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

Abstract

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.

• Authors: C Yu, G Dasmahapatra, P Dent, S Grant
• Journal: Leukemia (Leukemia) Vol. 19 Issue 9 Pg. 1579-89 (Sep 2005) ISSN: 0887-6924 [Print] England
• PMID: 16015388 (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., Research Support, U.S. Gov't, P.H.S., Retracted Publication)

Chemical References

• 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
• Antigens, CD34
• Benzamides
• Butadienes
• Butyrates
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Nitriles
• U 0126
• Vorinostat
• Fusion Proteins, bcr-abl
• Mitogen-Activated Protein Kinase Kinases
• Caspases

Topics

• Antigens, CD34 (drug effects, metabolism)
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Bone Marrow Cells (drug effects)
• Butadienes (pharmacology)
• Butyrates (pharmacology)
• Caspases (drug effects, metabolism)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Fusion Proteins, bcr-abl (drug effects, metabolism)
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (pharmacology)
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism)
• Mitochondria (drug effects, metabolism)
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Nitriles (pharmacology)
• Vorinostat