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Apoptosis Inducer

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Junzo Sasaki – One of the best experts on this subject based on the ideXlab platform.

  • α-Tocopheryl succinate induces rapid and reversible phosphatidylserine externalization in histiocytic lymphoma through the caspase-independent pathway
    Molecular and Cellular Biochemistry, 2010
    Co-Authors: Hirofumi Fujita, Daisuke Shiva, Toshihiko Utsumi, Tetsuya Ogino, Tomohiro Ogawa, Tatsuji Yasuda, Kozo Utsumi, Junzo Sasaki

    Abstract:

    Phosphatidylserine (PS) externalization is a key feature of apoptotic cell death and plays an important role in clearance of apoptotic cells by phagocytes. PS externalization during Apoptosis is generally an irreversible event mediated by caspase activation and is accompanied by other apoptotic events. We report here that an Apoptosis Inducer α-tocopheryl succinate (TOS) can induce PS externalization that is independent of Apoptosis and reversible in the absence of fetal bovine serum (FBS) in histiocytic lymphoma U937 cells. In the presence of FBS, TOS induced PS externalization via a caspase-dependent mechanism accompanied by mitochondrial depolarization, cell shrinkage, increase of caspase-3 activity, and chromatin condensation. In contrast, in the absence of FBS, TOS induced the rapid PS externalization which was not accompanied by other apoptotic events. The PS externalization was reversible by removing TOS and was not involved in Ca^2+-dependent scramblase activation and thiol oxidation of aminophospholipid translocase. A similar PS externalization was also induced by cholesteryl hemisuccinate (CS), the other succinate ester. These results suggested that the mechanism of TOS- and CS-induced PS externalization in the absence of FBS was different from it occurring during typical Apoptosis.

  • Alpha-tocopheryl succinate induces rapid and reversible phosphatidylserine externalization in histiocytic lymphoma through the caspase-independent pathway.
    Molecular and cellular biochemistry, 2009
    Co-Authors: Hirofumi Fujita, Daisuke Shiva, Toshihiko Utsumi, Tetsuya Ogino, Tomohiro Ogawa, Tatsuji Yasuda, Kozo Utsumi, Junzo Sasaki

    Abstract:

    Phosphatidylserine (PS) externalization is a key feature of apoptotic cell death and plays an important role in clearance of apoptotic cells by phagocytes. PS externalization during Apoptosis is generally an irreversible event mediated by caspase activation and is accompanied by other apoptotic events. We report here that an Apoptosis Inducer alpha-tocopheryl succinate (TOS) can induce PS externalization that is independent of Apoptosis and reversible in the absence of fetal bovine serum (FBS) in histiocytic lymphoma U937 cells. In the presence of FBS, TOS induced PS externalization via a caspase-dependent mechanism accompanied by mitochondrial depolarization, cell shrinkage, increase of caspase-3 activity, and chromatin condensation. In contrast, in the absence of FBS, TOS induced the rapid PS externalization which was not accompanied by other apoptotic events. The PS externalization was reversible by removing TOS and was not involved in Ca(2+)-dependent scramblase activation and thiol oxidation of aminophospholipid translocase. A similar PS externalization was also induced by cholesteryl hemisuccinate (CS), the other succinate ester. These results suggested that the mechanism of TOS- and CS-induced PS externalization in the absence of FBS was different from it occurring during typical Apoptosis.

Buket Kosova – One of the best experts on this subject based on the ideXlab platform.

  • Repression of STAT3, STAT5A, and STAT5B expressions in chronic myelogenous leukemia cell line K–562 with unmodified or chemically modified siRNAs and induction of Apoptosis
    Annals of Hematology, 2013
    Co-Authors: Burcin Tezcanli Kaymaz, Nur Selvi, Cumhur Gunduz, Cagdas Aktan, Aysegul Dalmizrak, Guray Saydam, Buket Kosova

    Abstract:

    Signal transducers and activators of transcription (STAT) proteins are latent cytoplasmic transcription factors that affect several cellular processes including cell growth, proliferation, differentiation, and survival. Following phosphorylation, STATs are activated, and their upregulated expressions increase in malignancies with playing a role in the development of leukemia. In this study, transfection of K–562 cells with either unmodified or chemically modified anti-STAT3, -STAT5A, -STAT5B siRNAs for duration of 12 days, determining gene silencing at mRNA and protein levels, evaluating Apoptosis rate, and detecting JAK/STAT pathway members’ gene expression profiles via array method were aimed. Quantitative RT-PCR and Western blot assays indicated that STAT expressions were downregulated both at mRNA and protein levels, and TUNEL assay showed that leukemic cell Apoptosis was induced due to inhibition of STATs. Array analysis resulted with decreases in signal transducer, phosphorylation Inducer, and oncogene expressions, whereas increased expressions in STAT inhibitor and Apoptosis Inducer genes were observed. These results point out that siRNA application could constitute a new and alternative curative method for supporting therapy of CML-diagnosed patients in the future.

  • repression of stat3 stat5a and stat5b expressions in chronic myelogenous leukemia cell line k 562 with unmodified or chemically modified sirnas and induction of Apoptosis
    Annals of Hematology, 2013
    Co-Authors: Burcin Tezcanli Kaymaz, Nur Selvi, Cumhur Gunduz, Cagdas Aktan, Aysegul Dalmizrak, Guray Saydam, Buket Kosova

    Abstract:

    Signal transducers and activators of transcription (STAT) proteins are latent cytoplasmic transcription factors that affect several cellular processes including cell growth, proliferation, differentiation, and survival. Following phosphorylation, STATs are activated, and their upregulated expressions increase in malignancies with playing a role in the development of leukemia. In this study, transfection of K–562 cells with either unmodified or chemically modified anti-STAT3, -STAT5A, -STAT5B siRNAs for duration of 12 days, determining gene silencing at mRNA and protein levels, evaluating Apoptosis rate, and detecting JAK/STAT pathway members’ gene expression profiles via array method were aimed. Quantitative RT-PCR and Western blot assays indicated that STAT expressions were downregulated both at mRNA and protein levels, and TUNEL assay showed that leukemic cell Apoptosis was induced due to inhibition of STATs. Array analysis resulted with decreases in signal transducer, phosphorylation Inducer, and oncogene expressions, whereas increased expressions in STAT inhibitor and Apoptosis Inducer genes were observed. These results point out that siRNA application could constitute a new and alternative curative method for supporting therapy of CML-diagnosed patients in the future.

John Drewe – One of the best experts on this subject based on the ideXlab platform.

  • synthesis of caged 2 3 3a 7a tetrahydro 3 6 methanobenzofuran 7 6h ones evaluating the minimum structure for Apoptosis induction by gambogic acid
    Bioorganic & Medicinal Chemistry, 2008
    Co-Authors: Jared Kuemmerle, Ben Tseng, Shailaja Kasibhatla, Songchun Jiang, John Drewe

    Abstract:

    Abstract We have reported the discovery of gambogic acid (GA) as a potent Apoptosis Inducer and the identification of transferrin receptor as its molecular target. In order to understand the basic pharmacophore of GA for inducing Apoptosis and to discover novel and simplified derivatives as potential anti-cancer agents, we explored the synthesis of caged 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6 H )-ones (4-oxatricyclo[4.3.1.0]decan-2-ones). Three types of 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6 H )-ones based on xanthone, 2-phenylchromene-4-one and benzophenone, were synthesized using a Claisen/Diels–Alder reaction cascade. All the reactions produced the targeted caged compound as well as its neo-isomer. The caged compounds based on xanthone and 2-phenylchromene-4-one were found to maintain the Apoptosis inducing and cell growth inhibiting activity of GA, although with less potency. The caged compounds based on benzophenone were found to be inactive. Our study determined the minimum structure of GA for its Apoptosis inducing activity, which could lead to the development of simple derivatives as potential anti-cancer drugs.

  • discovery of 4 aryl 4h chromenes as a new series of Apoptosis Inducers using a cell and caspase based high throughput screening assay 4 structure activity relationships of n alkyl substituted pyrrole fused at the 7 8 positions
    Journal of Medicinal Chemistry, 2008
    Co-Authors: William Kemnitzer, John Drewe, Songchun Jiang, Hong Zhang, Denis Labreque, Candace Crogangrundy, Real Denis, Monica Bubenick, Giorgio Attardo, Serge Lamothe

    Abstract:

    In our continuing effort to discover and develop Apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the structure−activity relationship (SAR) of alkyl substituted pyrrole fused at the 7,8-positions. A methyl group substituted at the nitrogen in the 7-position of the pyrrole ring led to a series of potent Apoptosis Inducers with potency in the low nanomolar range. These compounds were also found to be low nanomolar or subnanomolar inhibitors of cell growth, and they inhibited tubulin polymerization, indicating that methylation of the 7-position nitrogen does not change the mechanism of action of these chromenes. Compound 2d was identified as a highly potent Apoptosis Inducer with an EC50 value of 2 nM and a highly potent inhibitor of cell growth with a GI50 value of 0.3 nM in T47D cells.

  • discovery of 4 aryl 4h chromenes as a new series of Apoptosis Inducers using a cell and caspase based high throughput screening assay 1 structure activity relationships of the 4 aryl group
    Journal of Medicinal Chemistry, 2004
    Co-Authors: William Kemnitzer, John Drewe, John Herich, Songchun Jiang, Hong Zhang, Jianghong Zhao, Denis Labreque, Richard Storer, Karen Meerovitch

    Abstract:

    By applying a novel cell- and caspase-based HTS assay, 2-amino-3-cyano-7-(dimethylamino)-4-(3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene (1a) has been identified as a potent Apoptosis Inducer. Compound 1a was found to induce nuclear fragmentation and PARP cleavage, as well as to arrest cells at the G2/M stage and to induce Apoptosis as determined by the flow cytometry analysis assay in multiple human cell lines (e.g. Jurkat, T47D). Through structure−activity relationship (SAR) studies of the 4-aryl group, a 4- and 7-fold increase in potency was obtained from the screening hit 1a to the lead compounds 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-(dimethylamino)-4H-chromene (1c) and 2-amino-3-cyano-7-(dimethylamino)-4-(5-methyl-3-pyridyl)-4H-chromene (4e), with an EC50 of 19 and 11 nM in the caspase activation assay in T47D breast cancer cells, respectively. The 2-amino-4-aryl-3-cyano-7-(dimethylamino)-4H-chromenes also were found to be highly active in the growth inhibition MTT assay, with GI50 val…