The Experts below are selected from a list of 109224 Experts worldwide ranked by ideXlab platform
Junzo Sasaki - One of the best experts on this subject based on the ideXlab platform.
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α-Tocopheryl succinate induces rapid and reversible phosphatidylserine externalization in histiocytic lymphoma through the caspase-independent pathway
Molecular and Cellular Biochemistry, 2010Co-Authors: Hirofumi Fujita, Daisuke Shiva, Toshihiko Utsumi, Tetsuya Ogino, Tatsuji Yasuda, Kozo Utsumi, Tomohiro Ogawa, Junzo SasakiAbstract: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.
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Alpha-tocopheryl succinate induces rapid and reversible phosphatidylserine externalization in histiocytic lymphoma through the caspase-independent pathway.
Molecular and cellular biochemistry, 2009Co-Authors: Hirofumi Fujita, Daisuke Shiva, Toshihiko Utsumi, Tetsuya Ogino, Tatsuji Yasuda, Kozo Utsumi, Tomohiro Ogawa, Junzo SasakiAbstract: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.
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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, 2013Co-Authors: Burcin Tezcanli Kaymaz, Nur Selvi, Cumhur Gunduz, Cagdas Aktan, Aysegul Dalmizrak, Guray Saydam, Buket KosovaAbstract: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.
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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, 2013Co-Authors: Burcin Tezcanli Kaymaz, Nur Selvi, Cumhur Gunduz, Cagdas Aktan, Aysegul Dalmizrak, Guray Saydam, Buket KosovaAbstract: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.
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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, 2008Co-Authors: Jared Kuemmerle, Songchun Jiang, Ben Tseng, Shailaja Kasibhatla, John DreweAbstract: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.
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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, 2008Co-Authors: William Kemnitzer, John Drewe, Denis Labreque, Songchun Jiang, Candace Crogangrundy, Real Denis, Hong Zhang, Monica Bubenick, Giorgio Attardo, Serge LamotheAbstract: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.
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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, 2004Co-Authors: William Kemnitzer, John Herich, John Drewe, Denis Labreque, Jianghong Zhao, Richard Storer, Songchun Jiang, Hong Zhang, Karen MeerovitchAbstract: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...
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discovery characterization and sar of gambogic acid as a potent Apoptosis Inducer by a hts assay
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Hanzhong Zhang, John Guastella, John Herich, Ben Tseng, Shailaja Kasibhatla, Yan Wang, John DreweAbstract:Gambogic acid (2), a natural product isolated from the resin of Garcinia hurburyi tree, was discovered to be a potent Apoptosis Inducer using our cell- and caspase-based high-throughput screening assays. Gambogic acid was found to have an EC50 of 0.78 μM in the caspase activation assay in T47D breast cancer cells. The Apoptosis-inducing activity of gambogic acid was further characterized by a nuclear fragmentation assay and flow cytometry analysis in human breast tumor cells T47D. Gambogic acid was found to induce Apoptosis independent of cell cycle, which is different from paclitaxel that arrests cells in the G2/M phase. To understand the structure–activity relationship (SAR) of gambogic acid, derivatives of 2 with modifications to different function groups were prepared. SAR studies of gambogic acid, as measured by the caspase activation assay, showed that the 9,10 carbon–carbon double bond of the α,β-unsaturated ketone is important for biological activity, while the 6-hydroxy and 30-carboxy group can tolerate a variety of modifications. The importance of the 9,10 carbon–carbon double bond was confirmed by the traditional growth inhibition assay. The high potency of 2 as an Inducer of Apoptosis, its novel mechanism of action, easy isolation and abundant supply, as well as the fact that it is amenable to chemical modification, makes gambogic acid an attractive molecule for the development of anticancer agents.
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discovery characterization and sar of gambogic acid as a potent Apoptosis Inducer by a hts assay
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Hanzhong Zhang, John Guastella, John Herich, Ben Tseng, Shailaja Kasibhatla, Yan Wang, John DreweAbstract:Gambogic acid (2), a natural product isolated from the resin of Garcinia hurburyi tree, was discovered to be a potent Apoptosis Inducer using our cell- and caspase-based high-throughput screening assays. Gambogic acid was found to have an EC50 of 0.78 μM in the caspase activation assay in T47D breast cancer cells. The Apoptosis-inducing activity of gambogic acid was further characterized by a nuclear fragmentation assay and flow cytometry analysis in human breast tumor cells T47D. Gambogic acid was found to induce Apoptosis independent of cell cycle, which is different from paclitaxel that arrests cells in the G2/M phase. To understand the structure–activity relationship (SAR) of gambogic acid, derivatives of 2 with modifications to different function groups were prepared. SAR studies of gambogic acid, as measured by the caspase activation assay, showed that the 9,10 carbon–carbon double bond of the α,β-unsaturated ketone is important for biological activity, while the 6-hydroxy and 30-carboxy group can tolerate a variety of modifications. The importance of the 9,10 carbon–carbon double bond was confirmed by the traditional growth inhibition assay. The high potency of 2 as an Inducer of Apoptosis, its novel mechanism of action, easy isolation and abundant supply, as well as the fact that it is amenable to chemical modification, makes gambogic acid an attractive molecule for the development of anticancer agents.
Le G Moignemuller - One of the best experts on this subject based on the ideXlab platform.
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trail induces necroptosis involving ripk1 ripk3 dependent parp 1 activation
Cell Death & Differentiation, 2012Co-Authors: S Jouanlanhouet, Corinne Martinchouly, Le G Moignemuller, Muhammad Imran Arshad, Claire PiquetpellorceAbstract:Although TRAIL (tumor necrosis factor (TNF)-related Apoptosis inducing ligand) is a well-known Apoptosis Inducer, we have previously demonstrated that acidic extracellular pH (pHe) switches TRAIL-induced Apoptosis to regulated necrosis (or necroptosis) in human HT29 colon and HepG2 liver cancer cells. Here, we investigated the role of RIPK1 (receptor interacting protein kinase 1), RIPK3 and PARP-1 (poly (ADP-ribose) polymerase-1) in TRAIL-induced necroptosis in vitro and in concanavalin A (Con A)-induced murine hepatitis. Pretreatment of HT29 or HepG2 with pharmacological inhibitors of RIPK1 or PARP-1 (Nec-1 or PJ-34, respectively), or transient transfection with siRNAs against RIPK1 or RIPK3, inhibited both TRAIL-induced necroptosis and PARP-1-dependent intracellular ATP depletion demonstrating that RIPK1 and RIPK3 were involved upstream of PARP-1 activation and ATP depletion. In the mouse model of Con A-induced hepatitis, where death of mouse hepatocytes is dependent on TRAIL and NKT (Natural Killer T) cells, PARP-1 activity was positively correlated with liver injury and hepatitis was prevented both by Nec-1 or PJ-34. These data provide new insights into TRAIL-induced necroptosis with PARP-1 being active effector downstream of RIPK1/RIPK3 initiators and suggest that pharmacological inhibitors of RIPKs and PARP-1 could be new treatment options for immune-mediated hepatitis.
Songchun Jiang - One of the best experts on this subject based on the ideXlab platform.
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discovery of n 4 methoxyphenyl n 2 dimethylquinazolin 4 amine a potent Apoptosis Inducer and efficacious anticancer agent with high blood brain barrier penetration
Journal of Medicinal Chemistry, 2009Co-Authors: Nilantha Sudath Sirisoma, Songchun Jiang, Shailaja Kasibhatla, Hong Zhang, Azra Pervin, Adam J Willardsen, Mark B Anderson, Gary Mather, Christopher M Pleiman, Ben TsengAbstract:As a continuation of our structure−activity relationship (SAR) studies on 4-anilinoquinazolines as potent Apoptosis Inducers and to identify anticancer development candidates, we explored the replacement of the 2-Cl group in our lead compound 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (6b, EP128265, MPI-0441138) by other functional groups. This SAR study and lead optimization resulted in the identification of N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine (6h, EP128495, MPC-6827) as an anticancer clinical candidate. Compound 6h was found to be a potent Apoptosis Inducer with EC50 of 2 nM in our cell-based Apoptosis induction assay. It also has excellent blood brain barrier penetration, and is highly efficacious in human MX-1 breast and other mouse xenograft cancer models.
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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, 2008Co-Authors: Jared Kuemmerle, Songchun Jiang, Ben Tseng, Shailaja Kasibhatla, John DreweAbstract: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.
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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, 2008Co-Authors: William Kemnitzer, John Drewe, Denis Labreque, Songchun Jiang, Candace Crogangrundy, Real Denis, Hong Zhang, Monica Bubenick, Giorgio Attardo, Serge LamotheAbstract: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.
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discovery of 4 aryl 4h chromenes as a new series of Apoptosis Inducers using a cell and caspase based high throughput screening assay 2 structure activity relationships of the 7 and 5 6 8 positions
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: William Kemnitzer, Lifen Xu, Nancy Barriault, Jianghong Zhao, Songchun Jiang, Shailaja Kasibhatla, Candace Crogangrundy, Real Denis, Hong Zhang, Louis VaillancourtAbstract:As a continuation of our efforts to discover and develop the Apoptosis-inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the SAR of fused rings at the 7,8-positions. It was found that a five-member aromatic ring, such as pyrrolo with nitrogen at either the 7- or 9-position, is preferred. A six-member aromatic ring, such as benzo or pyrido, also led to potent compounds. The SAR of the 4-aryl group was found to be similar for chromenes with a fused ring at the 7,8-positions. These compounds were found to inhibit tubulin polymerization, indicating that cyclization of the 7,8-positions into a ring does not change the mechanism of action. Compound 2h was identified to be a highly potent Apoptosis Inducer with an EC50 of 5 nM and a highly potent inhibitor of cell proliferation with a GI50 of 8 nM in T47D cells.
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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, 2004Co-Authors: William Kemnitzer, John Herich, John Drewe, Denis Labreque, Jianghong Zhao, Richard Storer, Songchun Jiang, Hong Zhang, Karen MeerovitchAbstract: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...
