Synergistic interactions between DMAG and mitogen- activated protein kinase kinase 1/2 inhibitors in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate

Tri K. Nguyen, Mohamed Rahmani, Ning Gao, Lora Kramer, Amie S. Corbin, Brian Druker, Paul Dent, Steven Grant

Research output: Contribution to journalArticle

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Abstract

Purpose: To characterize interactions between the heat shock protein 90 antagonist 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and the mitogen-activated protein kinase/extracellular signal - regulated kinase (ERK) kinase 1/2 inhibitor PD184352 in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate. Experimental Design: K562 and LAMA 84 cells were exposed to varying concentrations of DMAG and PD184352 for 48 hours; after which, mitochondrial integrity, caspase activation, and apoptosis were monitored. Parallel studies were done in imatinib mesylate - resistant cells, including BaF3 cells transfected with plasmids encoding clinically relevant Bcr/abl mutations conferring imatinib mesylate resistance (e.g., E255K, M351T, and T315I) and primary CD34+ bone marrow cells from patients refractory to imatinib mesylate. Results: Cotreatment of Bcr/abl+ cells with minimally toxic concentrations of DMAG and PD184352 resulted in synergistic induction of mitochondrial injury (cytochrome c release and Bax conformational change), events associated with the pronounced and sustained inactivation of ERK1/2 accompanied by down-regulation of Bcl-xL. Conversely, cells ectopically expressing Bcl-xL displayed significant protection against PD184352/DMAG - mediated lethality. This regimen effectively induced apoptosis in K562 cells overexpressing Bcr/abl, in BaF3 cells expressing various clinically relevant Bcr/abl mutations, and in primary CD34+ cells from patients resistant to imatinib mesylate, but was relatively sparing of normal CD34+ bone marrow cells. Conclusions: A regimen combining the heat shock protein 90 antagonist DMAG and the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor potently induces apoptosis in Bcr/abl+ cells, including those resistant to imatinib mesylate through various mechanisms including Bcr/abl kinase mutations, through a process that may involve sustained ERK1/2 inactivation and Bcl-xL down-regulation. This strategy warrants further attention in Bcr/abl+ hematopoietic malignancies, particularly those resistant to Bcr/abl kinase inhibitors.

Original languageEnglish (US)
Pages (from-to)2239-2247
Number of pages9
JournalClinical Cancer Research
Volume12
Issue number7 I
DOIs
StatePublished - Apr 1 2006

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MAP Kinase Kinase 2
MAP Kinase Kinase 1
Leukemia
Phosphotransferases
HSP90 Heat-Shock Proteins
Extracellular Signal-Regulated MAP Kinases
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
Apoptosis
Mitogen-Activated Protein Kinases
Bone Marrow Cells
Mutation
Down-Regulation
Imatinib Mesylate
K562 Cells
Poisons
Hematologic Neoplasms
Caspases
Cytochromes c
Plasmids
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Synergistic interactions between DMAG and mitogen- activated protein kinase kinase 1/2 inhibitors in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate. / Nguyen, Tri K.; Rahmani, Mohamed; Gao, Ning; Kramer, Lora; Corbin, Amie S.; Druker, Brian; Dent, Paul; Grant, Steven.

In: Clinical Cancer Research, Vol. 12, No. 7 I, 01.04.2006, p. 2239-2247.

Research output: Contribution to journalArticle

Nguyen, Tri K. ; Rahmani, Mohamed ; Gao, Ning ; Kramer, Lora ; Corbin, Amie S. ; Druker, Brian ; Dent, Paul ; Grant, Steven. / Synergistic interactions between DMAG and mitogen- activated protein kinase kinase 1/2 inhibitors in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 7 I. pp. 2239-2247.
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abstract = "Purpose: To characterize interactions between the heat shock protein 90 antagonist 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and the mitogen-activated protein kinase/extracellular signal - regulated kinase (ERK) kinase 1/2 inhibitor PD184352 in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate. Experimental Design: K562 and LAMA 84 cells were exposed to varying concentrations of DMAG and PD184352 for 48 hours; after which, mitochondrial integrity, caspase activation, and apoptosis were monitored. Parallel studies were done in imatinib mesylate - resistant cells, including BaF3 cells transfected with plasmids encoding clinically relevant Bcr/abl mutations conferring imatinib mesylate resistance (e.g., E255K, M351T, and T315I) and primary CD34+ bone marrow cells from patients refractory to imatinib mesylate. Results: Cotreatment of Bcr/abl+ cells with minimally toxic concentrations of DMAG and PD184352 resulted in synergistic induction of mitochondrial injury (cytochrome c release and Bax conformational change), events associated with the pronounced and sustained inactivation of ERK1/2 accompanied by down-regulation of Bcl-xL. Conversely, cells ectopically expressing Bcl-xL displayed significant protection against PD184352/DMAG - mediated lethality. This regimen effectively induced apoptosis in K562 cells overexpressing Bcr/abl, in BaF3 cells expressing various clinically relevant Bcr/abl mutations, and in primary CD34+ cells from patients resistant to imatinib mesylate, but was relatively sparing of normal CD34+ bone marrow cells. Conclusions: A regimen combining the heat shock protein 90 antagonist DMAG and the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor potently induces apoptosis in Bcr/abl+ cells, including those resistant to imatinib mesylate through various mechanisms including Bcr/abl kinase mutations, through a process that may involve sustained ERK1/2 inactivation and Bcl-xL down-regulation. This strategy warrants further attention in Bcr/abl+ hematopoietic malignancies, particularly those resistant to Bcr/abl kinase inhibitors.",
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T1 - Synergistic interactions between DMAG and mitogen- activated protein kinase kinase 1/2 inhibitors in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate

AU - Nguyen, Tri K.

AU - Rahmani, Mohamed

AU - Gao, Ning

AU - Kramer, Lora

AU - Corbin, Amie S.

AU - Druker, Brian

AU - Dent, Paul

AU - Grant, Steven

PY - 2006/4/1

Y1 - 2006/4/1

N2 - Purpose: To characterize interactions between the heat shock protein 90 antagonist 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and the mitogen-activated protein kinase/extracellular signal - regulated kinase (ERK) kinase 1/2 inhibitor PD184352 in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate. Experimental Design: K562 and LAMA 84 cells were exposed to varying concentrations of DMAG and PD184352 for 48 hours; after which, mitochondrial integrity, caspase activation, and apoptosis were monitored. Parallel studies were done in imatinib mesylate - resistant cells, including BaF3 cells transfected with plasmids encoding clinically relevant Bcr/abl mutations conferring imatinib mesylate resistance (e.g., E255K, M351T, and T315I) and primary CD34+ bone marrow cells from patients refractory to imatinib mesylate. Results: Cotreatment of Bcr/abl+ cells with minimally toxic concentrations of DMAG and PD184352 resulted in synergistic induction of mitochondrial injury (cytochrome c release and Bax conformational change), events associated with the pronounced and sustained inactivation of ERK1/2 accompanied by down-regulation of Bcl-xL. Conversely, cells ectopically expressing Bcl-xL displayed significant protection against PD184352/DMAG - mediated lethality. This regimen effectively induced apoptosis in K562 cells overexpressing Bcr/abl, in BaF3 cells expressing various clinically relevant Bcr/abl mutations, and in primary CD34+ cells from patients resistant to imatinib mesylate, but was relatively sparing of normal CD34+ bone marrow cells. Conclusions: A regimen combining the heat shock protein 90 antagonist DMAG and the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor potently induces apoptosis in Bcr/abl+ cells, including those resistant to imatinib mesylate through various mechanisms including Bcr/abl kinase mutations, through a process that may involve sustained ERK1/2 inactivation and Bcl-xL down-regulation. This strategy warrants further attention in Bcr/abl+ hematopoietic malignancies, particularly those resistant to Bcr/abl kinase inhibitors.

AB - Purpose: To characterize interactions between the heat shock protein 90 antagonist 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and the mitogen-activated protein kinase/extracellular signal - regulated kinase (ERK) kinase 1/2 inhibitor PD184352 in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate. Experimental Design: K562 and LAMA 84 cells were exposed to varying concentrations of DMAG and PD184352 for 48 hours; after which, mitochondrial integrity, caspase activation, and apoptosis were monitored. Parallel studies were done in imatinib mesylate - resistant cells, including BaF3 cells transfected with plasmids encoding clinically relevant Bcr/abl mutations conferring imatinib mesylate resistance (e.g., E255K, M351T, and T315I) and primary CD34+ bone marrow cells from patients refractory to imatinib mesylate. Results: Cotreatment of Bcr/abl+ cells with minimally toxic concentrations of DMAG and PD184352 resulted in synergistic induction of mitochondrial injury (cytochrome c release and Bax conformational change), events associated with the pronounced and sustained inactivation of ERK1/2 accompanied by down-regulation of Bcl-xL. Conversely, cells ectopically expressing Bcl-xL displayed significant protection against PD184352/DMAG - mediated lethality. This regimen effectively induced apoptosis in K562 cells overexpressing Bcr/abl, in BaF3 cells expressing various clinically relevant Bcr/abl mutations, and in primary CD34+ cells from patients resistant to imatinib mesylate, but was relatively sparing of normal CD34+ bone marrow cells. Conclusions: A regimen combining the heat shock protein 90 antagonist DMAG and the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor potently induces apoptosis in Bcr/abl+ cells, including those resistant to imatinib mesylate through various mechanisms including Bcr/abl kinase mutations, through a process that may involve sustained ERK1/2 inactivation and Bcl-xL down-regulation. This strategy warrants further attention in Bcr/abl+ hematopoietic malignancies, particularly those resistant to Bcr/abl kinase inhibitors.

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