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  • Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. 1907934

    Interferons have been shown to be potential anti-cancer agents and to inhibit tumor cell growth in culture. The in vivo mechanism of the anti-proliferative effect may be direct or indirect through the immune system; however, in vitro a primary mechanism of cytotoxicity is through the depletion of tryptophan. In particular, interferon-gamma (IFN-gamma) induces an enzyme of tryptophan catabolism, indoleamine 2,3-dioxygenase (IDO), which is responsible for conversion of tryptophan and other indole derivatives to kynurenine. The inhibitory effect of interferon on many intracellular parasites such as Toxoplasma gondii and Chlamydia trachomatis is by the same mechanism. Elevated kynurenine levels have been found in humans in a number of diseases and after interferon treatment, and the enzyme is induced in rodents after administration of interferon inducers, or influenza virus. IDO induction also occurs in vivo during rejection of allogeneic tumors, indicating a possible role for this enzyme in the tumor rejection process. The gene for IDO has been cloned and shown to be differentially regulated by IFN-alpha and IFN-gamma. IDO induction has been correlated with induction of GTP-cyclohydrolase, the key enzyme in pteridine biosynthesis. A direct role for IDO in pteridine synthesis has not been shown, and this parallel induction may reflect coordinate regulation of genes induced by IFN-gamma. A possible role for IDO in O2-radical scavenging and in inflammation is discussed.
    Document Type:
    Reference
    Product Catalog Number:
    05-840
    Product Catalog Name:
    Anti-IDO (Indoleamine 2,3-Dioxygenase) Antibody, clone 10.1

  • Targeting of aryl hydrocarbon receptor-mediated activation of cyclooxygenase-2 expression by the indole-3-carbinol metabolite 3,3'-diindolylmethane in breast cancer cells ... 19056653

    Ligands of the aryl hydrocarbon receptor (AhR) include the environmental xenobiotic 2,3,7,8 tetrachlorodibenzo(p)dioxin (TCDD), polycyclic aryl hydrocarbons, and the dietary compounds 3, 3'-diindolylmethane (DIM), a condensation product of indol-3-carbinol found in Brassica vegetables, and the phytoalexin resveratrol (RES). The AhR and its cofactors regulate the expression of target genes at pentameric (GCGTG) xenobiotic responsive elements (XRE). Because the activation of cyclooxygenase-2 (COX-2) expression by AhR ligands may contribute to inflammation and tumorigenesis, we investigated the epigenetic regulation of the COX-2 gene by TCDD and the reversal effects of DIM in MCF-7 breast cancer cells. Results of DNA binding and chromatin immunoprecipitation (ChIP) studies documented that the treatment with TCDD induced the association of the AhR to XRE harbored in the COX-2 promoter and control CYP1A1 promoter oligonucleotides. The TCDD-induced binding of the AhR was reduced by small-interfering RNA for the AhR or the cotreatment with synthetic (3-methoxy-4-naphthoflavone) or dietary AhR antagonists (DIM, RES). In time course ChIP studies, TCDD induced the rapid (15 min) occupancy by the AhR, the histone acetyl transferase p300, and acetylated histone H4 (AcH4) at the COX-2 promoter. Conversely, the cotreatment of MCF-7 cells with DIM (10 micromol/L) abrogated the TCDD-induced recruitment of the AhR and AcH4 to the COX-2 promoter and the induction of COX-2 mRNA and protein levels. Taken together, these data suggest that naturally occurring modulators of the AhR such as DIM may be effective agents for dietary strategies against epigenetic activation of COX-2 expression by AhR agonists.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • In Vitro Suppression of Growth of Murine WEHI-3 Leukemia Cells and in Vivo Promotion of Phagocytosis in a Leukemia Mice Model by Indole-3-carbinol. 22775144

    Indole-3-carbinol (I3C), a potential anticancer substance, can be found in cruciferous (cabbage family) vegetables, mainly cauliflower and Chinese cabbage. However, the bioactivity of I3C on the apoptotic effects of murine leukemia WEHI-3 cells and promotion of immune responses in leukemia mice model are unclear. In this study, we investigated the effect of I3C on cell-cycle arrest and apoptosis in vitro and immunomodulation in vivo. I3C decreased the viable WEHI-3 cells and caused morphological changes in a concentration- and time-dependent manner. I3C also led to G0/G1 phase arrest, decreased the levels of cyclin A, cyclin D, and CDK2, and increased the level of p21(WAF1/CIP1). Flow cytometric analyses further proved that I3C promoted ROS and intracellular Ca(2+) production and decreased the levels of ΔΨ(m) in WEHI-3 cells. Cells after exposure to I3C for 24 h showed DNA fragmentation and chromatin condensation. Comet assay also indicated that I3C induced DNA damage in examined cells. I3C increased the levels of cytochrome c, FADD, GADD153, GRP78, and caspase-12 as well as induced activities of caspase-3, -8, and -9. Moreover, I3C attenuated NF-κB DNA binding activity in I3C-treated WEHI-3 cells as shown by EMSA and Western blotting analyses. In the in vivo study, we examined the effects of I3C on WEHI-3 leukemia mice. Results showed that I3C increased the level of T cells and decreased the level of macrophages. I3C also reduced the weights of liver and spleen, and it promoted phagocytosis by macrophages as compared to the nontreated leukemia mice group. On the basis of our results, I3C affects murine leukemia WEHI-3 cells both in vitro and in vivo.
    Document Type:
    Reference
    Product Catalog Number:
    07-687
    Product Catalog Name:
    Anti-Cyclin E Antibody

  • Induction of growth arrest and apoptosis in human breast cancer cells by 3,3-diindolylmethane is associated with induction and nuclear localization of p27kip. 18281517

    3,3'-Diindolylmethane (DIM) is a stable condensation product of indole-3-carbanol, a potential breast cancer chemoprevention agent. Human breast cancer cell lines were studied to better understand its mechanisms. In vitro experiments were done in MCF-7, T47D, BT-20 and BT-474 cells using MTT, ELISA, immunoblotting assays, reverse transcription-PCR, protein half-life, confocal microscopy, cell fractionation, and immunoprecipitation assays. We found that DIM inhibited the growth of all four breast cancer cell lines (IC(50)s, 25-56 micromol/L). Because BT-20 and BT-474 overexpressed Her-2 and activated Akt, and BT-20 lacks estrogen receptor, these were studied further. In both cell lines, DIM appeared to induce expression of p27(kip) protein before the loss of cell viability and apoptosis. In BT-20 cells, DIM also inhibited expression of activated Akt, but this appeared after p27(kip) induction. In both cell lines, DIM induced p27(kip) transcript expression within 6 h. DIM prolonged the p27(kip) protein half-life in BT-20 but not BT-474 cells. We also showed, for the first time, that DIM induced nuclear localization of p27(kip) in both cell lines. Moreover, in BT-20 cells, DIM induced a decrease in p27(kip) phosphorylation at Thr(187), and its association with the 14-3-3 protein, which helped to explain the protein half-life increase and nuclear localization, respectively. DIM modulates p27(kip) through transcription, prolongation of protein half-life, and nuclear localization. These effects appear to be independent of Her-2, Akt, or estrogen receptor status and should support further study for its chemoprevention potential in breast cancer.
    Document Type:
    Reference
    Product Catalog Number:
    12-371
    Product Catalog Name:
    Normal Mouse IgG

  • Securin enhances the anti-cancer effects of 6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole (BPR0L075) in human colorectal cancer cells. 22563433

    BPR0L075 [6-methoxy-3-(3',4',5'-trimethoxy-benzoyl)-1H-indole] is a novel anti-microtubule drug with anti-tumor and anti-angiogenic activities in vitro and in vivo. Securin is required for genome stability, and is expressed abundantly in most cancer cells, promoting cell proliferation and tumorigenesis. In this study, we found that BPR0L075 efficiently induced cell death of HCT116 human colorectal cancer cells that have higher expression levels of securin. The cytotoxicity of BPR0L075 was attenuated in isogenic securin-null HCT116 cells. BPR0L075 induced DNA damage response, G(2)/M arrest, and activation of the spindle assembly checkpoint in HCT116 cells. Interestingly, BPR0L075 induced phosphorylation of securin. BPR0L075 withdrawal resulted in degradation of securin, mitotic exit, and mitotic catastrophe, which were attenuated in securin-null cells. Inhibition of cdc2 decreased securin phosphorylation, G(2)/M arrest and cell death induced by BPR0L075. Moreover, BPR0L075 caused cell death through a caspase-independent mechanism and activation of JNK and p38 MAPK pathways. These findings provided evidence for the first time that BPR0L075 treatment is beneficial for the treatment of human colorectal tumors with higher levels of securin. Thus, we suggest that the expression levels of securin may be a predictive factor for application in anti-cancer therapy with BPR0L075 in human cancer cells.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Chemoprevention of aflatoxin B1 hepatocarcinogenesis by coumarin, a natural benzopyrone that is a potent inducer of aflatoxin B1-aldehyde reductase, the glutathione S-tra ... 10706111

    Structurally diverse compounds can confer resistance to aflatoxin B1 (AFB1) hepatocarcinogenesis in the rat. Treatment with either phytochemicals [benzyl isothiocyanate, coumarin (CMRN), or indole-3-carbinol] or synthetic antioxidants and other drugs (butylated hydroxyanisole, diethyl maleate, ethoxyquin, beta-naphthoflavone, oltipraz, phenobarbital, or trans-stilbene oxide) has been found to increase hepatic aldo-keto reductase activity toward AFB1-dialdehyde and glutathione S-transferase (GST) activity toward AFB1-8,9-epoxide in both male and female rats. Under the conditions used, the natural benzopyrone CMRN was a major inducer of the AFB1 aldehyde reductase (AFAR) and the aflatoxin-conjugating class-alpha GST A5 subunit in rat liver, causing elevations of between 25- and 35-fold in hepatic levels of these proteins. Induction was not limited to AFAR and GSTA5: treatment with CMRN caused similar increases in the amount of the class-pi GST P1 subunit and NAD(P)H: quinone oxidoreductase in rat liver. Immunohistochemistry demonstrated that the overexpression of AFAR, GSTA5, GSTP1, and NAD(P)H:quinone oxidoreductase affected by CMRN is restricted to the centrilobular (periacinar) zone of the lobule, sometimes extending almost as far as the portal tract. This pattern of induction was also observed with ethoxyquin, oltipraz, and trans-stilbene oxide. By contrast, induction of these proteins by beta-naphthoflavone and diethyl maleate was predominantly periportal. Northern blotting showed that induction of these phase II drug-metabolizing enzymes by CMRN was accompanied by similar increases in the levels of their mRNAs. To assess the biological significance of enzyme induction by dietary CMRN, two intervention studies were performed in which the ability of the benzopyrone to inhibit either AFB1-initiated preneoplastic nodules (at 13 weeks) or AFB1-initiated liver tumors (at 50 weeks) was investigated. Animals pretreated with CMRN for 2 weeks prior to administration of AFB1, and with continued treatment during exposure to the carcinogen for a further 11 weeks, were protected completely from development of hepatic preneoplastic lesions by 13 weeks. In the longer-term dietary intervention, treatment with CMRN before and during exposure to AFB1 for a total of 24 weeks was found to significantly inhibit the number and size of tumors that subsequently developed by 50 weeks. These data suggest that consumption of a CMRN-containing diet provides substantial protection against the initiation of AFB1 hepatocarcinogenesis in the rat.
    Document Type:
    Reference
    Product Catalog Number:
    ABS1650
    Product Catalog Name:
    Anti-Gstp1 Antibody

  • Identification of eusynstyelamide B as a potent cell cycle inhibitor following the generation and screening of an ascidian-derived extract library using a real time cell ... 25329705

    Ascidians are marine invertebrates that have been a source of numerous cytotoxic compounds. Of the first six marine-derived drugs that made anticancer clinical trials, three originated from ascidian specimens. In order to identify new anti-neoplastic compounds, an ascidian extract library (143 samples) was generated and screened in MDA-MB-231 breast cancer cells using a real-time cell analyzer (RTCA). This resulted in 143 time-dependent cell response profiles (TCRP), which are read-outs of changes to the growth rate, morphology, and adhesive characteristics of the cell culture. Twenty-one extracts affected the TCRP of MDA-MB-231 cells and were further investigated regarding toxicity and specificity, as well as their effects on cell morphology and cell cycle. The results of these studies were used to prioritize extracts for bioassay-guided fractionation, which led to the isolation of the previously identified marine natural product, eusynstyelamide B (1). This bis-indole alkaloid was shown to display an IC50 of 5 µM in MDA-MB-231 cells. Moreover, 1 caused a strong cell cycle arrest in G2/M and induced apoptosis after 72 h treatment, making this molecule an attractive candidate for further mechanism of action studies.
    Document Type:
    Reference
    Product Catalog Number:
    04-1116