Synergistic interactions between MEK1 2 and histone deacetylase inhibitors in BCR ABL+ human leukemia cells

• Published in: Leukemia Vol. 19; no. 9; pp. 1579 - 1589
• Main Authors: YU, C, DASMAHAPATRA, G, DENT, P, GRANT, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.09.2005; Nature Publishing Group
• Subjects: Abl gene; AKT protein; Antigens, CD34 - drug effects; Antigens, CD34 - metabolism; Apoptosis; Apoptosis - drug effects; Apoptosis-inducing factor; BCR gene; BCR protein; Benzamides - pharmacology; Biological and medical sciences; Bone marrow; Bone Marrow Cells - drug effects; Butadienes - pharmacology; Butyrates - pharmacology; Caspase; Caspases - drug effects; Caspases - metabolism; CD34 antigen; Cell Line, Tumor; Chromosome aberrations; Cyclin D1; Cyclin-dependent kinase inhibitor p21; Cytochrome; Cytochrome c; Cytochromes; Deactivation; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors - pharmacology; Fusion Proteins, bcr-abl - drug effects; Fusion Proteins, bcr-abl - metabolism; Hematologic and hematopoietic diseases; Histone deacetylase; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids - pharmacology; Imatinib; Inactivation; Inhibitors; K562 Cells; Lama; Lethality; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical genetics; Medical sciences; Metabolic pathways; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Nitriles - pharmacology; Pharmacology; Sodium butyrate; Chromosomal aberration; Human; Hematology; Enzyme; Transferases; Leukemia; p21CIP1; Malignant hemopathy; MEK1/2 inhibitors; Synergism; Philadelphia chromosome; Abnormal chromosome C9; Histone deacetylase inhibitor; Protein kinase; Bcr-abl protein; Abnormal chromosome G22; Abnormal chromosome; Drug interaction; Hybrid gene; Chromosome translocation; histone deacetylase inhibitors
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2403868

Interactions between the histone deacetylase inhibitor SAHA and the pharmacologic MEK1/2 inhibitor PD184352 were examined in Bcr/Abl+ human leukemia cells. Coadministration of minimally toxic concentrations of SAHA (or sodium butyrate) and PD184352 (or U0126) resulted in a synergistic increase in mitochondrial damage, caspase activation, and apoptosis in K562 and LAMA 84 cells. Similar interactions were observed in CD34+ cells from two patients with CML and in imatinib mesylate-resistant K562 cells but not in normal human CD34+ bone marrow cells. These events were associated with a marked increase in ROS generation, inactivation of ERK and Akt, downregulation of p21CIP1, Bcr/Abl, and cyclin D1, and activation of JNK. Of these events, ROS generation, ERK inactivation, and cytochrome c/AIF release were largely caspase-independent, whereas the other phenomena displayed varying degrees of caspase-dependence. Using pharmacologic and genetic approaches, generation of ROS, p21CIP1 downregulation, and inactivation of Akt and MEK were found to play significant functional roles in SAHA/PD184352-mediated lethality, whereas JNK activation and Raf-1 downregulation were determined to represent secondary events. These findings indicate that interruption of the MEK/ERK pathway substantially lowers the threshold for HDAC inhibitor-mediated oxidative injury, mitochondrial dysfunction, and apoptosis, suggesting that this approach warrants further examination in Bcr/Abl+-related malignancies.