Nguyen, Duong; Lialiutska, Tetiana; Bortolazzo, Anthony; Sivryuk, Valentin; Bremer, Martina; White, J Brandon

    2012-10-01

    Flavonoids have been shown to be cytotoxic to cancer cells. However, the mechanism of cytotoxicity has not been clearly defined. It has previously been reported that HER2/ERBB2, the estrogen receptor, progesterone receptor, and p53 were required for flavonoid induced cytotoxicity in breast cancer cell lines. We have used a panel of breast cancer cell lines, known to contain as well as be deficient in these signaling pathways, to screen fourteen different flavonoids. Comparing the cytotoxicity for all flavonoids allows us to determine if a structure-functional relationship exists between cytotoxicity and flavonoid, and if a particular signaling pathway is required for cytotoxicity. We show that several flavonoids are cytotoxic to all cell lines including primary mammary epithelial cells tested. The cytotoxic flavonoids are also able to inhibit Mitochondrial Outer Membrane Permeability while at the same time stimulate ATP levels whereas the non-cytotoxic flavonoids are not able to do this. We also show that both cytotoxic and non-cytotoxic flavonoids can transverse the cell membrane to enter MDA-MB-231 cells at different levels. Finally, all flavonoids regardless of their cytotoxicity were able to induce some form of cell cycle arrest. We conclude that for flavonoids to be strongly cytotoxic, they must possess the 2,3-double bond in the C-ring and we believe the cytotoxicity occurs through mitochondrial poisoning in both cancer and normal cells.

  9. New cytotoxic diarylheptanoids from the rhizomes of Alpinia officinarum Hance.

    PubMed

    Liu, Dan; Liu, Yan-Wen; Guan, Fu-Qin; Liang, Jing-Yu

    2014-07-01

    Two new dimeric diarylheptanoids, named Alpinin C (1) and D (2), a new natural product of diarylheptanoid (3) along with three known diarylheptanoids (4-6) were isolated from the rhizomes of Alpinia officinarum Hance. Their structures were elucidated based on extensive spectroscopic analyses (1D and 2D NMR, HRTOFMS, IR). The isolated compounds were evaluated for their cytotoxicity against human tumor cell lines HepG2, MCF-7, T98G and B16-F10. Compound 1 showed selective cytotoxicity against cell lines of MCF-7 and T98G, while compound 6 showed significant cytotoxicity to the all tested tumor cell lines with IC50 in the range from 8.46 to 22.68 μmol/L. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Tomoeones A-H, cytotoxic phloroglucinol derivatives from Hypericum ascyron.

    PubMed

    Hashida, Waka; Tanaka, Naonobu; Kashiwada, Yoshiki; Sekiya, Michiko; Ikeshiro, Yasumasa; Takaishi, Yoshihisa

    2008-08-01

    Phloroglucinol derivatives tomoeones A-H (1-8) and three known compounds were isolated from leaves of Hypericum ascyron. Their structures were established based on spectroscopic analyses. They are all acylphloroglucinol derivatives possessing a spiro skeleton with geminal isoprenyl groups and a monoterpene moiety, and they are stereoisomers to each other at C-4 and C-13. They appear to be a class of phloroglucinol derivatives. Cytotoxicities of the isolated phloroglucinol derivatives against human tumor cell lines, including multidrug-resistant (MDR) cancer cell lines, were evaluated. Tomoeone F (6) demonstrated significant cytotoxicity against KB cells with an IC50 value of 6.2 microM. Compound 6 was also cytotoxic against MDR cancer cell lines (KB-C2 and K562/Adr), which was more potent than doxorubicin.

  11. In vitro cytotoxicity of gold nanorods in A549 cells.

    PubMed

    Tang, Ying; Shen, Yafeng; Huang, Libin; Lv, Gaojian; Lei, Changhai; Fan, Xiaoyan; Lin, Fangxing; Zhang, Yuxia; Wu, Lihui; Yang, Yongji

    2015-03-01

    Gold nanoparticles, which have unique physicochemical characteristics, are being used for an increasingly wide range of applications in biomedical research. In this study, gold nanorods (width of 25 nm, length of 52 nm) were found to be internalized by A549 cells and were primarily localized in the lysosomes and membranous vesicles. The integrity of the membranes of A549 cells exposed to gold nanorods for 4h was damaged, as indicated by laser scanning confocal microscopy (LSCM). Increased lactate dehydrogenase (LDH) leakage and decreased cell viability further indicated the concentration-dependent cytotoxicity of the gold nanorods to the A549 cells. Reactive oxygen species (ROS) production was induced in the A549 cells by the gold nanorods, and this effect was positively correlated with the concentration of the gold nanorods. The results of this study indicated that exposure to gold nanorods caused dose-dependent cytotoxicity in A549 cells and that oxidative stress may be the main factor causing cytotoxicity.

  12. Cytotoxic bibenzyl dimers from the stems of Dendrobium fimbriatum Hook.

    PubMed

    Xu, Feng-Qing; Xu, Fang-Cheng; Hou, Bo; Fan, Wei-Wei; Zi, Cheng-Ting; Li, Yan; Dong, Fa-Wu; Liu, Yu-Qing; Sheng, Jun; Zuo, Zhi-Li; Hu, Jiang-Miao

    2014-11-15

    The bioassay-guided chemical investigation of the stems of Dendrobium fimbriatum Hook led to the isolation of seven first reported bibenzyl dimers with a linkage of a methylene moiety, fimbriadimerbibenzyls A-G (1-7), together with a new dihydrophenanthrene derivative (S)-2,4,5,9-tetrahydroxy-9,10-dihydrophenanthrene (8) and thirteen known compounds (9-21). The structure of the new compound was established by spectroscopic analysis. Biological evaluation of bibenzyl derivatives against five human cell lines indicated that seven of those compounds exhibited broad-spectrum and cytotoxic activities with IC50 values ranging from 2.2 to 21.2 μM. Those rare bibenzyl dimers exhibited cytotoxic activities in vitro and the cytotoxicity decreased as the number of oxygen-containing groups in the structure decreases.

  13. Cytotoxic constituents from the stems of Clausena lansium (Lour.) Skeels.

    PubMed

    Jiang, Hai Yan; Wang, Cheng Fang; Fan, Li; Yang, Kai; Feng, Jiang Bin; Geng, Zhu Feng; Xu, Jing; Deng, Zhi Wei; Du, Shu Shan; Yin, Hai Bo

    2013-09-03

    Six compounds were isolated from the stems of Clausena lansium (Lour.) Skeels by repeated sillica gel column chromatography. Their chemical structures were elucidated on the basic of physicochemical and spectroscopic data. Among them, 8-geranyloxypsolaren (3) and 2-methoxy-1-(3-methyl-buten-1-yl)-9H-carbazole-3-carbaldehyde (6) were isolated for the first time from this plant. These compounds were screened for cytotoxicity in human cervical cancer (Hela), leukemia (K562), lung cancer (A549), non-small lung carcinoma (H1299) and liver cancer (SMMC-7721). Within the series of cytotoxic tests, compounds 4-6 displayed potent cytotoxic activity against H1299 and SMMC-7721, with the IC₅₀ values of 6.19 to 26.84 μg/mL.

  14. Cytotoxicity study of rock wool by cell magnetometric evaluation.

    PubMed

    Kudo, Yuichiro; Kotani, Makoto; Aizawa, Yoshiharu

    2009-11-01

    The cytotoxicity of rock wool (RW), an asbestos substitute, was evaluated by cell magnetometry. Alveolar macrophages were isolated from male Fisher rats. Following addition of triiron tetraoxide (Fe(3)O(4)) to macrophages, RW was added. Then, the remnant magnetic field strength was measured for 20min after magnetization by an external field. Relaxation, an indicator of decay of cytotoxicity, was observed by cell magnetometry immediately postmagnetization in the group to which RW was added. In general, materials phagocytosed by macrophages are ingested into phagosomes and digested while migrating. This migration of phagosomes occurs by polymerization and depolymerization of the cytoskeleton. As a result of evaluation, relaxation was not delayed by addition of RW, since RW caused no effect on the cytoskeleton. It was suggested that RW has no cytotoxicity as evaluated by cell magnetometry.

  15. Novel cytotoxic chalcones from Litsea rubescens and Litsea pedunculata.

    PubMed

    Li, Liang; Zhao, Xing-Tang; Luo, Yi-Ping; Zhao, Jing-Feng; Yang, Xiao-Dong; Zhang, Hong-Bing

    2011-12-15

    Two novel flavonoids with chalcone skeleton, together with seven known flavonoids, were isolated from the stem barks of Litsea rubescens and Litsea pedunculata. The structures of the new compounds were elucidated on the basis of spectral methods including IR, UV, 1D and 2D NMR. The new chalcones were found to contain the rare epoxy or ethylidenedioxy group. This is the first report on the presence of chalcone in the plant genus Litsea. The cytotoxic potential of two new chalcones was evaluated in vitro against three human tumor cell lines. Both new chalcones displayed potent cytotoxic activities against myeloid leukaemia (HL-60) and epidermoid carcinoma (A431) cell lines and more active than cisplatin (DDP). Interestingly, compound 1 exhibited cytotoxic activity against HL-60 with IC(50) value 2.1-fold more sensitive to DDP. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Design, synthesis and potent cytotoxic activity of novel podophyllotoxin derivatives.

    PubMed

    Li, Wen-Qun; Wang, Xu-Li; Qian, Keduo; Liu, Ying-Qian; Wang, Chih-Ya; Yang, Liu; Tian, Jin; Morris-Natschke, Susan L; Zhou, Xing-Wen; Lee, Kuo-Hsiung

    2013-04-15

    Twenty new acyl thiourea derivatives of podophyllotoxin and 4'-demethylepipodophyllotoxin were prepared and screened for their cytotoxicity against four human tumor cell lines, A-549, DU-145, KB, and KBvin. With IC50 values of 0.098-1.13 μM, compounds 13b, 13c, and 13o displayed much better cytotoxic activity than the control etoposide. Most importantly, 13b and 13o exhibited promising cytotoxicity against the drug resistant tumor cell line KBvin with IC50 values of 0.098 and 0.13 μM, respectively, while etoposide lost activity completely. Structure-activity relationship (SAR) correlations of the new derivatives have been established. Compounds 13b and 13o merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.

  17. Carbon fiber reinforced root canal posts. Mechanical and cytotoxic properties.

    PubMed

    Torbjörner, A; Karlsson, S; Syverud, M; Hensten-Pettersen, A

    1996-01-01

    The aim of this study was to compare the mechanical properties of a prefabricated root canal post made of carbon fiber reinforced composites (CFRC) with metal posts and to assess the cytotoxic effects elicited. Flexural modulus and ultimate flexural strength was determined by 3 point loading after CRFC posts had been stored either dry or in water. The bending test was carried out with and without preceding thermocycling of the CFRC posts. The cytotoxicity was evaluated by an agar overlay method after dry and wet storage. The values of flexural modulus and ultimate flexural strength were for dry stored CFRC post 82 +/- 6 GPa and 1154 +/- 65 MPa respectively. The flexural values decreased significantly after water storage and after thermocycling. No cytotoxic effects were observed adjacent to any CFRC post. Although fiber reinforced composites may have the potential to replace metals in many clinical situations, additional research is needed to ensure a satisfying life-span.

  18. Genotoxic and cytotoxic effects of testosterone cypionate (deposteron(®)).

    PubMed

    Meireles, José Roberto C; Oliveira, Susie V; Costa-Neto, Antônio O; Cerqueira, Eneida M M

    2013-05-15

    The indiscriminate use of anabolic androgenic steroids (AAS) has motivated researchers to investigate the mutagenic action of these substances. The present study, using the mouse bone marrow micronucleus test, evaluates the genotoxic potential of testosterone cypionate (deposteron). Male Swiss mice received intramuscular injections of deposteron at three doses. The animals were sacrificed 24, 48, or 72h after treatment and bone marrow was removed immediately, followed by scoring to count the micronuclei in 2000 polychromatic erythrocytes (PCE). Two hundred erythrocytes/animal were analyzed to determine the PCE-NCE (normochromatic erythrocyte) relationship and to determine the cytotoxic effects. The animals treated with deposteron at the highest dose presented greater numbers of micronuclei. The highest dose caused a decrease in the PCE/NCE relationship, indicating a cytotoxic effect. We conclude that deposteron is genotoxic and cytotoxic in mice.

  19. Cytotoxic components of Pereskia bleo (Kunth) DC. (Cactaceae) leaves.

    PubMed

    Malek, Sri Nurestri Abdul; Shin, Sim Kae; Wahab, Norhanom Abdul; Yaacob, Hashim

    2009-05-06

    Dihydroactinidiolide (1) and a mixture of sterols [campesterol (2), stigmasterol (3) and beta-sitosterol (4)], together with the previously isolated individual compounds beta-sitosterol (4), 2,4-di-tert-butylphenol (5), alpha-tocopherol (6), phytol (7) were isolated from the active ethyl acetate fraction of Pereskia bleo (Kunth) DC. (Cactaceae) leaves. Cytotoxic activities of the above mentioned compounds against five human carcinoma cell lines, namely the human nasopharyngeal epidermoid carcinoma cell line (KB), human cervical carcinoma cell line (CasKi), human colon carcinoma cell line (HCT 116), human hormone-dependent breast carcinoma cell line (MCF7) and human lung carcinoma cell line (A549); and non-cancer human fibroblast cell line (MRC-5) were investigated. Compound 5 possessed very remarkable cytotoxic activity against KB cells, with an IC(50 )value of 0.81microg/mL. This is the first report on the cytotoxic activities of the compounds isolated from Pereskia bleo.

  20. Compounds Combining Aminoadamantane and Monoterpene Moieties: Cytotoxicity and Mutagenic Effects.

    PubMed

    Suslov, Evgeniy V; Ponomarev, Konstantin Yu; Rogachev, Artem D; Pokrovsky, Michail A; Pokrovsky, Andrey G; Pykhtina, Maria B; Beklemishev, Anatoly B; Korchagina, Dina V; Volcho, Konstantin P; Salakhutdinov, Nariman F

    2015-01-01

    A series of secondary amines combining monoterpenoid and aminoadamantane moieties have been synthesized. Their cytotoxic activity against human cancer cells CEM-13, MT-4, and U-937 has been studied for the first time. Most of the obtained compounds exhibited a significant cytotoxic activity with the median cytotoxic dose (CTD50) ranging from 6 to 84 µM. The most promising results were obtained for compound 2b which was synthesized from 1-aminoadamantane and (-)-myrtenal and revealed a high activity against all tumor lines used (CTD50 = 12 ÷ 21 µM) along with low toxicity with respect to MDCK cells (CTD50 = 1500 µM). The synthesized amines do not exert the genotoxic effect on cells of the biosensor strain based on recombinant E. coli cells bearing the pRAC-gfp plasmid.

  1. Internalization of Ineffective Platinum Complex in Nanocapsules Renders It Cytotoxic.

    PubMed

    Vrana, Oldrich; Novohradsky, Vojtech; Medrikova, Zdenka; Burdikova, Jana; Stuchlikova, Olga; Kasparkova, Jana; Brabec, Viktor

    2016-02-18

    Anticancer therapy by platinum complexes, based on nanocarrier-based delivery, may offer a new approach to improve the efficacy and tolerability of the platinum family of anticancer drugs. The original rules for the design of new anticancer platinum drugs were affected by the fact that, although cisplatin (cis-[PtCl2 (NH3)2) was an anticancer drug, its isomer transplatin was not cytotoxic. For the first time, it is demonstrated that simple encapsulation of an inactive platinum compound in phospholipid bilayers transforms it into an efficient cytotoxic agent. Notably, the encapsulation of transplatin makes it possible to overcome the resistance mechanisms operating in cancer cells treated with cisplatin and prevents inactivation of transplatin in the extracellular environment. It is also shown that transplatin delivered to the cells in nanocapsules, in contrast to free (nonencapsulated) complex, forms cytotoxic cross-links on DNA.

  2. Human colonic mononuclear cells: studies of cytotoxic function.

    PubMed Central

    Falchuk, Z M; Barnhard, E; Machado, I

    1981-01-01

    We isolated lymphocytes from the lamina propria of colon from 19 patients with inflammatory bowel disease, colon cancer, and certain benign conditions to determine: (1) if these lymphocytes could mediate mitogen-induced (MICC) and spontaneous cell-mediated cytotoxicity (SCMC), and (2) if there were any differences in cytotoxic effectiveness which could relate to the underlying disease. We found that lamina propria lymphocytes functioned well in MICC reactions with phytohaemagglutinin, but not concanavalin A as the inducing mitogen (specific lysis 28 5% vs 5 3%). Lamina propria lymphocytes did not mediate SCMC (specific lysis 0.3%). Neither the presence of inflammation not the underlying disease of the patient influenced the cytotoxic activity. Peripheral blood lymphocytes from normal subjects and patients performed well in MICC assay with both phytohaemagglutinin and concanvalin A as the inducing mitogen and were equally effective in SCMC reactions. PMID:6972335

  3. Antioxidant and cytotoxic agent from the rhizomes of Kaempferia pandurata

    PubMed Central

    Tanjung, Mulyadi; Tjahjandarie, Tjitjik Srie; Sentosa, Mulya Hadi

    2013-01-01

    Objective To determine antioxidant and cytotoxic activity of two flavanones, pinocembrin (1) and pinostrobin (2) from the rhizomes of Kaempferia pandurata. The chemical structures of both compounds were determined based on spectroscopic data, including UV, IR, MS and NMR spectra. Methods The antioxidant activities of pinocembrin (1) and pinostrobin (2) were assayed by using 2,2-diphenyl-1-picrylhydrazyl. Cytotoxic assay was done by using brine shrimp lethality test, and cytotoxic properties was tested against murine leukemia P-388 cells. Results Compounds 1-2 were evaluated for their antioxidant properties against DPPH, showing their IC50 were 5 816 and 6 268 µmol/L; brine shrimp lethality test: LC50 23.3 and 60.5 µg/mL; murine leukemia P-388: IC50 176.3 and 218.5 µmol/L. Conclutions The results indicated that pinocembrin (1) was slightly more active than pinostrobin (2).

  4. Antimicrobial and cytotoxicity activities of the medicinal plant Primula macrophylla.

    PubMed

    Najmus-Saqib, Qazi; Alam, Fiaz; Ahmad, Mansoor

    2009-06-01

    Primula macrophylla (Primulaceae) is reported as to be useful in asthma, restlessness, insomnia and fish poisoning. Antifungal and toxic activities of crude extract, fractions and a pure isolated compound exhibited statistically significant activities. Excellent antifungal activity was found in the crude extract, benzene and ethyl acetate fractions against T. longifusis and against M. canis with different MIC values. Antileishmanial activity (IC(50) = 50ug/mL) was observed as compared to standard drug Amphotericin B, and cytotoxic activity (LD(50) = 47.919microg/mL) was also found in the chloroform fraction. While pure compound 2-phenylchromone (Flavone) isolated from the chloroform fraction showed good activity (IC(50) = 25microg/mL) against Leishmania and cytotoxicity (LD(50) = 2.0116 microg/mL) in Brine Shrimp experiments. From antileishmanial and cytotoxic activity it can be concluded that 2-phenylchromone is the major compound responsible for these activities.

  5. Mediation of mouse natural cytotoxic activity by tumour necrosis factor

    NASA Astrophysics Data System (ADS)

    Ortaldo, John R.; Mason, Llewellyn H.; Mathieson, Bonnie J.; Liang, Shu-Mei; Flick, David A.; Herberman, Ronald B.

    1986-06-01

    Natural cell-mediated cytotoxic activity in the mouse has been associated with two types of effector cells, the natural killer (NK) cell and the natural cytotoxic (NC) cell, which seem to differ with regard to their patterns of target selectivity, cell surface characteristics and susceptibility to regulatory factors1. During studies on the mechanism of action of cytotoxic molecules, it became evident that WEHI-164, the prototype NC target cell, was highly susceptible to direct lysis by both human and mouse recombinant tumour necrosis factor (TNF). Here we show that NC, but not NK activity mediated by normal splenocytes, is abrogated by rabbit antibodies to recombinant and natural TNF, respectively. Thus, the cell-mediated activity defined as NC is due to release of TNF by normal spleen cells and does not represent a unique natural effector mechanism.

  6. Intracellular routing of cytotoxic pancreatic-type ribonucleases.

    PubMed

    Benito, Antoni; Vilanova, Maria; Ribó, Marc

    2008-06-01

    In addition to their ribonucleolytic activity, several ribonucleases (RNases) play important roles in other specific biological activities, such as dendritic cell activation, certain pollen-induced allergies, blood vessel formation and defense against parasitic or microbial infections. Among these diverse actions, cytotoxic activity, which relies in most cases on ribonucleolytic activity, has attracted a considerable attention because of the potential for using RNases as therapeutic agents for the treatment of different malignancies. In addition to use naturally existing RNases, major efforts have been made in the development of engineered variants, which display more potent cytotoxic activity and greater selectivity for malignant cells. This review focuses on the molecular and cellular aspects of the internalization, intracellular trafficking and final sorting of cytotoxic RNases. Knowledge about the strategies used by these promising toxins provides us with essential information about the mechanisms that can be used to gain access to different subcellular compartments and intracellular sorting.

  7. Cytotoxic alkaloids from stems, leaves and twigs of Dasymaschalon blumei.

    PubMed

    Chanakul, Waraporn; Tuchinda, Patoomratana; Anantachoke, Natthinee; Pohmakotr, Manat; Piyachaturawat, Pawinee; Jariyawat, Surawat; Suksen, Kanoknetr; Jaipetch, Tharworn; Nuntasaen, Narong; Reutrakul, Vichai

    2011-10-01

    Bioassay-guided fractionation of the cytotoxic ethyl acetate extract from the stems of Dasymaschalon blumei (Annonaceae) led to the isolation of four aristololactam alkaloids, including the hitherto unknown 3,5-dihydroxy-2,4-dimethoxyaristolactam (1), as well as the three known compounds, aristolactam BI, goniopedaline, and griffithinam. Additionally, the cytotoxic extract from the combined leaves and twigs of the same plant yielded three known oxoaporphine alkaloids, oxodiscoguattine, dicentrinone, and duguevalline. The structures of aristolactams and oxoaporphine alkaloids were elucidated on the basis of spectroscopic methods. All isolates were evaluated for cytotoxicity against a panel of mammalian cancer cell lines and a noncancerous human embryonic kidney cell Hek 293. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. State of water, molecular structure, and cytotoxicity of silk hydrogels.

    PubMed

    Numata, Keiji; Katashima, Takuya; Sakai, Takamasa

    2011-06-13

    A novel technique was developed to regulate the bulk water content of silk hydrogels by adjusting the concentrations of silk proteins, which is helpful to investigate the effects of the state of water in polymeric hydrogel on its biological functions, such as cytotoxicity. Gelation of the silk hydrogel was induced with ethanol and its gelation behavior was analyzed by rheometry. The silk hydrogels prepared at various silk concentrations were characterized with respect to their water content, molecular and network structures, state of water, mechanical properties, and cytotoxicity to human mesenchymal stem cells. The network structure of silk hydrogel was heterogeneous with β-sheet and fibrillar structures. The influence of the state of water in the silk hydrogel on the cytotoxicity was recognized by means of differential scanning calorimetry and cell proliferation assay, which revealed that the bound water will support cell-adhesion proteins in the cellular matrix to interact with the surface of the silk hydrogels.

  9. Cytotoxicity and structure activity relationships of phytosterol from Phyllanthus emblica.

    PubMed

    Qi, Wei-Yan; Li, Ya; Hua, Lei; Wang, Ke; Gao, Kun

    2013-01-01

    Fourteen sterols (1-14), including two new sterols, trihydroxysitosterol (2) and 5α,6β,7α-7α-acetoxysitosterol (3), were isolated from the branches and leaves of Phyllanthus emblica L. The isolated compounds and a structurally related sterol 15 from Aphanamixis grandifolia were screened for cytotoxicity in two tumor cell lines (HL-60 and SMMC-7721) and a non-tumor cell line (HL-7702) using RSB assay. Within the series of phytosterol derivatives tested, compound 15 was the most active, displaying potent cytotoxicity against HL-60 with IC(50) of 5.10μmol/L, and most of the active compounds showed selective cytotoxicity against tumor and non-tumor cell lines, especially compound 10 with a safety index of 4.42.

  10. Evaluation of Environmental Cytotoxic Drug Contamination in a Clinical Setting.

    PubMed

    Higginbotham, Mary Lynn; Fritz, Sara E

    The use of cytotoxic drugs to treat neoplastic conditions is increasing in veterinary practices. Many agents have the potential to be genotoxic and evidence of exposure to cytotoxic drugs has been found in healthcare workers handling these pharmaceuticals. To date, limited contamination evaluations have been performed in veterinary practices. Evaluation for carboplatin contamination was performed at a veterinary teaching hospital involving twelve areas in the dispensary and treatment room. Detectable levels of platinum were found on the surface of the biological safety cabinet where drugs are transferred from vial to administration device. Results indicate contamination did occur and care must be taken during all phases of cytotoxic drug preparation and administration; precautionary procedures must be in place to limit the spread of surface contamination and personnel exposure.

  11. Phytochemistry, cytotoxicity and antiviral activity of Eleusine indica (sambau)

    NASA Astrophysics Data System (ADS)

    Iberahim, Rashidah; Yaacob, Wan Ahmad; Ibrahim, Nazlina

    2015-09-01

    Goose grass also known as Eleusine indica (EI) is a local medicinal plant that displays antioxidant, antimicrobial and anticancer activities. The present study is to determine the phytochemical constituents, cytotoxicity and antiviral activities for both crude extract and fraction obtained from the plant. The crude extract contained more secondary metabolites compared to the hexane fraction as gauged using standard phytochemical tests. Cytotoxicity screening against Vero cells using MTT assay showed that the CC50 values for crude extract and hexane fraction were 2.07 and 5.62 mg/ml respectively. The antiviral activity towards Herpes Simplex Virus type 1 (HSV-1) was determined using plaque reduction assay. The selective indices (SI = CC50 / EC50) for both methanol extract and hexane fraction were 12.2 and 6.2 respectively. These results demonstrate that the extract prepared from E. indica possesses phytochemical compound that was non cytotoxic to the cell with potential antiviral activity.

  12. A simple method to measure NK cell cytotoxicity in vivo.

    PubMed

    Saudemont, Aurore; Burke, Shannon; Colucci, Francesco

    2010-01-01

    Natural killer (NK) cells were discovered in the 1970 s and named after their naturally occurring cytotoxic activity against tumor cells. It has recently become clear that NK cells are not just killers and that malignancy is unlikely to be the selective pressure driving the evolution of NK cells. Indeed, NK cells secrete a host of cytokines and chemokines that contribute to tissue remodeling at the feto-maternal interface and to both innate and adaptive immunity during infection. Moreover, in certain conditions, they cannot deliver functions cell autonomously, as they require priming from other cells, namely dendritic cells. Nevertheless, natural cytotoxicity is still considered an important parameter used to evaluate NK cell biology, both in the clinic and in the research lab. In this chapter we describe a simple method to quantify spontaneous NK cell cytotoxicity in vivo.

  13. Evaluation of antioxidative, protective effect against H2O2 induced cytotoxicity, and cytotoxic activities of three different Quercus species.

    PubMed

    Söhretoğlu, Didem; Sabuncuoğlu, Suna; Harput, U Şebnem

    2012-02-01

    Quercus species are used as antidiarrheic, for the treatment of hemorrhoid, oral and anal mucosa inflammation. These tree species have been of interest to researchers because of their usage in folk medicine, consumption as food, beverage and especially usage of oak woods for construction in wine barrels. The DPPH, SO and NO radical scavenging activities, protective effect against H2O2 induced cytotoxicity as well as their cytotoxic activity against Hep-2 human larynx epidermoid carcinoma cell line of the MeOH and water extracts of the barks of Quercus cerris var. cerris, Quercusmacranthera subsp. syspirensis and Quercus aucheri were investigated for the first time. Total phenolic content of the extracts was also evaluated by Folin-Ciocalteu method. Results demonstrated that the extracts showed strong radical scavenging activity comparable to those of standard compounds. Extracts also showed good protective effect against H2O2 induced cytotoxicity on human erythrocytes comparing to ascorbic acid. On the other hand, while each extract showed dose dependent cytotoxic activity, MeOH extract of Q.macranthera subsp. syspirensis showed the strongest cytotoxicity against the tested cell line. Taken together, the results showed that Quercus species may be a promising alternative to synthetic substances as natural compound with high antioxidant and antiproliferative activities.

  14. Association of thymidylate synthase variants with 5-fluorouracil cytotoxicity.

    PubMed

    Peters, Eric J; Kraja, Aldi T; Lin, Shiow J; Yen-Revollo, Jane L; Marsh, Sharon; Province, Michael A; McLeod, Howard L

    2009-05-01

    Identifying relevant cytotoxicity genes using an ex-vivo lymphoblastoid cell line (LCLs) model has distinct advantages for pharmacogenomic discovery studies of cancer chemotherapy, including standardized treatment conditions, availability of large numbers of samples, and publicly available genotypic data. However, there is little proof of principal data to confirm the promise of this approach. One of the known targets of 5-fluorouracil (5-FU) treatment is thymidylate synthase (TYMS). We hypothesized that genetic variants in TYMS would alter cytotoxicity because of 5-FU treatment using a LCL model system. LCLs from the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees (N=427) were treated with eight concentrations of 5-FU for 72 h, and cytotoxicity was determined using an Alamar Blue assay. For a subset of the 30 International Haplotype Mapping project (HapMap) trios, genotype data for 46 single-nucleotide polymorphism (SNP) variants encompassing the TYMS gene were downloaded from the HapMap website. Using a mixed models approach, each SNP was tested for association to 5-FU cytotoxicity in the subset of HapMap trios. Putatively associated SNPs (P<0.01), were then genotyped in the remaining LCLs in the CEPH pedigrees and tested for association. Two intronic SNPs in TYMS (rs2847153 and rs2853533) were significantly associated (P<0.01) with 5-FU cytotoxicity in the HapMap subset using the mixed models approach. After genotyping these SNPs in the full CEPH pedigrees, the associations with cytotoxicity showed a more reliable significance (P<0.0005), as a result of the increase in sample size. These results highlight the importance of the TYMS gene variants in response to 5-FU treatment. Furthermore, they provide additional biological validation of the relevance of LCLs as a model for pharmacogenomic gene discovery in cancer chemotherapy.

  15. Enhancement of cisplatin cytotoxicity in combination with herniarin in vitro.

    PubMed

    Haghighitalab, Azadeh; Matin, Maryam M; Bahrami, Ahmad R; Iranshahi, Mehrdad; Haghighi, Fereshteh; Porsa, Hassan

    2014-04-01

    Combinatorial chemotherapy is a valuable route, which can be conducted by different approaches. Use of cisplatin has been approved by the U.S. Food and Drug Administration for different kinds of cancers including bladder cancer. Herniarin is a member of simple coumarins, which are a group of common secondary metabolites in plants. In this study, the enhancing effects of herniarin on cisplatin cytotoxicity were investigated. Cytotoxicity of herniarin on transitional cell carcinoma (TCC) cells was first investigated in comparison with umbelliferone, the parent compound for a large number of coumarins including herniarin, by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. In order to test the effects of herniarin on cisplatin cytotoxicity, TCC cells were also treated with various combining concentrations of herniarin and cisplatin. In these experiments same amounts of dimethyl sulfoxide were used as controls. After 24, 48 and 72 h of treatments, the effects of herniarin on cisplatin cytotoxicity were evaluated by MTT assay. The level of chromatin condensation which represents the apoptotic morphology was also investigated by 4',6-diamidino-2-phenylindole (DAPI) staining. Results indicated that unlike umbelliferone, its methoxy analog, herniarin, had no significant cytotoxicity on TCC cells. On the other hand, the combination of 80 µg/mL herniarin with 5 µg/mL cisplatin, significantly enhanced the cytotoxicity of cisplatin. Furtheremore, DAPI staining revealed that combining concentrations of herniarin and cisplatin resulted in increased chromatin condensation in comparison with controls. This study is another confirmation for bioactivity of herniarin and shows that it might be a good candidate for further experiments investigating its mechanism of action.

  16. An improved resazurin-based cytotoxicity assay for hepatic cells.

    PubMed

    McMillian, M K; Li, L; Parker, J B; Patel, L; Zhong, Z; Gunnett, J W; Powers, W J; Johnson, M D

    2002-01-01

    A simple resazurin-based cytotoxicity assay is presented for screening of cytotoxicity in hepatocytes and liver cell lines. Human hepatoma (HepG2) cells in 96-well culture plates were exposed to known toxic (cisplatin, 5-fluorouracil, ethionine, flufenamic acid, and diflunisal) and control (transplatin, 5-chlorouracil, methionine, and acetylsalicylic acid) compounds for 1-3 days, and resazurin (5 micromol/L) was added. A conventional short-term (1 h) assay was first performed, where cytotoxicity is indicated by decreased reduction of resazurin to its fluorescent product resorufin. Our improved assay consists of additionally measuring fluorescence 2-4 days later, when cytotoxicity is indicated by a striking increase in the concentration of resorufin, resulting from two distinct processes. First, viable liver-derived cells slowly convert resorufin to nonfluorescent metabolites. Fluorescence of control cell wells decreased to background during a 2- to 4-day exposure to resazurin. This metabolism of resorufin was largely blocked by dicumarol and to lesser extents by disulfiram and SKF525a. Second, dead or dying cells slowly convert resazurin to resorufin but do not further metabolize resorufin; thus this fluorescent metabolite accumulates to high levels in wells with dead cells by 2 to 4 days. A similar increase in fluorescence associated with cytotoxicity was observed in primary cultures of rat hepatocytes using the long-term resazurin-based assay. In addition to an improved signal relative to the short-term assay, the inversion of the fluorescent signal from high = alive short-term to high = dead long-term allows determination of two independent cytotoxicity endpoints after addition of one innocuous vital dye.

  17. Cytotoxic immunotherapy strategies for cancer: mechanisms and clinical development.

    PubMed

    Aguilar, Laura K; Guzik, Brian W; Aguilar-Cordova, Estuardo

    2011-08-01

    Traditional therapies for cancer include surgery, chemotherapy, and radiation. Chemotherapy has widespread systemic cytotoxic effects against tumor cells but also affects normal cells. Radiation has more targeted local cytotoxicity but is limited to killing cells in the radiation field. Immunotherapy has the potential for systemic, specific killing of tumor cells. However, if the immune response is specific to a single antigen, tumor evasion can occur by down-regulation of that antigen. An immunotherapy approach that induces polyvalent immunity to autologous tumor antigens can provide a personalized vaccine with less potential for immunologic escape. A cytotoxic immunotherapy strategy creates such a tumor vaccine in situ. Immunogenic tumor cell death provides tumor antigen targets for the adaptive immune response and stimulates innate immunity. Attraction and activation of antigen presenting cells such as dendritic cells is important to process and present tumor antigens to T cells. These include cytotoxic T cells that kill tumor cells and T cells which positively and negatively regulate immunity. Tipping the balance in favor of anti-tumor immunity is an important aspect of an effective strategy. Clinically, immunotherapies may be most effective when combined with standard therapies in a complimentary way. An example is gene-mediated cytotoxic immunotherapy (GMCI) which uses an adenoviral vector, AdV-tk, to deliver a cytotoxic and immunostimulatory gene to tumor cells in vivo in combination with standard therapies creating an immunostimulatory milieu. This approach, studied extensively in animal models and early stage clinical trials, is now entering a definitive Phase 3 trial for prostate cancer.

  18. New Cytotoxic Cembranoid from Indonesian Soft Coral Sarcophyton sp.

    PubMed Central

    Januar, Hedi Indra; Zamani, Neviaty Putri; Soedharma, Dedi; Chasanah, Ekowati

    2017-01-01

    Context: Sarcophyton is a soft coral species that contains various secondary metabolites with cytotoxic activity. The production of cytotoxic compounds in soft corals is suggested as their allelochemical to win space competition. Therefore, if a particular soft coral species dominates a reef area, it may suggest to contain interesting bioactive compounds. Aims: This research aimed to characterize the cytotoxic compounds in dominant soft coral species (Sarcophyton sp.) on the reef at the Western side of Mahengetang Island, Indonesia. Subjects and Methods: Isolation of cytotoxic compounds through ethanol extracts had been done with preparative high-performance liquid chromatography and bioassay-guided fractionation by MCF-7 (breast) cancer cell lines. The structures of each cytotoxic compounds were elucidated on the basis of mass and nuclear magnetic resonance spectroscopic studies. Results: Elucidation through all compounds found a new cembranoid, namely, 2-hydroxy-crassocolide E (1), alongside with 5 known cembranoids; sarcophytoxide (2), sarcrassin E (3), 3,7,11-cembreriene-2,15-diol (4), 11,12-epoxy-Sarcophytol A (5), and sarcophytol A (6). All of these cembranoids were showed to inhibit the growth of MCF-7 (breast) cancer, with 50% inhibition of tumor cell lines growth lower than 30 mg/L. Conclusions: Results of this study suggest that a soft coral species which dominate a reef area is a potential source for various bioactive compounds. SUMMARY Elucidation of cytotoxic compounds from Sarcophyton sp. that dominate the reef at Mahengetang Island Indonesia revealed a new compound (2-hydroxy-crassocolide E) alongside with 5 known cembranoid compounds. Abbreviations Used: SCUBA: Self-contained underwater breathing apparatus; HPLC: High performance liquid chromatography; NMR: Nuclear magnetic resonance; IT-TOF: Ion trap-time of flight; MTT: 3-(4,5-dimethylthiazol-2-yl)-2; 5-diphenyltetrazolinon bromide; DEPT: Distortionless enhancement by polarisation transfer; COSY

  19. Genetic and epigenetic variants contributing to clofarabine cytotoxicity.

    PubMed

    Eadon, Michael T; Wheeler, Heather E; Stark, Amy L; Zhang, Xu; Moen, Erika L; Delaney, Shannon M; Im, Hae Kyung; Cunningham, Patrick N; Zhang, Wei; Dolan, M Eileen

    2013-10-01

    2-chloro-2-fluoro-deoxy-9-D-arabinofuranosyladenine (Clofarabine), a purine nucleoside analog, is used in the treatment of hematologic malignancies and as induction therapy for stem cell transplantation. The discovery of pharmacogenomic markers associated with chemotherapeutic efficacy and toxicity would greatly benefit the utility of this drug. Our objective was to identify genetic and epigenetic variants associated with clofarabine toxicity using an unbiased, whole genome approach. To this end, we employed International HapMap lymphoblastoid cell lines (190 LCLs) of European (CEU) or African (YRI) ancestry with known genetic information to evaluate cellular sensitivity to clofarabine. We measured modified cytosine levels to ascertain the contribution of genetic and epigenetic factors influencing clofarabine-mediated cytotoxicity. Association studies revealed 182 single nucleotide polymorphisms (SNPs) and 143 modified cytosines associated with cytotoxicity in both populations at the threshold P ≤ 0.0001. Correlation between cytotoxicity and baseline gene expression revealed 234 genes at P ≤ 3.98 × 10(-6). Six genes were implicated as: (i) their expression was directly correlated to cytotoxicity, (ii) they had a targeting SNP associated with cytotoxicity, and (iii) they had local modified cytosines associated with gene expression and cytotoxicity. We identified a set of three SNPs and three CpG sites targeting these six genes explaining 43.1% of the observed variation in phenotype. siRNA knockdown of the top three genes (SETBP1, BAG3, KLHL6) in LCLs revealed altered susceptibility to clofarabine, confirming relevance. As clofarabine's toxicity profile includes acute kidney injury, we examined the effect of siRNA knockdown in HEK293 cells. siSETBP1 led to a significant change in HEK293 cell susceptibility to clofarabine.

  20. Cytotoxic activity screening of Bangladeshi medicinal plant extracts.

    PubMed

    Akter, Raushanara; Uddin, Shaikh J; Grice, I Darren; Tiralongo, Evelin

    2014-01-01

    The cytotoxic activity of 23 crude methanol extracts from 19 Bangladeshi medicinal plants was investigated against healthy mouse fibroblasts (NIH3T3), healthy monkey kidney (VERO) and four human cancer cell lines (gastric, AGS; colon, HT-29; and breast, MCF-7 and MDA-MB-231) using MTT assay. High cytotoxicity across all cell lines tested was exhibited by Aegiceras corniculatum (fruit) and Hymenodictyon excelsum (bark) extracts (IC50 values ranging from 0.0005 to 0.9980 and 0.08 to 0.44 mg/mL, respectively). Fourteen extracts from 11 plant species, namely Clitoria ternatea (flower and leaf), Dillenia indica (leaf), Diospyros peregrina (leaf), Dipterocarpus turbinatus (bark and leaf), Ecbolium viride (leaf), Glinus oppositifolius (whole plant), Gnaphalium luteoalbum (leaf), Jasminum sambac (leaf), Lannea coromandelica (bark and leaf), Mussaenda glabrata (leaf) and Saraca asoca (leaf), were also significantly cytotoxic (IC50 < 1.0 mg/mL) against at least one of the cancer cell lines tested. More selectively, Avicennia alba (leaf), C. ternatea (flower and leaf), Caesalpinia pulcherrima (leaf), E. viride (leaf) and G. oppositifolius (whole plant) showed cytotoxicity only against both of the breast cancer cell lines (MCF-7 and MDA-MB-231). In contrast, C. ternatea (flower and leaf) exhibited high cytotoxic activity against MDA-MB-231 (IC50 values of 0.11 and 0.49 mg/mL, respectively), whereas E. viride and G. oppositifolius whole plant extracts exhibited high activity against MCF-7 cells (IC50 values of 0.06 and 0.15 mg/mL, respectively). The cytotoxic activity test results for 9 of the plant species correlate with their traditional use as anticancer agents, thus making them interesting sources for further drug development.

  1. [Mechanism of the cytotoxic action of the natural zeolite clinoptilolite].

    PubMed

    Korkina, L G; Suslova, T B; Nikolova, S I; Kirov, G N; Velichkovskiĭ, B T

    1984-01-01

    Interaction between the natural ceolite clinoptilolite and cell suspensions has been investigated using rat peritoneal macrophages and erythrocytes. The ceolite under study has been demonstrated to exhibit a high hemolytic activity and cytotoxicity. The viability of macrophages was evaluated from the incorporation of trypane blue. The ability of macrophages to phagocytosis was measured by chemiluminescence with luminol. The modification of clinoptilolite surface by ammonia ions led to a decrease in its cytotoxic properties. Ethanol, mannit and sodium azide did not affect whereas catalase appreciably reduced the ability of CPT to damage the membranes of macrophages and red cells. The role of hydrogen peroxide in the mechanism of cell membrane damage is discussed.

  2. Chemical transformations on botryane skeleton. Effect on the cytotoxic activity.

    PubMed

    Reino, José L; Durán-Patrón, Rosa; Segura, Inmaculada; Hernández-Galán, Rosario; Riese, Hans H; Collado, Isidro G

    2003-03-01

    Eighteen compounds with a botryane skeleton have been obtained through chemical transformations of various toxins from the fungus Botrytis cinerea. During the course of these transformations, the C-10 carbon of the botryane skeleton was found to exhibit an interesting high regioselectivity to oxidizing and reducing agents. In addition, the cytotoxicity of 27 botryane derivatives was determined in vitro against Hs578T, MDA-MB-231, HT-1080, U87-MG, IMR-90, and HUVEC cell lines. The results of this study confirm that the cytotoxicity of botrydial (1) and its derivatives is related to the presence of a 1,5-dialdehyde functionality.

  3. Cytotoxicity testing of carrier-based microcomposites for DPI application.

    PubMed

    Ambrus, R; Pomázi, A; Réti-Nagy, K; Fenyvesi, F; Vecsernyés, M; Szabó-Révész, P

    2011-07-01

    Inhalation is an attractive delivery route for systemic and local therapy. High local drug concentrations may permit non-invasive delivery, lower therapeutic doses, reduced systemic side-effects, and reduced metabolic degradation of the drug in the liver. In our earlier study, carrier-based microcomposites were prepared and investigated. The present study introduces studies of the cytotoxicity of meloxicam-containing microcomposites on monolayers of Calu-3 cells, in order to acquire information on its availability in pulmonary formulations. By relating cytotoxicity and drug dissolution, the appropriate amount of meloxicam for dry powder inhalation could be determined.

  4. Insecticidal and cytotoxic effects of natural and hemisynthetic destruxins.

    PubMed

    Dumas, C; Robert, P; Pais, M; Vey, A; Quiot, J M

    1994-07-01

    The insecticidal and cytotoxic effects of 13 natural and hemisynthetic destruxins have been studied. DE shows insecticidal effects similar to those of DA, while DE and DA are more active than all the other natural compounds and analogues tested. Brominated destruxin is a relatively active analogue displaying particular modalities of cytotoxic effects which reflect a certain originality of its mode of action. The linear molecule resulting from the opening of the DA cycle is not toxic. The most hydrophilic destruxins showing e.g. charged radicals (COO-) appear the least toxic probably because they do not penetrate easily the cellular membranes.

  5. Cytotoxic activity of antioxidant constituents from Hypericum triquetrifolium Turra.

    PubMed

    Conforti, F; Loizzo, M R; Statti, A G; Menichini, F

    2007-01-01

    The Sulforodamine B (SRB) assay was used to test cytotoxicity against four human cancer cell lines and one normal cell line of antioxidant constituents isolated from Hypericum triquetrifolium Turra. Methanolic extract and pure compounds were tested against the large cell lung carcinoma cell line COR-L23, the hepatocellular carcinoma cell line HepG-2, renal cell adenocarcinoma ACHN, the amelanotic melanoma cell line C32 and normal human foetal lung MRC5. The results showed that I3-II8-biapigenin exhibited strong cytotoxic activity (IC50 = 5.73 micro g mL(-1)) showing a certain degree of selectivity against the different cell types.

  6. Polychlorinated biphenyls (PCBs) depress allogeneic natural cytotoxicity by earthworm coelomocytes

    SciTech Connect

    Suzuki, M.M.; Cooper, E.L.; Eyambe, G.S.; Goven, A.J.; Fitzpatrick, L.C.; Venables, B.J. |

    1995-10-01

    Coelomocytes of the earthworm Lumbricus terrestris caused significant spontaneous allogeneic cytotoxicity in a 24-h trypan blue assay, but not in an assay using lactate dehydrogenase (LDH) release. Allogeneic cytotoxicity assays using cells from worms exposed to polychlorinated biphenyls (PCBs) suggest that PCBs can suppress a natural killing (NK-like) reaction. The implications of this work are twofold: understanding the evolution of natural killing (NK-like) activity and providing preliminary information on how spontaneous killing, a component of cellular immunity, may be compromised by pollutants.

  7. New Cytotoxic 24-Homoscalarane Sesterterpenoids from the Sponge Ircinia felix

    PubMed Central

    Lai, Ya-Yuan; Chen, Li-Chai; Wu, Chug-Fung; Lu, Mei-Chin; Wen, Zhi-Hong; Wu, Tung-Ying; Fang, Lee-Shing; Wang, Li-Hsueh; Wu, Yang-Chang; Sung, Ping-Jyun

    2015-01-01

    Two new 24-homoscalarane sesterterpenoids, felixins F (1) and G (2), were isolated from the sponge Ircinia felix. The structures of new homoscalaranes 1 and 2 were elucidated by extensive spectroscopic methods, particularly with one-dimensional (1D) and two-dimensional (2D) NMR, and, by comparison, the spectral data with those of known analogues. The cytotoxicity of 1 and 2 against the proliferation of a limited panel of tumor cell lines was evaluated and 1 was found to show cytotoxicity toward the leukemia K562, MOLT-4, and SUP-T1 cells (IC50 ≤ 5.0 μM). PMID:26378524

  8. Antiviral and cytotoxic activities of some Indonesian plants.

    PubMed

    Lohézic-Le Dévéhat, F; Bakhtiar, A; Bézivin, C; Amoros, M; Boustie, J

    2002-08-01

    Ten methanolic extracts from eight Indonesian medicinal plants were phytochemically screened and evaluated for antiviral (HSV-1 and Poliovirus) and cytotoxic activities on murine and human cancer lines (3LL, L1210, K562, U251, DU145, MCF-7). Besides Melastoma malabathricum (Melastomataceae), the Indonesian Loranthaceae species among which Elytranthe tubaeflora, E. maingayi, E. globosa and Scurrula ferruginea exhibited attractive antiviral and cytotoxic activities. Piper aduncum (Piperaceae) was found active on Poliovirus. S. ferruginea was selected for further studies because of its activity on the U251 glioblastoma cells.

  9. Four cytotoxic annonaceous acetogenins from the seeds of Annona squamosa.

    PubMed

    Miao, Y; Xu, X; Yuan, F; Shi, Y; Chen, Y; Chen, J; Li, X

    2016-06-01

    Four new annonaceous acetogenins (ACGs), squamocin-I (1), II (2) and III (3) and squamoxinone-D (4), together with seven known ACGs (5-11), were isolated from the seeds of Annona squamosa. The structures of all isolates were elucidated and characterised by spectral and chemical methods. Compounds 1-4 were evaluated for their cytotoxicities against Hep G2, SMMC 7721, BEL 7402, BGC 803 and H460 human cancer cell lines. Compound 1 exhibited better potent activity than the positive compound and compound 3 shows selectively cytotoxical activity against H460 with IC50 values of 0.0492 μg/ml.

  10. Synthesis of novel spirostanic saponins and their cytotoxic activity.

    PubMed

    Hernández, Juan C; León, Francisco; Brouard, Ignacio; Torres, Fernando; Rubio, Sara; Quintana, José; Estévez, Francisco; Bermejo, Jaime

    2008-02-15

    This study was carried out to assess the cytotoxicity of several new synthetic steroidal saponins against the human myeloid leukemia cell lines (HL-60 and U937) and against human melanoma cells (SK-MEL-1). Several diosgenyl glycosides analyzed showed strong cell growth inhibition which was associated with alterations in cell cycle progression and induction of apoptosis. Studies of cytochrome c release and caspase-9 activation suggest a main role of the intrinsic pathway of apoptosis in the mechanism of cytotoxicity caused by this kind of compounds.

  11. Synthesis and cytotoxicity assay of four ganglioside GM3 analogues.

    PubMed

    Qu, Huanhuan; Liu, Jian-Miao; Wdzieczak-Bakala, Joanna; Lu, Dan; He, Xianran; Sun, Wenji; Sollogoub, Matthieu; Zhang, Yongmin

    2014-03-21

    A concise and efficient synthetic route for preparation of four ganglioside GM3 analogues was described. The key step is a highly regioselective and stereoselective α-sialylation from a suitably protected glycoside acceptor with a sialyl xanthate to provide the sialo-oligosaccharide in good yield. The cytotoxic properties of the synthetic gangliosides were evaluated against normal human keratinocytes and human HCT116 and K562 cancer cells. Two of them exhibited good antiproliferative activity and displayed a better cytotoxicity against cancer cell than HaCaT normal cell. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  12. New alkaloids and cytotoxic principles from Sinomenium acutum.

    PubMed

    Cheng, Jing-Jy; Tsai, Tung-Hu; Lin, Lie-Chwen

    2012-11-01

    Two new alkaloids, 2-demethyl-oxypalmatine (1) and 5-ethoxycarbonylsinoracutine (2), were isolated from the rhizomes of Sinomenium acutum, along with thirty-four known compounds. Cytotoxicity of the isolated compounds was examined for the MCF-7, H460, HT-29, and CEM human cancer cell lines. Dauriporphine (16), 6-O-demethylmenisporphine (17), bianfugecine (18), menisporphine (19), and 6-O-demethyldauriporphine (20) showed differential effects in their cytotoxic activity on the target cancer cell lines. Significant angiogenesis inhibitions of 16 and 19 were also observed.

  13. Cytotoxicity of halothane on human gingival fibroblast cultures in vitro.

    PubMed

    Chang, Y C; Chou, M Y

    2001-02-01

    Recently halothane has been reported to be the most suitable alternative to chloroform in dissolving gutta-percha. Periapical tissue toxicity of halothane is not completely known. In this study gutta-percha dissolved by halothane was evaluated with the almar blue dye assay using human gingival fibroblast cultures. The cytotoxic effects of halothane on human gingival fibroblasts depended on the exposure dose, frequency, and duration. A reduced concentration and smaller amount of gutta-percha solvents may minimize the cytotoxic effects on host tissues.

  14. Cytotoxic biomonitored study of Euphorbia umbellata (Pax) Bruyns.

    PubMed

    Luz, Lívia Eidam Camargo; Kanunfre, Carla Cristine; Paludo, Katia Sabrina; da Silva Justo, Aline; Petry, Victor Kubaski; Lemes, Bruna Mikulis; Barison, Andersson; Nepel, Angelita; Wang, Mei; Avula, Bharathi; Khan, Ikhlas Ahmad; Beltrame, Flávio Luís

    2016-05-13

    Euphorbia umbellata latex (sap) has normally been used in folk medicine in southern Brazil to treat different types of cancers. To carry out a biomonitored investigation of partitioned latex using in vitro assay, to identify the main mechanisms related with the action of the most active fraction as well as to develop a phytochemical study with this material. Biological screening was performed with hexane, chloroform, ethyl acetate and methanol fractions from the latex of E. umbellata using MTT, trypan blue, and neutral red assays to determine the cytotoxicity against HRT-18, HeLa and Jurkat cells and flow cytometry, DNA quantification, acridine orange and Hoechst 33342 staining to investigate mechanisms of action for the hexane extract. The phytochemical study of the hexane fraction was performed by chromatographic procedures and the substances were identified by NMR analysis. The isolated terpenes were evaluated using MTT to determine the cytotoxicity against Jurkat cells. All the fractions presented concentration and time dependent cytotoxicity. The hexane fraction showed the highest cytotoxicity; whereas the Jurkat cell was the lineage with the highest sensitivity (IC50 1.87µg/mL). Fragmentation of DNA and apoptosis are two mechanisms related with the toxicity of hexane fraction. The hexane fraction arrested the cell cycle in the G0/G1 phase, and the selectivity index was 4.30. Phytochemical study of the hexane fraction led to isolation of euphol (main compound) and germanicol acetate. Both substances demonstrated some slight cytotoxic activity against Jurkat cells after 72h; however the activity was minimal compared to vincristine (anticancer standard drug). The current research proves that the fractions of the latex from E. umbellata have a cytotoxic effect against three different cancer cells lines. The hexane fraction showed high in vitro cytotoxic effects against Jurkat cells demonstrating that the effect may be due to non-polar constituents. The two

  15. Organometallic osmium arene complexes with potent cancer cell cytotoxicity.

    PubMed

    Fu, Ying; Habtemariam, Abraha; Pizarro, Ana M; van Rijt, Sabine H; Healey, David J; Cooper, Patricia A; Shnyder, Steven D; Clarkson, Guy J; Sadler, Peter J

    2010-11-25

    Iodido osmium(II) complexes [Os(η(6)-arene)(XY)I](+) (XY = p-hydroxy or p-dimethylaminophenylazopyridine, arene = p-cymene or biphenyl) are potently cytotoxic at nanomolar concentrations toward a panel of human cancer cell lines; e.g., IC(50) = 140 nM for [Os(η(6)-bip)(azpy-NMe(2))I](+) toward A2780 ovarian cancer cells. They exhibit low toxicity and negligible deleterious effects in a colon cancer xenograft model, giving rise to the possibility of a broad therapeutic window. The most active complexes are stable and inert toward aquation. Their cytotoxic activity appears to involve redox mechanisms.

  16. New cytotoxic clerodane diterpenes from the leaves of Premna tomentosa.

    PubMed

    Rekha, K; Richa, Pandey; Hymavathy, A; Suresh Babu, K; Madhusudana Rao, J; Neha R, Dhoke; Amitava, Das

    2016-01-01

    Bio-activity directed investigation of hexane extract from the leaves of Premna tomentosa led to the isolation of three new clerodane diterpenes (1-3) along with four known compounds (4-7). The structures of new compounds were established using IR, MS, 1D, and 2D NMR techniques. The in vitro cytotoxicity of the crude hexane extract and the isolated compounds were evaluated against seven human cancer cell lines and results indicated that compounds 2 and 4 depicted significant cytotoxicity against hepatocellular carcinoma cell line.

  17. Synthesis and cytotoxicity evaluation of novel podophyllotoxin derivatives.

    PubMed

    Chengniu, Wang; Zhonghua, Wu; Yu, Zhao; Chunyan, Ni; Xiaodong, Zhao; Li, Zhu

    2011-11-01

    Seven benzylamino derivatives of podophyllotoxin 8a-8g were synthesized and their chemical structures were confirmed by IR, ¹H-NMR, (13)C-NMR and ESI-MS spectral analyses. Their abilities to inhibit the growth of cancer cells A549, HCT-116 and HepG2, were investigated by MTT assay. Compound 8b possessed the highest cytotoxicity on cancer cell lines with average IC(50) values of 3.8 µM. All we synthetic compounds were cytotoxic against three cancer cell lines at the micromolar range, indicating podophyllotoxin derivatives with structural modification of benzylamino possess potent antitumor activity.

  18. Cytotoxic Steroids from the Vietnamese Soft Coral Sinularia conferta.

    PubMed

    Ngoc, Ninh Thi; Huong, Pham Thi Mai; Thanh, Nguyen Van; Chi, Nguyen Thi Phuong; Dang, Nguyen Hai; Cuong, Nguyen Xuan; Nam, Nguyen Hoai; Thung, Do Cong; Kiem, Phan Van; Minh, Chau Van

    2017-03-01

    Twelve steroids, including five new compounds 1-5, were isolated and structurally elucidated from a methanol extract of the Vietnamese soft coral Sinularia conferta. Their cytotoxic effects against three human cancer cell lines, lung carcinoma (A-549), cervical adenocarcinoma (HeLa), and pancreatic epithelioid carcinoma (PANC-1), were evaluated using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assays. Among isolated compounds, 10 exhibited potent cytotoxic effects on all three tested cell lines with IC50 values of 3.64±0.18, 19.34±0.42, and 1.78±0.69 µM, respectively.

  19. Synthesis and in vitro cytotoxicity of haloderivatives of noscapine.

    PubMed

    Verma, Akhilesh Kumar; Bansal, Sandhya; Singh, Jaspal; Tiwari, Rakesh Kumar; Kasi Sankar, V; Tandon, Vibha; Chandra, Ramesh

    2006-10-01

    Three haloderivatives of noscapine 2-4 were synthesized chemoselectively and their in vitro cytotoxicity was assessed by MTT assay on U-87 human glioblastoma cell lines. At 50 microM concentration after 72 h, 9-chloronoscapine 2, 9-bromonoscapine 3 (EM011), and 9-iodonoscapine 4 killed 87.8%, 51.2%, and 56.8% cells, respectively, however noscapine kills only 40% of the cells; revealing 9-chloronoscapine as a potential cytotoxic agent than noscapine and 9-bromonoscapine (EM011). At low concentration (1 microM) 9-bromonoscapine (46.7%) and 9-chloronoscapine (45.7%) did not show any significant difference.

  20. Natural cytotoxic (NC) activity in basophilic cells: mediation by a NC-specific cytotoxic factor

    SciTech Connect

    Okuno, T.; Takagaki, Y.; Pluznik, D.; Djeu, J.Y.

    1986-03-01

    Interleukin 3 (IL3) has recently been shown to be a mast cell/basophil growth factor. Based on the previous observations that IL3-dependent cells are capable of NC activity which are believed to be important in immunosurveillance, the authors attempted to define if the IL3-dependent NC cells were of basophilic origin. To approach this, the authors tested a murine IL3-dependent basophilic cell line and a rat basophilic leukemic cell line against various tumor targets in a 4h or 18h /sup 51/Cr release assay. Both basophilic cell types effectively lysed the NC target, WEHI-164, but not the NK targets, YAC-1, RLM1, RBL5. Moreover, triggering of the basophils by incubation at 37C with IgE-anti-IgE or IgE with specific antigen or by direct binding to anti-IgE receptor antibodies enhanced NC activity and at the same time induced the release of a soluble cytotoxic factor (CF). The CF lysed only WEHI but not YAC-1, RLM1 or RBL5 tumor cells, distinguishing it from NKCF. The release of the NCCF was dependent on the dose of the triggering agents, required extracellular Ca/sup + +/, and was detected within 15 min of triggering. It has a MW of 43,000 as determined by gel filtration. Basophils, therefore, are not only involved in inflammatory responses but also in tumor immunity, via the NC effector mechanism.