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Synergistic Interactions between DMAG and Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitors in Bcr/abl⁺ Leukemia Cells Sensitive and Resistant to Imatinib Mesylate

Authors' Affiliations: Departments of ¹ Medicine, ² Biochemistry, and ³ Pharmacology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia and ⁴ Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute, Portland, Oregon

Requests for reprints: Steven Grant, Division of Hematology/Oncology, Medical College of Virginia, Virginia Commonwealth University, MCV Station Box 230, Richmond, VA 23298. Phone: 804-828-5211; Fax: 804-828-8079; E-mail: stgrant{at}hsc.vcu.edu.

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.

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