The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Daniele Simoni - One of the best experts on this subject based on the ideXlab platform.
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hydropathic analysis and biological evaluation of stilbene derivatives as colchicine site Microtubule Inhibitors with anti leukemic activity
Journal of Enzyme Inhibition and Medicinal Chemistry, 2009Co-Authors: Ashutosh Tripathi, David Durrant, Daniele Simoni, Riccardo Baruchello, Romeo Romagnoli, Glen E KelloggAbstract:The crucial role of the Microtubule in cell division has identified tubulin as a target for the development of therapeutics for cancer; in particular, tubulin is a target for antineoplastic agents that act by interfering with the dynamic stability of Microtubules. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of stilbene-based tubulin Inhibitors that bind at the αβ-tubulin colchicine site. Computational docking along with HINT (Hydropathic INTeractions) score analysis fit ted these Inhibitors into the colchicine site and revealed detailed structure–activity information useful for inhibitor design. Quantitative analysis of the results was in good agreement with the in vitro antiproliferative activity of these derivatives (ranging from 3 nM to 100 μM) such that calculated and measured free energies of binding correlate with an r 2 of 0.89 (standard error ± 0.85 kcal mol −1 ). This correlation suggests that the activity of unknown compounds may be predicted.
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stilbene derivatives that are colchicine site Microtubule Inhibitors have antileukemic activity and minimal systemic toxicity
American Journal of Hematology, 2008Co-Authors: David Durrant, Ashutosh Tripathi, Schickwann Tsai, Glen E Kellogg, Daniele SimoniAbstract:Stilbenes are a group of natural compounds with many biological activities. Two highly potent stilbenes, cis-3,4 0 ,5-trimethoxy-3 0 -aminostilbene (stilbene 5c) and cis-3,4 0 ,5-trimethoxy-3 0 -hydroxystilbene (stilbene 6c) induce G2/M cell-cycle arrest and leukemic cell death in nanomolarity range without affecting normal bone marrow progenitor cells. The mechanism of stilbenes is mediated by interfering with Microtubule polymerization through the colchicine-binding site. Docking of the stilbenes into tubulin structure confirms that stilbenes fit into the colchicine-binding pocket. Animal studies show that stilbenes are well tolerated in mice and are capable of inducing more than 50% leukemic cell death by a single dose injection. A 5-day treatment with low-dose stilbenes suppresses tumor growth in mice with established tumor xenografts. No major organ damage was detected by histological section. Our results indicate that stilbene 5c is a Microtubule-interfering agent and can be potentially useful in leukemic therapy. Am. J. Hematol. 83:390–397, 2008. V V C 2008 Wiley-Liss, Inc.
Glen E Kellogg - One of the best experts on this subject based on the ideXlab platform.
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hydropathic analysis and biological evaluation of stilbene derivatives as colchicine site Microtubule Inhibitors with anti leukemic activity
Journal of Enzyme Inhibition and Medicinal Chemistry, 2009Co-Authors: Ashutosh Tripathi, David Durrant, Daniele Simoni, Riccardo Baruchello, Romeo Romagnoli, Glen E KelloggAbstract:The crucial role of the Microtubule in cell division has identified tubulin as a target for the development of therapeutics for cancer; in particular, tubulin is a target for antineoplastic agents that act by interfering with the dynamic stability of Microtubules. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of stilbene-based tubulin Inhibitors that bind at the αβ-tubulin colchicine site. Computational docking along with HINT (Hydropathic INTeractions) score analysis fit ted these Inhibitors into the colchicine site and revealed detailed structure–activity information useful for inhibitor design. Quantitative analysis of the results was in good agreement with the in vitro antiproliferative activity of these derivatives (ranging from 3 nM to 100 μM) such that calculated and measured free energies of binding correlate with an r 2 of 0.89 (standard error ± 0.85 kcal mol −1 ). This correlation suggests that the activity of unknown compounds may be predicted.
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stilbene derivatives that are colchicine site Microtubule Inhibitors have antileukemic activity and minimal systemic toxicity
American Journal of Hematology, 2008Co-Authors: David Durrant, Ashutosh Tripathi, Schickwann Tsai, Glen E Kellogg, Daniele SimoniAbstract:Stilbenes are a group of natural compounds with many biological activities. Two highly potent stilbenes, cis-3,4 0 ,5-trimethoxy-3 0 -aminostilbene (stilbene 5c) and cis-3,4 0 ,5-trimethoxy-3 0 -hydroxystilbene (stilbene 6c) induce G2/M cell-cycle arrest and leukemic cell death in nanomolarity range without affecting normal bone marrow progenitor cells. The mechanism of stilbenes is mediated by interfering with Microtubule polymerization through the colchicine-binding site. Docking of the stilbenes into tubulin structure confirms that stilbenes fit into the colchicine-binding pocket. Animal studies show that stilbenes are well tolerated in mice and are capable of inducing more than 50% leukemic cell death by a single dose injection. A 5-day treatment with low-dose stilbenes suppresses tumor growth in mice with established tumor xenografts. No major organ damage was detected by histological section. Our results indicate that stilbene 5c is a Microtubule-interfering agent and can be potentially useful in leukemic therapy. Am. J. Hematol. 83:390–397, 2008. V V C 2008 Wiley-Liss, Inc.
David Durrant - One of the best experts on this subject based on the ideXlab platform.
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hydropathic analysis and biological evaluation of stilbene derivatives as colchicine site Microtubule Inhibitors with anti leukemic activity
Journal of Enzyme Inhibition and Medicinal Chemistry, 2009Co-Authors: Ashutosh Tripathi, David Durrant, Daniele Simoni, Riccardo Baruchello, Romeo Romagnoli, Glen E KelloggAbstract:The crucial role of the Microtubule in cell division has identified tubulin as a target for the development of therapeutics for cancer; in particular, tubulin is a target for antineoplastic agents that act by interfering with the dynamic stability of Microtubules. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of stilbene-based tubulin Inhibitors that bind at the αβ-tubulin colchicine site. Computational docking along with HINT (Hydropathic INTeractions) score analysis fit ted these Inhibitors into the colchicine site and revealed detailed structure–activity information useful for inhibitor design. Quantitative analysis of the results was in good agreement with the in vitro antiproliferative activity of these derivatives (ranging from 3 nM to 100 μM) such that calculated and measured free energies of binding correlate with an r 2 of 0.89 (standard error ± 0.85 kcal mol −1 ). This correlation suggests that the activity of unknown compounds may be predicted.
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stilbene derivatives that are colchicine site Microtubule Inhibitors have antileukemic activity and minimal systemic toxicity
American Journal of Hematology, 2008Co-Authors: David Durrant, Ashutosh Tripathi, Schickwann Tsai, Glen E Kellogg, Daniele SimoniAbstract:Stilbenes are a group of natural compounds with many biological activities. Two highly potent stilbenes, cis-3,4 0 ,5-trimethoxy-3 0 -aminostilbene (stilbene 5c) and cis-3,4 0 ,5-trimethoxy-3 0 -hydroxystilbene (stilbene 6c) induce G2/M cell-cycle arrest and leukemic cell death in nanomolarity range without affecting normal bone marrow progenitor cells. The mechanism of stilbenes is mediated by interfering with Microtubule polymerization through the colchicine-binding site. Docking of the stilbenes into tubulin structure confirms that stilbenes fit into the colchicine-binding pocket. Animal studies show that stilbenes are well tolerated in mice and are capable of inducing more than 50% leukemic cell death by a single dose injection. A 5-day treatment with low-dose stilbenes suppresses tumor growth in mice with established tumor xenografts. No major organ damage was detected by histological section. Our results indicate that stilbene 5c is a Microtubule-interfering agent and can be potentially useful in leukemic therapy. Am. J. Hematol. 83:390–397, 2008. V V C 2008 Wiley-Liss, Inc.
Ashutosh Tripathi - One of the best experts on this subject based on the ideXlab platform.
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hydropathic analysis and biological evaluation of stilbene derivatives as colchicine site Microtubule Inhibitors with anti leukemic activity
Journal of Enzyme Inhibition and Medicinal Chemistry, 2009Co-Authors: Ashutosh Tripathi, David Durrant, Daniele Simoni, Riccardo Baruchello, Romeo Romagnoli, Glen E KelloggAbstract:The crucial role of the Microtubule in cell division has identified tubulin as a target for the development of therapeutics for cancer; in particular, tubulin is a target for antineoplastic agents that act by interfering with the dynamic stability of Microtubules. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of stilbene-based tubulin Inhibitors that bind at the αβ-tubulin colchicine site. Computational docking along with HINT (Hydropathic INTeractions) score analysis fit ted these Inhibitors into the colchicine site and revealed detailed structure–activity information useful for inhibitor design. Quantitative analysis of the results was in good agreement with the in vitro antiproliferative activity of these derivatives (ranging from 3 nM to 100 μM) such that calculated and measured free energies of binding correlate with an r 2 of 0.89 (standard error ± 0.85 kcal mol −1 ). This correlation suggests that the activity of unknown compounds may be predicted.
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stilbene derivatives that are colchicine site Microtubule Inhibitors have antileukemic activity and minimal systemic toxicity
American Journal of Hematology, 2008Co-Authors: David Durrant, Ashutosh Tripathi, Schickwann Tsai, Glen E Kellogg, Daniele SimoniAbstract:Stilbenes are a group of natural compounds with many biological activities. Two highly potent stilbenes, cis-3,4 0 ,5-trimethoxy-3 0 -aminostilbene (stilbene 5c) and cis-3,4 0 ,5-trimethoxy-3 0 -hydroxystilbene (stilbene 6c) induce G2/M cell-cycle arrest and leukemic cell death in nanomolarity range without affecting normal bone marrow progenitor cells. The mechanism of stilbenes is mediated by interfering with Microtubule polymerization through the colchicine-binding site. Docking of the stilbenes into tubulin structure confirms that stilbenes fit into the colchicine-binding pocket. Animal studies show that stilbenes are well tolerated in mice and are capable of inducing more than 50% leukemic cell death by a single dose injection. A 5-day treatment with low-dose stilbenes suppresses tumor growth in mice with established tumor xenografts. No major organ damage was detected by histological section. Our results indicate that stilbene 5c is a Microtubule-interfering agent and can be potentially useful in leukemic therapy. Am. J. Hematol. 83:390–397, 2008. V V C 2008 Wiley-Liss, Inc.
Mitsuo Oshimura - One of the best experts on this subject based on the ideXlab platform.
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recurrent micronucleation through cell cycle progression in the presence of Microtubule Inhibitors
Cell Structure and Function, 2015Co-Authors: Yuji Nakayama, Toshiaki Inoue, Yamato Mizoguchi, Shinya Komoto, Yasuhiro Kazuki, Eiji Nanba, Mitsuo OshimuraAbstract:: Although most cell lines undergo mitotic arrest after prolonged exposure to Microtubule Inhibitors, some cells subsequently exit this state and become tetraploid. Among these cells, limited numbers of rodent cells are known to undergo multinucleation to generate multiple small independent nuclei, or micronuclei by prolonged colcemid treatment. Micronuclei are thought to be formed when cells shift to a pseudo G1 phase, during which the onset of chromosomal decondensation allows individual chromosomes distributed throughout the cell to serve as sites for the reassembly of nuclear membranes. To better define this process, we used long-term live cell imaging to observe micronucleation induced in mouse A9 cells by treating with the Microtubule inhibitor colcemid. Our observations confirm that nuclear envelope formation occurs when mitotic-arrested cells shift to a pseudo G1 phase and adopt a tetraploid state, accompanied by chromosome decondensation. Unexpectedly, only a small number of cells containing large micronuclei were formed. We found that tetraploid micronucleated cells proceeded through an additional cell cycle, shifting to a pseudo G1 phase and forming octoploid micronucleated cells that were smaller and more numerous compared with the tetraploid micronucleated cells. Our data suggest that micronucleation occur when cells shift from mitotic arrest to a pseudo G1 phase, and demonstrate that, rather than being a single event, micronucleation is an inducible recurrent process that leads to the formation of progressively smaller and more numerous micronuclei.
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sirt2 knockdown increases basal autophagy and prevents postslippage death by abnormally prolonging the mitotic arrest that is induced by Microtubule Inhibitors
FEBS Journal, 2014Co-Authors: Toshiaki Inoue, Yuji Nakayama, Motonobu Katoh, Yanze Li, Haruka Matsumori, Haruka Takahashi, Hirotada Kojima, Hideki Wanibuchi, Mitsuo OshimuraAbstract:Mitotic catastrophe, a form of cell death that occurs during mitosis and after mitotic slippage to a tetraploid state, plays important roles in the efficacy of cancer cell killing by Microtubule Inhibitors (MTIs). Prolonged mitotic arrest by the spindle assembly checkpoint is a well-known requirement for mitotic catastrophe, and thus for conferring sensitivity to MTIs. We previously reported that turning off spindle assembly checkpoint activation after a defined period of time is another requirement for efficient postslippage death from a tetraploid state, and we identified SIRT2, a member of the sirtuin protein family, as a regulator of this process. Here, we investigated whether SIRT2 regulates basal autophagy and whether, in that case, autophagy regulation by SIRT2 is required for postslippage death, by analogy with previous insights into SIRT1 functions in autophagy. We show, by combined knockdown of autophagy genes and SIRT2, that SIRT2 serves this function at least partially by suppressing basal autophagy levels. Notably, increased autophagy induced by rapamycin and mild starvation caused mitotic arrest for an abnormally long period of time in the presence of MTIs, and this was followed by delayed postslippage death, which was also observed in cells with SIRT2 knockdown. These results underscore a causal association among increased autophagy levels, mitotic arrest for an abnormally long period of time after exposure to MTIs, and resistance to MTIs. Although autophagy acts as a tumor suppressor mechanism, this study highlights its negative aspects, as increased autophagy may cause mitotic catastrophe malfunction. Thus, SIRT2 offers a novel target for tumor therapy.
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sirt2 downregulation confers resistance to Microtubule Inhibitors by prolonging chronic mitotic arrest
Cell Cycle, 2009Co-Authors: Toshiaki Inoue, Yuji Nakayama, Hidetoshi Yamada, Yanze C Li, Shigeyuki Yamaguchi, Mitsuhiko Osaki, Akihiro Kurimasa, Masaharu Hiratsuka, Motonobu Katoh, Mitsuo OshimuraAbstract:We previously identified SIRT2, a deacetylase for tubulin and histone H4, as a protein down-regulated in gliomas, and reported that exogenously-expressed SIRT2 arrests the cell cycle prior to entry into mitosis to prevent chromosomal instability in response to Microtubule Inhibitors (MTIs) such as nocodazole, characteristics previously reported for the CHFR protein. We herein investigated the effects of SIRT2 downregulation on sensitivity to MTIs using HCT116 cells, a mitotic checkpoint-proficient near-diploid cancer cell line used for studying checkpoints. We found that SIRT2 downregulation confers resistance to MTIs as well as that of BubR1, a well-characterized mitotic checkpoint protein, though by a different mechanism. While BubR1 suppression abolished spindle checkpoint functions, which is a requirement for cell death after release from the spindle checkpoint, SIRT2 downregulation prolonged chronic mitotic arrest from sustained activation of the mitotic checkpoint and consequently prevented a shift ...