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John H. Miller - One of the best experts on this subject based on the ideXlab platform.
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Induction of accelerated senescence by the microtubule-Stabilizing Agent peloruside A
Investigational New Drugs, 2017Co-Authors: Ariane Chan, Connie Gilfillan, Nikki Templeton, Ian Paterson, P. T. Northcote, John H. MillerAbstract:Chemotherapeutic Agents can induce accelerated senescence in tumor cells, an irreversible state of cell cycle arrest. Paclitaxel, a microtubule-Stabilizing Agent used to treat solid tumors of the breast, ovary, and lung and discodermolide, another Stabilizing Agent from a marine sponge, induce senescence in cultured cancer cells. The aim of this study was to determine if the microtubule-Stabilizing Agent peloruside A, a polyketide natural product from a marine sponge, can induce accelerated senescence in a breast cancer cell line MCF7. Doxorubicin, a DNA-damaging Agent, paclitaxel, and discodermolide were used as positive controls. Senescence-associated-β-galactosidase activity was increased by peloruside A, similar to paclitaxel, discodermolde, and doxorubicin, with a potency heirarchy of doxorubicin > paclitaxel > discodermolide > peloruside, based on IC_25 concentrations that inhibit proliferation. Clonogenic survival was significantly decreased by peloruside A, similar to doxorubicin and the two other microtubule-Stabilizing Agents. The tumor suppressor protein p53 increased after treatment, whereas pRb decreased in response to all four compounds. It was concluded that in addition to apoptosis, peloruside A causes accelerated senescence in a subpopulation of MCF7 cells that contributes to its potential anticancer activity in a breast cancer cell line.
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Peloruside A, a microtubule-Stabilizing Agent, induces aneuploidy in ovarian cancer cells
Investigational New Drugs, 2016Co-Authors: Ariane Chan, P. T. Northcote, A. Jonathan Singh, John H. MillerAbstract:To ensure proper chromosome segregation, mitosis is tightly regulated by the spindle assembly checkpoint (SAC). Low concentrations of microtubule-Stabilizing Agents can induce aneuploid populations of cells in the absence of G_2/M block, suggesting pertubation of the spindle checkpoint. We investigated the effects of peloruside A, a microtubule-Stabilizing Agent, on expression levels of several key cell cycle proteins, MAD2, BUBR1, p55CDC and cyclin B1. Synchronized 1A9 ovarian carcinoma cells were allowed to progress through the cell cycle in the presence or absence of peloruside A. Co-immunoprecipitation and Western blotting were used to probe the cell cycle kinetics of MAD2 and BUBR1 dissociation from p55CDC. Using confocal microscopy, we investigated whether premature dissociation of MAD2 and BUBR1 at low (40 nM) but not high (100 nM) concentrations of peloruside A was caused by defects in the attachment of chromosomes to the mitotic spindle. An increased frequency of polar chromosomes was observed at low concentrations of peloruside A, suggesting that an increased frequency of pseudo-metaphase cells, which are not detected by the spindle assembly checkpoint, may be underlying the induction of aneuploidy.
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Inhibition of human vascular endothelial cell migration and capillary-like tube formation by the microtubule-Stabilizing Agent peloruside A
Investigational New Drugs, 2015Co-Authors: Ariane Chan, P. T. Northcote, A. Jonathan Singh, John H. MillerAbstract:Peloruside A is a microtubule-Stabilizing Agent that is currently under investigation as a potential anticancer Agent. Peloruside A binds to a site on β-tubulin that is distinct to that of the taxanes (paclitaxel and docetaxel) and the epothilones. An attractive clinical quality of microtubule-Stabilizing Agents is their ability to target multiple mechanisms of tumour growth. In addition to inducing tumour cell apoptosis by arresting cells in mitosis, microtubule-Stabilizing Agents also inhibit angiogenesis, a process needed by tumor cells for growth and metastasis. In this study, the effects of peloruside A on endothelial cell processes important for angiogenesis were assessed in comparison to docetaxel. Both peloruside A and docetaxel potently inhibited the proliferation of human umbilical vein endothelial cells, with IC_50 values of 1.4 and 1.7 nM, respectively. Peloruside also potently blocked endothelial cell migration during wound closure and the three-dimensional organization of the endothelial cells into capillary-like tubes. In the wound scratch assay, peloruside A inhibited wound recovery with an IC_50 of 6.3 nM after 18 h. Docetaxel was approximately 3-fold more potent than peloruside A. The number of capillary-like tubes that formed after 16 h culture in Matrigel™ was also inhibited in a dose-dependent manner with an IC_50 of 4.5 nM. Docetaxel was about 2-fold more potent than peloruside A in preventing tube formation. This inhibition of endothelial cell function occurred at relatively non-cytotoxic concentrations over the 16–18 h incubations for both Stabilizing Agents, suggesting that anti-angiogenic effects are likely to occur before therapeutically relevant doses begin to inhibit tumor growth or adverse side effects develop.
Susan Band Horwitz - One of the best experts on this subject based on the ideXlab platform.
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Taxol®: The First Microtubule Stabilizing Agent.
International journal of molecular sciences, 2017Co-Authors: Chia Ping Huang Yang, Susan Band HorwitzAbstract:Taxol®, an antitumor drug with significant activity, is the first microtubule Stabilizing Agent described in the literature. This short review of the mechanism of action of Taxol® emphasizes the research done in the Horwitz’ laboratory. It discusses the contribution of photoaffinity labeled analogues of Taxol® toward our understanding of the binding site of the drug on the microtubule. The importance of hydrogen/deuterium exchange experiments to further our insights into the stabilization of microtubules by Taxol® is addressed. The development of drug resistance, a major problem that arises in the clinic, is discussed. Studies describing differential drug binding to distinct β-tubulin isotypes are presented. Looking forward, it is suggested that the β-tubulin isotype content of a tumor may influence its responses to Taxol®.
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abstract 1228 resistance to discodermolide a microtubule Stabilizing Agent and senescence inducer is 4e bp1 dependent
Cancer Research, 2011Co-Authors: Suzan K Chao, Jurriaan Brouwervisser, Hayley M Mcdaid, Susan Band HorwitzAbstract:Discodermolide is a microtubule Stabilizing Agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild type 4E-BP1 in AD32 cells increased the proliferation rate and reverted resistance to discodermolide via restoration of discodermolide-induced accelerated senescence. Consistent with this, cell growth and response to discodermolide was confirmed in vivo using tumor xenograft models. Furthermore, re-introduction of a non-phosphorylatable mutant (Thr 37/46 Ala) of 4E-BP1 was able to partially restore sensitivity and enhance proliferation in AD32 cells, suggesting that these effects are independent of phosphorylation by mTORC1. Microarray profiling of AD32 resistant cells versus sensitive A549 cells, and subsequent unbiased gene ontology analysis, identified molecular pathways and functional groupings of differentially expressed mRNAs implicated in overcoming discodermolide-induced senescence. The most-statistically significant classes of differentially expressed genes included p53 signaling, G2/M checkpoint regulation and genes involved in the role of BRCA1 in the DNA damage response. Consistent with this, p53 protein expression was up-regulated and had increased nuclear localization in AD32 cells relative to parental A549 cells. Furthermore, the stability of p53 was enhanced in AD32 cells. Our studies propose a role for 4E-BP1 as a regulator of discodermolide-induced accelerated senescence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1228. doi:10.1158/1538-7445.AM2011-1228
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resistance to discodermolide a microtubule Stabilizing Agent and senescence inducer is 4e bp1 dependent
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Suzan K Chao, Amos B Smith, Jurriaan Brouwervisser, Susan Band Horwitz, Hayley M McdaidAbstract:Discodermolide is a microtubule-Stabilizing Agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild-type 4E-BP1 in AD32 cells increased the proliferation rate and reverted resistance to discodermolide via restoration of discodermolide-induced accelerated senescence. Consistent with this, cell growth and response to discodermolide was confirmed in vivo using tumor xenograft models. Furthermore, reintroduction of a nonphosphorylatable mutant (Thr-37/46 Ala) of 4E-BP1 was able to partially restore sensitivity and enhance proliferation in AD32 cells, suggesting that these effects are independent of phosphorylation by mTORC1. Microarray profiling of AD32-resistant cells versus sensitive A549 cells, and subsequent unbiased gene ontology analysis, identified molecular pathways and functional groupings of differentially expressed mRNAs implicated in overcoming discodermolide-induced senescence. The most statistically significant classes of differentially expressed genes included p53 signaling, G2/M checkpoint regulation, and genes involved in the role of BRCA1 in the DNA damage response. Consistent with this, p53 protein expression was up-regulated and had increased nuclear localization in AD32 cells relative to parental A549 cells. Furthermore, the stability of p53 was enhanced in AD32 cells. Our studies propose a role for 4E-BP1 as a regulator of discodermolide-induced accelerated senescence.
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Resistance to discodermolide, a microtubule-Stabilizing Agent and senescence inducer, is 4E-BP1–dependent
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Suzan K Chao, Amos B Smith, Jurriaan Brouwer-visser, Susan Band Horwitz, Hayley M McdaidAbstract:Discodermolide is a microtubule-Stabilizing Agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild-type 4E-BP1 in AD32 cells increased the proliferation rate and reverted resistance to discodermolide via restoration of discodermolide-induced accelerated senescence. Consistent with this, cell growth and response to discodermolide was confirmed in vivo using tumor xenograft models. Furthermore, reintroduction of a nonphosphorylatable mutant (Thr-37/46 Ala) of 4E-BP1 was able to partially restore sensitivity and enhance proliferation in AD32 cells, suggesting that these effects are independent of phosphorylation by mTORC1. Microarray profiling of AD32-resistant cells versus sensitive A549 cells, and subsequent unbiased gene ontology analysis, identified molecular pathways and functional groupings of differentially expressed mRNAs implicated in overcoming discodermolide-induced senescence. The most statistically significant classes of differentially expressed genes included p53 signaling, G2/M checkpoint regulation, and genes involved in the role of BRCA1 in the DNA damage response. Consistent with this, p53 protein expression was up-regulated and had increased nuclear localization in AD32 cells relative to parental A549 cells. Furthermore, the stability of p53 was enhanced in AD32 cells. Our studies propose a role for 4E-BP1 as a regulator of discodermolide-induced accelerated senescence.
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the microtubule Stabilizing Agent discodermolide is a potent inducer of accelerated cell senescence
Cell Cycle, 2005Co-Authors: Laura E Klein, Amos B Smith, Scott B Freeze, Susan Band HorwitzAbstract:Discodermolide is a microtubule Stabilizing Agent that suppresses dynamic instability and blocks cells in mitosis. Selection of A549 non-small cell lung carcinoma cells with increasing concentrations of discodermolide yielded a clone that proliferated in 8nM. When these cells were exposed to any concentration greater than 8nM, replication ceased and the cells developed a flattened, enlarged, granular morphology. Accelerated senescence was demonstrated by a functional β-galactosidase activity at pH 6. When parental A549 cells were treated with IC50-concentrations of doxorubicin, Taxol or discodermolide, the latter two drugs quickly produced aberrant mitosis. However, discodermolide, but not Taxol, also produced a large increase in senescence-associated β-galactosidase activity and altered levels of known senescence markers. Although some of these differences between Taxol and discodermolide were dose dependent, only discodermolide produced a doxorubicin-like induction of a senescence phenotype, i...
Ariane Chan - One of the best experts on this subject based on the ideXlab platform.
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Induction of accelerated senescence by the microtubule-Stabilizing Agent peloruside A
Investigational New Drugs, 2017Co-Authors: Ariane Chan, Connie Gilfillan, Nikki Templeton, Ian Paterson, P. T. Northcote, John H. MillerAbstract:Chemotherapeutic Agents can induce accelerated senescence in tumor cells, an irreversible state of cell cycle arrest. Paclitaxel, a microtubule-Stabilizing Agent used to treat solid tumors of the breast, ovary, and lung and discodermolide, another Stabilizing Agent from a marine sponge, induce senescence in cultured cancer cells. The aim of this study was to determine if the microtubule-Stabilizing Agent peloruside A, a polyketide natural product from a marine sponge, can induce accelerated senescence in a breast cancer cell line MCF7. Doxorubicin, a DNA-damaging Agent, paclitaxel, and discodermolide were used as positive controls. Senescence-associated-β-galactosidase activity was increased by peloruside A, similar to paclitaxel, discodermolde, and doxorubicin, with a potency heirarchy of doxorubicin > paclitaxel > discodermolide > peloruside, based on IC_25 concentrations that inhibit proliferation. Clonogenic survival was significantly decreased by peloruside A, similar to doxorubicin and the two other microtubule-Stabilizing Agents. The tumor suppressor protein p53 increased after treatment, whereas pRb decreased in response to all four compounds. It was concluded that in addition to apoptosis, peloruside A causes accelerated senescence in a subpopulation of MCF7 cells that contributes to its potential anticancer activity in a breast cancer cell line.
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Peloruside A, a microtubule-Stabilizing Agent, induces aneuploidy in ovarian cancer cells
Investigational New Drugs, 2016Co-Authors: Ariane Chan, P. T. Northcote, A. Jonathan Singh, John H. MillerAbstract:To ensure proper chromosome segregation, mitosis is tightly regulated by the spindle assembly checkpoint (SAC). Low concentrations of microtubule-Stabilizing Agents can induce aneuploid populations of cells in the absence of G_2/M block, suggesting pertubation of the spindle checkpoint. We investigated the effects of peloruside A, a microtubule-Stabilizing Agent, on expression levels of several key cell cycle proteins, MAD2, BUBR1, p55CDC and cyclin B1. Synchronized 1A9 ovarian carcinoma cells were allowed to progress through the cell cycle in the presence or absence of peloruside A. Co-immunoprecipitation and Western blotting were used to probe the cell cycle kinetics of MAD2 and BUBR1 dissociation from p55CDC. Using confocal microscopy, we investigated whether premature dissociation of MAD2 and BUBR1 at low (40 nM) but not high (100 nM) concentrations of peloruside A was caused by defects in the attachment of chromosomes to the mitotic spindle. An increased frequency of polar chromosomes was observed at low concentrations of peloruside A, suggesting that an increased frequency of pseudo-metaphase cells, which are not detected by the spindle assembly checkpoint, may be underlying the induction of aneuploidy.
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Inhibition of human vascular endothelial cell migration and capillary-like tube formation by the microtubule-Stabilizing Agent peloruside A
Investigational New Drugs, 2015Co-Authors: Ariane Chan, P. T. Northcote, A. Jonathan Singh, John H. MillerAbstract:Peloruside A is a microtubule-Stabilizing Agent that is currently under investigation as a potential anticancer Agent. Peloruside A binds to a site on β-tubulin that is distinct to that of the taxanes (paclitaxel and docetaxel) and the epothilones. An attractive clinical quality of microtubule-Stabilizing Agents is their ability to target multiple mechanisms of tumour growth. In addition to inducing tumour cell apoptosis by arresting cells in mitosis, microtubule-Stabilizing Agents also inhibit angiogenesis, a process needed by tumor cells for growth and metastasis. In this study, the effects of peloruside A on endothelial cell processes important for angiogenesis were assessed in comparison to docetaxel. Both peloruside A and docetaxel potently inhibited the proliferation of human umbilical vein endothelial cells, with IC_50 values of 1.4 and 1.7 nM, respectively. Peloruside also potently blocked endothelial cell migration during wound closure and the three-dimensional organization of the endothelial cells into capillary-like tubes. In the wound scratch assay, peloruside A inhibited wound recovery with an IC_50 of 6.3 nM after 18 h. Docetaxel was approximately 3-fold more potent than peloruside A. The number of capillary-like tubes that formed after 16 h culture in Matrigel™ was also inhibited in a dose-dependent manner with an IC_50 of 4.5 nM. Docetaxel was about 2-fold more potent than peloruside A in preventing tube formation. This inhibition of endothelial cell function occurred at relatively non-cytotoxic concentrations over the 16–18 h incubations for both Stabilizing Agents, suggesting that anti-angiogenic effects are likely to occur before therapeutically relevant doses begin to inhibit tumor growth or adverse side effects develop.
David C Myles - One of the best experts on this subject based on the ideXlab platform.
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Total synthesis of the potent microtubule-Stabilizing Agent (+)-discodermolide.
Journal of Organic Chemistry, 2003Co-Authors: Scott S Harried, Ge Yang, David C MylesAbstract:The total synthesis of the potent microtubule-Stabilizing, antimitotic Agent (+)-discodermolide is described. The convergent synthetic strategy takes advantage of the diastereoselective alkylation of a ketone enolate to establish the key C15-C16 bond. The synthesis is amenable to preparation of gram-scale quantities of (+)-discodermolide and analogues.
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total synthesis of the potent microtubule Stabilizing Agent discodermolide
Journal of Organic Chemistry, 2003Co-Authors: Scott S Harried, Ge Yang, David C MylesAbstract:The total synthesis of the potent microtubule-Stabilizing, antimitotic Agent (+)-discodermolide is described. The convergent synthetic strategy takes advantage of the diastereoselective alkylation of a ketone enolate to establish the key C15-C16 bond. The synthesis is amenable to preparation of gram-scale quantities of (+)-discodermolide and analogues.
Amos B Smith - One of the best experts on this subject based on the ideXlab platform.
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The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012Co-Authors: Bin Zhang, Jenna C Carroll, Yuemang Yao, Justin S Potuzak, Annemarie L Hogan, Michiyo Iba, Sharon X Xie, Carlo Ballatore, John Q. Trojanowski, Amos B SmithAbstract:Neurodegenerative tauopathies, such as Alzheimer's disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-Stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-Stabilizing compound will provide benefit in a transgenic model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-Stabilizing Agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-Stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.
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resistance to discodermolide a microtubule Stabilizing Agent and senescence inducer is 4e bp1 dependent
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Suzan K Chao, Amos B Smith, Jurriaan Brouwervisser, Susan Band Horwitz, Hayley M McdaidAbstract:Discodermolide is a microtubule-Stabilizing Agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild-type 4E-BP1 in AD32 cells increased the proliferation rate and reverted resistance to discodermolide via restoration of discodermolide-induced accelerated senescence. Consistent with this, cell growth and response to discodermolide was confirmed in vivo using tumor xenograft models. Furthermore, reintroduction of a nonphosphorylatable mutant (Thr-37/46 Ala) of 4E-BP1 was able to partially restore sensitivity and enhance proliferation in AD32 cells, suggesting that these effects are independent of phosphorylation by mTORC1. Microarray profiling of AD32-resistant cells versus sensitive A549 cells, and subsequent unbiased gene ontology analysis, identified molecular pathways and functional groupings of differentially expressed mRNAs implicated in overcoming discodermolide-induced senescence. The most statistically significant classes of differentially expressed genes included p53 signaling, G2/M checkpoint regulation, and genes involved in the role of BRCA1 in the DNA damage response. Consistent with this, p53 protein expression was up-regulated and had increased nuclear localization in AD32 cells relative to parental A549 cells. Furthermore, the stability of p53 was enhanced in AD32 cells. Our studies propose a role for 4E-BP1 as a regulator of discodermolide-induced accelerated senescence.
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Resistance to discodermolide, a microtubule-Stabilizing Agent and senescence inducer, is 4E-BP1–dependent
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Suzan K Chao, Amos B Smith, Jurriaan Brouwer-visser, Susan Band Horwitz, Hayley M McdaidAbstract:Discodermolide is a microtubule-Stabilizing Agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild-type 4E-BP1 in AD32 cells increased the proliferation rate and reverted resistance to discodermolide via restoration of discodermolide-induced accelerated senescence. Consistent with this, cell growth and response to discodermolide was confirmed in vivo using tumor xenograft models. Furthermore, reintroduction of a nonphosphorylatable mutant (Thr-37/46 Ala) of 4E-BP1 was able to partially restore sensitivity and enhance proliferation in AD32 cells, suggesting that these effects are independent of phosphorylation by mTORC1. Microarray profiling of AD32-resistant cells versus sensitive A549 cells, and subsequent unbiased gene ontology analysis, identified molecular pathways and functional groupings of differentially expressed mRNAs implicated in overcoming discodermolide-induced senescence. The most statistically significant classes of differentially expressed genes included p53 signaling, G2/M checkpoint regulation, and genes involved in the role of BRCA1 in the DNA damage response. Consistent with this, p53 protein expression was up-regulated and had increased nuclear localization in AD32 cells relative to parental A549 cells. Furthermore, the stability of p53 was enhanced in AD32 cells. Our studies propose a role for 4E-BP1 as a regulator of discodermolide-induced accelerated senescence.
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the microtubule Stabilizing Agent discodermolide is a potent inducer of accelerated cell senescence
Cell Cycle, 2005Co-Authors: Laura E Klein, Amos B Smith, Scott B Freeze, Susan Band HorwitzAbstract:Discodermolide is a microtubule Stabilizing Agent that suppresses dynamic instability and blocks cells in mitosis. Selection of A549 non-small cell lung carcinoma cells with increasing concentrations of discodermolide yielded a clone that proliferated in 8nM. When these cells were exposed to any concentration greater than 8nM, replication ceased and the cells developed a flattened, enlarged, granular morphology. Accelerated senescence was demonstrated by a functional β-galactosidase activity at pH 6. When parental A549 cells were treated with IC50-concentrations of doxorubicin, Taxol or discodermolide, the latter two drugs quickly produced aberrant mitosis. However, discodermolide, but not Taxol, also produced a large increase in senescence-associated β-galactosidase activity and altered levels of known senescence markers. Although some of these differences between Taxol and discodermolide were dose dependent, only discodermolide produced a doxorubicin-like induction of a senescence phenotype, i...
