The Experts below are selected from a list of 258 Experts worldwide ranked by ideXlab platform
Cecilia Trinks - One of the best experts on this subject based on the ideXlab platform.
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Summary Recent findings have indicated...
2014Co-Authors: A Nordigården, Cecilia Trinks, Henrik Green, Jenny Zetterblad, Pernilla Eliasson, Pia Druid, Kourosh Lotfi, Lars Ronnstr, Thomas Walz, Janingvar JonssonAbstract:Irreversible pan-ERBB inhibitor Canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mic
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Canertinib induced leukemia cell death signaling effects of a pan erbb inhibitor
2012Co-Authors: Cecilia TrinksAbstract:Acute myelogenous leukemia (AML) is the most common acute leukemia affecting adults, the second most frequent leukemia in children, and remains one of the most difficult to cure. Despite a substant ...
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the pan erbb receptor tyrosine kinase inhibitor Canertinib promotes apoptosis of malignant melanoma in vitro and displays anti tumor activity in vivo
Biochemical and Biophysical Research Communications, 2011Co-Authors: Emelie Severinsson, Cecilia Trinks, Henrik Green, Annalotta Hallbeck, Avni Abdiu, Olle Stal, Thomas M WalzAbstract:The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor Canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 μM and by 5 μM both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 μM Canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 μM Canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses ≤ 5μM Canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, Canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.
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irreversible pan erbb inhibitor Canertinib elicits anti leukaemic effects and induces the regression of flt3 itd transformed cells in mice
British Journal of Haematology, 2011Co-Authors: Amanda Nordigarden, Cecilia Trinks, Henrik Green, Thomas M Walz, Jenny Zetterblad, Pernilla Eliasson, Pia Druid, Kourosh Lotfi, Lars Ronnstrand, Janingvar JonssonAbstract:Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor Canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by Canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that Canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.
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the pan erbb tyrosine kinase inhibitor Canertinib induces caspase mediated cell death in human t cell leukemia jurkat cells
Biochemical and Biophysical Research Communications, 2011Co-Authors: Cecilia Trinks, Emelie Severinsson, Birgitta Holmlund, Anna Green, Henrik Green, Janingvar Jonsson, Annalotta Hallbeck, Thomas M WalzAbstract:Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that Canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that Canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with Canertinib at a concentration of 2 μM caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by Canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of Canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.
Thomas M Walz - One of the best experts on this subject based on the ideXlab platform.
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the pan erbb receptor tyrosine kinase inhibitor Canertinib promotes apoptosis of malignant melanoma in vitro and displays anti tumor activity in vivo
Biochemical and Biophysical Research Communications, 2011Co-Authors: Emelie Severinsson, Cecilia Trinks, Henrik Green, Annalotta Hallbeck, Avni Abdiu, Olle Stal, Thomas M WalzAbstract:The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor Canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 μM and by 5 μM both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 μM Canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 μM Canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses ≤ 5μM Canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, Canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.
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irreversible pan erbb inhibitor Canertinib elicits anti leukaemic effects and induces the regression of flt3 itd transformed cells in mice
British Journal of Haematology, 2011Co-Authors: Amanda Nordigarden, Cecilia Trinks, Henrik Green, Thomas M Walz, Jenny Zetterblad, Pernilla Eliasson, Pia Druid, Kourosh Lotfi, Lars Ronnstrand, Janingvar JonssonAbstract:Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor Canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by Canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that Canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.
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the pan erbb tyrosine kinase inhibitor Canertinib induces caspase mediated cell death in human t cell leukemia jurkat cells
Biochemical and Biophysical Research Communications, 2011Co-Authors: Cecilia Trinks, Emelie Severinsson, Birgitta Holmlund, Anna Green, Henrik Green, Janingvar Jonsson, Annalotta Hallbeck, Thomas M WalzAbstract:Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that Canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that Canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with Canertinib at a concentration of 2 μM caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by Canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of Canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.
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the pan erbb receptor tyrosine kinase inhibitor Canertinib induces erbb independent apoptosis in human leukemia hl 60 and u 937 cells
Biochemical and Biophysical Research Communications, 2010Co-Authors: Cecilia Trinks, Janingvar Jonsson, Annalotta Hallbeck, Emelie A Djerf, Thomas M WalzAbstract:Epidermal growth factor (EGF) receptor tyrosine kinase inhibitors have recently been shown to display anti-neoplastic effects in human malignant myeloid cells. Our study was initiated in order to determine the effect of the pan-ErbB receptor tyrosine kinase inhibitor, Canertinib (CI-1033), on growth and survival of human leukemia (HL-60 and U-937) cells. We show that treatment of HL-60 and U-937 cells with Canertinib significantly inhibits growth of both cell lines in a dose-dependent manner; half maximal effective dose (IC(50)) in HL-60 and U-937 cells was approximately 2.5 microM and 1.0 microM, respectively. Treatment with 2 microM Canertinib promoted a G(1) cell cycle arrest, whereas doses of 5 microM or more induced apoptosis as determined by the Annexin V method and cleavage of poly-(ADP-ribose) polymerase (PARP). HL-60 and U-937 cells lacked EGF-receptor transcript but expressed ErbB2-4 mRNA as determined by RT-PCR. However, none of the corresponding ErbB-receptor proteins could be detected by Western blot analysis. We conclude that Canertinib induces apoptosis in HL-60 and U-937 cells devoid of functional ErbB1-4 receptors. Our results suggest that Canertinib could be of potential clinical interest in the treatment of acute myeloid leukemia.
Janingvar Jonsson - One of the best experts on this subject based on the ideXlab platform.
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Summary Recent findings have indicated...
2014Co-Authors: A Nordigården, Cecilia Trinks, Henrik Green, Jenny Zetterblad, Pernilla Eliasson, Pia Druid, Kourosh Lotfi, Lars Ronnstr, Thomas Walz, Janingvar JonssonAbstract:Irreversible pan-ERBB inhibitor Canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mic
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irreversible pan erbb inhibitor Canertinib elicits anti leukaemic effects and induces the regression of flt3 itd transformed cells in mice
British Journal of Haematology, 2011Co-Authors: Amanda Nordigarden, Cecilia Trinks, Henrik Green, Thomas M Walz, Jenny Zetterblad, Pernilla Eliasson, Pia Druid, Kourosh Lotfi, Lars Ronnstrand, Janingvar JonssonAbstract:Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor Canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by Canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that Canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.
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the pan erbb tyrosine kinase inhibitor Canertinib induces caspase mediated cell death in human t cell leukemia jurkat cells
Biochemical and Biophysical Research Communications, 2011Co-Authors: Cecilia Trinks, Emelie Severinsson, Birgitta Holmlund, Anna Green, Henrik Green, Janingvar Jonsson, Annalotta Hallbeck, Thomas M WalzAbstract:Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that Canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that Canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with Canertinib at a concentration of 2 μM caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by Canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of Canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.
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the pan erbb receptor tyrosine kinase inhibitor Canertinib induces erbb independent apoptosis in human leukemia hl 60 and u 937 cells
Biochemical and Biophysical Research Communications, 2010Co-Authors: Cecilia Trinks, Janingvar Jonsson, Annalotta Hallbeck, Emelie A Djerf, Thomas M WalzAbstract:Epidermal growth factor (EGF) receptor tyrosine kinase inhibitors have recently been shown to display anti-neoplastic effects in human malignant myeloid cells. Our study was initiated in order to determine the effect of the pan-ErbB receptor tyrosine kinase inhibitor, Canertinib (CI-1033), on growth and survival of human leukemia (HL-60 and U-937) cells. We show that treatment of HL-60 and U-937 cells with Canertinib significantly inhibits growth of both cell lines in a dose-dependent manner; half maximal effective dose (IC(50)) in HL-60 and U-937 cells was approximately 2.5 microM and 1.0 microM, respectively. Treatment with 2 microM Canertinib promoted a G(1) cell cycle arrest, whereas doses of 5 microM or more induced apoptosis as determined by the Annexin V method and cleavage of poly-(ADP-ribose) polymerase (PARP). HL-60 and U-937 cells lacked EGF-receptor transcript but expressed ErbB2-4 mRNA as determined by RT-PCR. However, none of the corresponding ErbB-receptor proteins could be detected by Western blot analysis. We conclude that Canertinib induces apoptosis in HL-60 and U-937 cells devoid of functional ErbB1-4 receptors. Our results suggest that Canertinib could be of potential clinical interest in the treatment of acute myeloid leukemia.
Henrik Green - One of the best experts on this subject based on the ideXlab platform.
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Summary Recent findings have indicated...
2014Co-Authors: A Nordigården, Cecilia Trinks, Henrik Green, Jenny Zetterblad, Pernilla Eliasson, Pia Druid, Kourosh Lotfi, Lars Ronnstr, Thomas Walz, Janingvar JonssonAbstract:Irreversible pan-ERBB inhibitor Canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mic
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the pan erbb receptor tyrosine kinase inhibitor Canertinib promotes apoptosis of malignant melanoma in vitro and displays anti tumor activity in vivo
Biochemical and Biophysical Research Communications, 2011Co-Authors: Emelie Severinsson, Cecilia Trinks, Henrik Green, Annalotta Hallbeck, Avni Abdiu, Olle Stal, Thomas M WalzAbstract:The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor Canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 μM and by 5 μM both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 μM Canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 μM Canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses ≤ 5μM Canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, Canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.
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irreversible pan erbb inhibitor Canertinib elicits anti leukaemic effects and induces the regression of flt3 itd transformed cells in mice
British Journal of Haematology, 2011Co-Authors: Amanda Nordigarden, Cecilia Trinks, Henrik Green, Thomas M Walz, Jenny Zetterblad, Pernilla Eliasson, Pia Druid, Kourosh Lotfi, Lars Ronnstrand, Janingvar JonssonAbstract:Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor Canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by Canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that Canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.
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the pan erbb tyrosine kinase inhibitor Canertinib induces caspase mediated cell death in human t cell leukemia jurkat cells
Biochemical and Biophysical Research Communications, 2011Co-Authors: Cecilia Trinks, Emelie Severinsson, Birgitta Holmlund, Anna Green, Henrik Green, Janingvar Jonsson, Annalotta Hallbeck, Thomas M WalzAbstract:Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that Canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that Canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with Canertinib at a concentration of 2 μM caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by Canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of Canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.
Gordon B. Mills - One of the best experts on this subject based on the ideXlab platform.
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Small Molecule ErbB Inhibitors Decrease Proliferative Signaling and Promote Apoptosis in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia
2016Co-Authors: Mary E Irwin, Phillip D Knouse, Claudia P Miller, Shana L Palla, Laura D. Nelson, Doris R. Siwak, Gordon B. Mills, Janice M. Santiago-o’farrill, Zeev EstrovAbstract:The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph+ALL) is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI) that target BCR/ABL, such as imatinib, have improved treatment of Ph+ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50 % of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2) is expressed in,30 % of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA) with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56 % of Ph+ALL as compared to just 4.8 % of Ph2ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with Canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60 % in Z119 and 39 % in Z181 cells at 3 mM). Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91 % in both cell lines at 3 mM). Canertinib treatment increased expression of the pro-apoptoti
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small molecule erbb inhibitors decrease proliferative signaling and promote apoptosis in philadelphia chromosome positive acute lymphoblastic leukemia
PLOS ONE, 2013Co-Authors: Mary E Irwin, Janice Santiagoofarrill, Phillip D Knouse, Claudia P Miller, Shana L Palla, Laura D. Nelson, Doris R. Siwak, Gordon B. MillsAbstract:The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph+ALL) is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI) that target BCR/ABL, such as imatinib, have improved treatment of Ph+ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2) is expressed in ∼30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA) with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph+ALL as compared to just 4.8% of Ph−ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with Canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60% in Z119 and 39% in Z181 cells at 3 µM). Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91% in both cell lines at 3 µM). Canertinib treatment increased expression of the pro-apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both Canertinib and the FDA-approved ErbB1/2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph+ALL and encourage the development of clinical strategies combining ErbB and BCR/ABL kinase inhibitors for this subset of ALL patients.
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Small molecule ErbB2 inhibitors increase sensitivity to BCR/ABL-directed TKI.
2013Co-Authors: Mary E Irwin, Phillip D Knouse, Claudia P Miller, Shana L Palla, Laura D. Nelson, Doris R. Siwak, Gordon B. Mills, Janice M. Santiago-o’farrill, Zeev EstrovAbstract:Z119 cells were treated with indicated doses Canertinib or lapatinib and (A) imatinib, (B) nilotinib or (C) dasatinib for 72 hours. Cells were stained with PI and the subdiploid population was measured by flow cytometry. Bars indicate the mean and SEM of at least three independent experiments.
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Decreased proliferation of ErbB2+Ph+ALL cells is induced by ErbB inhibition.
2013Co-Authors: Mary E Irwin, Phillip D Knouse, Claudia P Miller, Shana L Palla, Laura D. Nelson, Doris R. Siwak, Gordon B. Mills, Janice M. Santiago-o’farrill, Zeev EstrovAbstract:Z119 and Z181 cells were treated with indicated doses of (A) Canertinib or (B) lapatinib and allowed to proliferate for 96 hours. Cell viability and total cell number were determined every 24 hours by trypan blue exclusion. Points indicate the mean and SEM of viable cell numbers in at least three independent experiments.
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Apoptosis of ErbB2+Ph+ALL cell lines is induced by Canertinib.
2013Co-Authors: Mary E Irwin, Phillip D Knouse, Claudia P Miller, Shana L Palla, Laura D. Nelson, Doris R. Siwak, Gordon B. Mills, Janice M. Santiago-o’farrill, Zeev EstrovAbstract:(A and B, upper panels) Z119 and Z181 cells were treated with Canertinib for 18 hours and lysates were subjected to SDS-PAGE followed by immunoblotting with the indicated antibodies. (A and B, lower panels) Protein expression values from RPPA analyses were quantified, and expression relative to the mean graphed. Triangles indicate drug doses of 0–5 µM. *p
