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Peter J Houghton - One of the best experts on this subject based on the ideXlab platform.
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et 59development and characterization of a mek1 inhibitor azd6244 sensitive childhood Astrocytoma Cell Line
Neuro-oncology, 2014Co-Authors: Adam W Studebaker, Doris A Phelps, Peter J HoughtonAbstract:We previously characterized the development and reversal of acquired resistance to the MEK1 inhibitor AZD6244 in an in vivo model of childhood Astrocytoma. The BT-40 Astrocytoma xenograft model expresses mutated BRAFV600E and is highly sensitive to AZD6244, but acquires resistance, which can be overcome with the addition of the STAT3 inhibitor LLL12. The purpose of this current study was to establish and characterize a Cell Line derived from the xenograft model as well as develop an orthotopic mouse model. Sensitivity to AZD6244 and LLL12, expression-profiling assessment of MEK signature and compensatory pathways, and cytokine levels were assessed in the newly developed BT-40 Cell Line. The BT-40 Cell Line exhibited sensitivity to AZD6244 and LLL12 with IC50 values of 350nM and 1 µM, respectively. Combination treatment was additive. Treatment with AZD6244 inhibited p-Erk and the mTOR downstream signaling molecule p-S6, while p-Akt, p-STAT3, p-4E-BP1 increased. Kinase expression arrays performed on Cells treated with AZD6244 showed a decrease in IL-1α, G-CSF, and IL-6 and an increase in CXCL10. The decrease in IL-6 was restored to baseLine levels with the addition of LLL12. Interestingly, the JAK2 inhibitor AZD1480 failed to restore the IL-6 levels. The IL-6 results observed in the expression arrays were confirmed by ELISA. The BT-40 Cell Line, along with a Cell Line stably expressing luciferase (BT-40Luc), were implanted into the caudate putamen using stereotaxic guidance. The BT-40Luc Cells exhibited exponential growth over time as evaluated with bioluminescent imaging. In conclusion, a Cell Line derived from a previously described in vivo model of childhood Astrocytoma was developed that closely recapitulated our original findings in the xenograft model following treatment with the MEK1 inhibitor AZD6244. Furthermore, an orthotopic model of these Cells was developed, which will allow us to characterize response to established and novel therapeutic agents. Supported by PHS award {"type":"entrez-nucleotide","attrs":{"text":"CA169368","term_id":"35091720","term_text":"CA169368"}}CA169368.
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abstract 2775 development and characterization of a mek1 inhibitor azd6244 sensitive childhood Astrocytoma Cell Line
Cancer Research, 2014Co-Authors: Adam W Studebaker, Doris A Phelps, Peter J HoughtonAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA We previously characterized the development and reversal of acquired resistance to the MEK1 inhibitor AZD6244 in an in vivo model of childhood Astrocytoma. The BT-40 Astrocytoma xenograft model expresses mutated BRAFV600E and is highly sensitive to AZD6244, but acquires resistance, which can be overcome with the addition of the STAT3 inhibitor LLL12. The purpose of this current study was to establish and characterize a Cell Line derived from the xenograft model as well as develop an orthotopic mouse model. Sensitivity to AZD6244 and LLL12, expression-profiling assessment of MEK signature and compensatory pathways, and cytokine levels were assessed in the newly developed BT-40 Cell Line. The BT-40 Cell Line exhibited sensitivity to AZD6244 and LLL12 with IC50 values of 350nM and 1µM, respectively. Combination treatment was additive. Treatment of the Cells with AZD6244 inhibited p-Erk and the mTOR downstream signaling molecule p-S6, while p-Akt, p-STAT3, p-4E-BP1 increased. Kinase expression arrays performed on Cells treated with AZD6244 displayed a decrease in IL-1α, G-CSF, and IL-6 and an increase in CXCL10. The decrease in IL-6 was restored to baseLine levels with the addition of LLL12. Interestingly, the JAK2 inhibitor AZD1480 failed to restore the IL-6 levels. The IL-6 results observed in the expression arrays were confirmed by ELISA, where AZD6244 decreased soluble IL-6 levels and LLL12, but not AZD1480, restored IL-6 levels to baseLine. The BT-40 Cell Line, along with a Cell Line stably expressing luciferase (BT-40Luc), were implanted into the caudate putamen using stereotaxic guidance. The BT-40Luc Cells exhibited exponential growth over time as evaluated with bioluminescent imaging. In conclusion, a Cell Line derived from a previously described in vivo model of childhood Astrocytoma was developed that closely recapitulated our original findings in the xenograft model following treatment with the MEK1 inhibitor AZD6244. Furthermore, an orthotopic model of these Cells was developed, which will allow us to characterize response to established and novel therapeutic agents. Supported by PHS award CA169368. Citation Format: Adam W. Studebaker, Hemant K. Bid, Doris A. Phelps, Peter J. Houghton. Development and characterization of a MEK1 inhibitor (AZD6244) sensitive childhood Astrocytoma Cell Line. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2775. doi:10.1158/1538-7445.AM2014-2775
Adam W Studebaker - One of the best experts on this subject based on the ideXlab platform.
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et 59development and characterization of a mek1 inhibitor azd6244 sensitive childhood Astrocytoma Cell Line
Neuro-oncology, 2014Co-Authors: Adam W Studebaker, Doris A Phelps, Peter J HoughtonAbstract:We previously characterized the development and reversal of acquired resistance to the MEK1 inhibitor AZD6244 in an in vivo model of childhood Astrocytoma. The BT-40 Astrocytoma xenograft model expresses mutated BRAFV600E and is highly sensitive to AZD6244, but acquires resistance, which can be overcome with the addition of the STAT3 inhibitor LLL12. The purpose of this current study was to establish and characterize a Cell Line derived from the xenograft model as well as develop an orthotopic mouse model. Sensitivity to AZD6244 and LLL12, expression-profiling assessment of MEK signature and compensatory pathways, and cytokine levels were assessed in the newly developed BT-40 Cell Line. The BT-40 Cell Line exhibited sensitivity to AZD6244 and LLL12 with IC50 values of 350nM and 1 µM, respectively. Combination treatment was additive. Treatment with AZD6244 inhibited p-Erk and the mTOR downstream signaling molecule p-S6, while p-Akt, p-STAT3, p-4E-BP1 increased. Kinase expression arrays performed on Cells treated with AZD6244 showed a decrease in IL-1α, G-CSF, and IL-6 and an increase in CXCL10. The decrease in IL-6 was restored to baseLine levels with the addition of LLL12. Interestingly, the JAK2 inhibitor AZD1480 failed to restore the IL-6 levels. The IL-6 results observed in the expression arrays were confirmed by ELISA. The BT-40 Cell Line, along with a Cell Line stably expressing luciferase (BT-40Luc), were implanted into the caudate putamen using stereotaxic guidance. The BT-40Luc Cells exhibited exponential growth over time as evaluated with bioluminescent imaging. In conclusion, a Cell Line derived from a previously described in vivo model of childhood Astrocytoma was developed that closely recapitulated our original findings in the xenograft model following treatment with the MEK1 inhibitor AZD6244. Furthermore, an orthotopic model of these Cells was developed, which will allow us to characterize response to established and novel therapeutic agents. Supported by PHS award {"type":"entrez-nucleotide","attrs":{"text":"CA169368","term_id":"35091720","term_text":"CA169368"}}CA169368.
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abstract 2775 development and characterization of a mek1 inhibitor azd6244 sensitive childhood Astrocytoma Cell Line
Cancer Research, 2014Co-Authors: Adam W Studebaker, Doris A Phelps, Peter J HoughtonAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA We previously characterized the development and reversal of acquired resistance to the MEK1 inhibitor AZD6244 in an in vivo model of childhood Astrocytoma. The BT-40 Astrocytoma xenograft model expresses mutated BRAFV600E and is highly sensitive to AZD6244, but acquires resistance, which can be overcome with the addition of the STAT3 inhibitor LLL12. The purpose of this current study was to establish and characterize a Cell Line derived from the xenograft model as well as develop an orthotopic mouse model. Sensitivity to AZD6244 and LLL12, expression-profiling assessment of MEK signature and compensatory pathways, and cytokine levels were assessed in the newly developed BT-40 Cell Line. The BT-40 Cell Line exhibited sensitivity to AZD6244 and LLL12 with IC50 values of 350nM and 1µM, respectively. Combination treatment was additive. Treatment of the Cells with AZD6244 inhibited p-Erk and the mTOR downstream signaling molecule p-S6, while p-Akt, p-STAT3, p-4E-BP1 increased. Kinase expression arrays performed on Cells treated with AZD6244 displayed a decrease in IL-1α, G-CSF, and IL-6 and an increase in CXCL10. The decrease in IL-6 was restored to baseLine levels with the addition of LLL12. Interestingly, the JAK2 inhibitor AZD1480 failed to restore the IL-6 levels. The IL-6 results observed in the expression arrays were confirmed by ELISA, where AZD6244 decreased soluble IL-6 levels and LLL12, but not AZD1480, restored IL-6 levels to baseLine. The BT-40 Cell Line, along with a Cell Line stably expressing luciferase (BT-40Luc), were implanted into the caudate putamen using stereotaxic guidance. The BT-40Luc Cells exhibited exponential growth over time as evaluated with bioluminescent imaging. In conclusion, a Cell Line derived from a previously described in vivo model of childhood Astrocytoma was developed that closely recapitulated our original findings in the xenograft model following treatment with the MEK1 inhibitor AZD6244. Furthermore, an orthotopic model of these Cells was developed, which will allow us to characterize response to established and novel therapeutic agents. Supported by PHS award CA169368. Citation Format: Adam W. Studebaker, Hemant K. Bid, Doris A. Phelps, Peter J. Houghton. Development and characterization of a MEK1 inhibitor (AZD6244) sensitive childhood Astrocytoma Cell Line. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2775. doi:10.1158/1538-7445.AM2014-2775
Doris A Phelps - One of the best experts on this subject based on the ideXlab platform.
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et 59development and characterization of a mek1 inhibitor azd6244 sensitive childhood Astrocytoma Cell Line
Neuro-oncology, 2014Co-Authors: Adam W Studebaker, Doris A Phelps, Peter J HoughtonAbstract:We previously characterized the development and reversal of acquired resistance to the MEK1 inhibitor AZD6244 in an in vivo model of childhood Astrocytoma. The BT-40 Astrocytoma xenograft model expresses mutated BRAFV600E and is highly sensitive to AZD6244, but acquires resistance, which can be overcome with the addition of the STAT3 inhibitor LLL12. The purpose of this current study was to establish and characterize a Cell Line derived from the xenograft model as well as develop an orthotopic mouse model. Sensitivity to AZD6244 and LLL12, expression-profiling assessment of MEK signature and compensatory pathways, and cytokine levels were assessed in the newly developed BT-40 Cell Line. The BT-40 Cell Line exhibited sensitivity to AZD6244 and LLL12 with IC50 values of 350nM and 1 µM, respectively. Combination treatment was additive. Treatment with AZD6244 inhibited p-Erk and the mTOR downstream signaling molecule p-S6, while p-Akt, p-STAT3, p-4E-BP1 increased. Kinase expression arrays performed on Cells treated with AZD6244 showed a decrease in IL-1α, G-CSF, and IL-6 and an increase in CXCL10. The decrease in IL-6 was restored to baseLine levels with the addition of LLL12. Interestingly, the JAK2 inhibitor AZD1480 failed to restore the IL-6 levels. The IL-6 results observed in the expression arrays were confirmed by ELISA. The BT-40 Cell Line, along with a Cell Line stably expressing luciferase (BT-40Luc), were implanted into the caudate putamen using stereotaxic guidance. The BT-40Luc Cells exhibited exponential growth over time as evaluated with bioluminescent imaging. In conclusion, a Cell Line derived from a previously described in vivo model of childhood Astrocytoma was developed that closely recapitulated our original findings in the xenograft model following treatment with the MEK1 inhibitor AZD6244. Furthermore, an orthotopic model of these Cells was developed, which will allow us to characterize response to established and novel therapeutic agents. Supported by PHS award {"type":"entrez-nucleotide","attrs":{"text":"CA169368","term_id":"35091720","term_text":"CA169368"}}CA169368.
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abstract 2775 development and characterization of a mek1 inhibitor azd6244 sensitive childhood Astrocytoma Cell Line
Cancer Research, 2014Co-Authors: Adam W Studebaker, Doris A Phelps, Peter J HoughtonAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA We previously characterized the development and reversal of acquired resistance to the MEK1 inhibitor AZD6244 in an in vivo model of childhood Astrocytoma. The BT-40 Astrocytoma xenograft model expresses mutated BRAFV600E and is highly sensitive to AZD6244, but acquires resistance, which can be overcome with the addition of the STAT3 inhibitor LLL12. The purpose of this current study was to establish and characterize a Cell Line derived from the xenograft model as well as develop an orthotopic mouse model. Sensitivity to AZD6244 and LLL12, expression-profiling assessment of MEK signature and compensatory pathways, and cytokine levels were assessed in the newly developed BT-40 Cell Line. The BT-40 Cell Line exhibited sensitivity to AZD6244 and LLL12 with IC50 values of 350nM and 1µM, respectively. Combination treatment was additive. Treatment of the Cells with AZD6244 inhibited p-Erk and the mTOR downstream signaling molecule p-S6, while p-Akt, p-STAT3, p-4E-BP1 increased. Kinase expression arrays performed on Cells treated with AZD6244 displayed a decrease in IL-1α, G-CSF, and IL-6 and an increase in CXCL10. The decrease in IL-6 was restored to baseLine levels with the addition of LLL12. Interestingly, the JAK2 inhibitor AZD1480 failed to restore the IL-6 levels. The IL-6 results observed in the expression arrays were confirmed by ELISA, where AZD6244 decreased soluble IL-6 levels and LLL12, but not AZD1480, restored IL-6 levels to baseLine. The BT-40 Cell Line, along with a Cell Line stably expressing luciferase (BT-40Luc), were implanted into the caudate putamen using stereotaxic guidance. The BT-40Luc Cells exhibited exponential growth over time as evaluated with bioluminescent imaging. In conclusion, a Cell Line derived from a previously described in vivo model of childhood Astrocytoma was developed that closely recapitulated our original findings in the xenograft model following treatment with the MEK1 inhibitor AZD6244. Furthermore, an orthotopic model of these Cells was developed, which will allow us to characterize response to established and novel therapeutic agents. Supported by PHS award CA169368. Citation Format: Adam W. Studebaker, Hemant K. Bid, Doris A. Phelps, Peter J. Houghton. Development and characterization of a MEK1 inhibitor (AZD6244) sensitive childhood Astrocytoma Cell Line. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2775. doi:10.1158/1538-7445.AM2014-2775
Rakesh Shukla - One of the best experts on this subject based on the ideXlab platform.
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evaluation of amentoflavone isolated from cnestis ferruginea vahl ex dc connaraceae on production of inflammatory mediators in lps stimulated rat Astrocytoma Cell Line c6 and thp 1 Cells
Journal of Ethnopharmacology, 2013Co-Authors: Rakesh Shukla, Ismail O Ishola, J P Chaturvedi, N Rajasekar, Olufunmilayo O Adeyemi, T NarenderAbstract:Abstract Ethnopharmacological relevance Cnestisferruginea (CF) Vahl ex DC (Connaraceae) is a shrub widely used in traditional African medicine for the treatment of various psychiatric illness and inflammatory conditions. Aim of the study This study was carried out to investigate the effect of amentoflavone isolated from methanolic root extract of CF on lipopolysaccharide (LPS)-induced neuroinflammatory cascade of events associated to the oxidative and nitrative stress, and TNF-α production in rat Astrocytoma Cell Line (C6) and human monocytic leukemia Cell Line (THP-1), respectively. Materials and methods Rat Astrocytoma Cells (C6) were stimulated with LPS (10 μg/ml) alone and in the presence of different concentrations of amentoflavone (0.1–3 μg/ml) for 24 h incubation period. Nitrite release, reactive oxygen species (ROS), malondialdehyde (MDA) and reduced-glutathione (GSH) in C6 Cells were estimated; while the TNF-α level was estimated in THP-1 Cell lysate. In vivo analgesic activity was evaluated using mouse writhing and hot plate tests while the anti-inflammatory effect was investigated using carrageenan-induced oedema test. Results LPS (10 μg/ml) significantly (P Discussion and conclusion Findings in this study demonstrate the anti-neuroinflammatory and antinoceptive effects of amentoflavone which may suggest its beneficial roles in neuroinflammation associated disorders.
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evaluation of guggulipid and nimesulide on production of inflammatory mediators and gfap expression in lps stimulated rat Astrocytoma Cell Line c6
Journal of Ethnopharmacology, 2010Co-Authors: Rituraj Niranjan, Pradeep Kumar Kamat, Chandishwar Nath, Rakesh ShuklaAbstract:Abstract Aim of the study The present study was designed to investigate effect of guggulipid, a drug developed by CDRI and nimesulide on LPS stimulated neuroinflammatory changes in rat Astrocytoma Cell Line (C6). Materials and methods Rat Astrocytoma Cells (C6) were stimulated with LPS (10 μg/ml) alone and in combinations with different concentrations of guggulipid or nimesulide for 24 h of incubation. Nitrite release in culture supernatant, ROS in Cells, expressions of COX-2, GFAP and TNF-α in Cell lysate were estimated. Results LPS (10 μg/ml) stimulated C6 Cells to release nitrite, ROS generation, up regulated COX-2 and GFAP expressions at protein level and TNF-α at mRNA level. Both guggulipid and nimesulide significantly attenuated nitrite release, ROS generation and also down regulated expressions of COX-2, GFAP and TNF-α. Guggulipid and nimesulide per se did not have any significant effect on C6 Cells. Conclusion Results demonstrate the anti-inflammatory effect of guggulipid comparable to nimesulide which suggest potential use of guggulipid in neuroinflammation associated conditions in CNS disorders.
Pasquale Ferrante - One of the best experts on this subject based on the ideXlab platform.
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1 40 β amyloid protein fragment modulates the expression of cd44 and cd71 on the Astrocytoma Cell Line in the presence of il1β and tnfα
Journal of Cellular Physiology, 2003Co-Authors: Livianna Speciale, Stefania Ruzzante, Elena Calabrese, Marina Saresella, Donatella Taramelli, C Mariani, Laura Bava, Renato Longhi, Pasquale FerranteAbstract:The modulation of CD44, VCAM-1 and CD71 expression was analysed by flow cytometry in the 1321N1 Astrocytoma Cell Line in the presence of interleukin-1β (IL1β), tumour necrosis factor-α (TNFα) and 1–40 or 25–35 β-amyloid (Aβ) fragments. The percentage of 1321N1 Astrocytoma Cell Line expressing these markers increased significantly after treatment with TNFα or IL1β. The presence of Aβ 1–40 fragment, alone or in combination with IL1β, induced an increase in the percentage of Cells expressing CD44, but not VCAM-1. However, the concomitant presence of Aβ 1–40 fragment and of IL1β or TNFα caused an increase in the percentage of CD71 positive Cells. In contrast, the shorter Aβ 25–35 fragment was always inactive. These results indicates that Aβ 1–40 fragment, in association with cytokines, can activate this astrocyte-derived Cell Line and add further elements in favour of the hypothesis that β-amyloid can act as immunological mediator. © 2003 Wiley-Liss, Inc.
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1–40 β-amyloid protein fragment modulates the expression of CD44 and CD71 on the Astrocytoma Cell Line in the presence of IL1β and TNFα
Journal of Cellular Physiology, 2003Co-Authors: Livianna Speciale, Stefania Ruzzante, Elena Calabrese, Marina Saresella, Donatella Taramelli, C Mariani, Laura Bava, Renato Longhi, Pasquale FerranteAbstract:The modulation of CD44, VCAM-1 and CD71 expression was analysed by flow cytometry in the 1321N1 Astrocytoma Cell Line in the presence of interleukin-1β (IL1β), tumour necrosis factor-α (TNFα) and 1–40 or 25–35 β-amyloid (Aβ) fragments. The percentage of 1321N1 Astrocytoma Cell Line expressing these markers increased significantly after treatment with TNFα or IL1β. The presence of Aβ 1–40 fragment, alone or in combination with IL1β, induced an increase in the percentage of Cells expressing CD44, but not VCAM-1. However, the concomitant presence of Aβ 1–40 fragment and of IL1β or TNFα caused an increase in the percentage of CD71 positive Cells. In contrast, the shorter Aβ 25–35 fragment was always inactive. These results indicates that Aβ 1–40 fragment, in association with cytokines, can activate this astrocyte-derived Cell Line and add further elements in favour of the hypothesis that β-amyloid can act as immunological mediator. © 2003 Wiley-Liss, Inc.