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

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-x(L). Conversely, cells ectopically expressing Bcl-x(L) 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-x(L) down-regulation. This strategy warrants further attention in Bcr/abl(+) hematopoietic malignancies, particularly those resistant to Bcr/abl kinase inhibitors.

• Authors: Tri K Nguyen, Mohamed Rahmani, Ning Gao, Lora Kramer, Amie S Corbin, Brian J Druker, Paul Dent, Steven Grant
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 7 Pt 1 Pg. 2239-47 (Apr 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16609040 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
• Antineoplastic Agents
• Benzamides
• Benzoquinones
• Enzyme Inhibitors
• Lactams, Macrocyclic
• Piperazines
• Pyrimidines
• Quinones
• 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
• Rifabutin
• tanespimycin
• Imatinib Mesylate
• Fusion Proteins, bcr-abl

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Benzoquinones
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Fusion Proteins, bcr-abl (drug effects, metabolism)
• Humans
• Imatinib Mesylate
• Lactams, Macrocyclic
• Leukemia (drug therapy, metabolism)
• Piperazines (pharmacology)
• Pyrimidines (pharmacology)
• Quinones (pharmacology)
• Rifabutin (analogs & derivatives, pharmacology)
• Sensitivity and Specificity
• Structure-Activity Relationship
• Time Factors
• Tumor Cells, Cultured