ABSTRACT
Heat-shock protein 90 (Hsp 90) acts as a molecular chaperone that maintains protein stability and regulates cell proliferation, survival, differentiation and apoptosis. The present study investigated the effect of Hsp90 inhibition on human acute myeloid leukemia (AML) cells using the novel small-molecule inhibitor SNX-2112. We found that SNX-2112 more potently inhibited KG-1a cell growth than the classical Hsp90 inhibitor 17-(2-dimethylaminoethyl)amino17-demethoxygeldanamycin as determined by CCK-8 assay. Flow cytometry was used to examine the cell cycle, differentiation, and apoptosis, and western blotting and qRT-PCR were used to analyze the underlying mechanism. The results revealed that low concentrations of SNX-2112 arrested the cells in the G2/M phase and induced their differentiation and apoptosis, possibly by suppressing Akt and inhibitor of κB kinase, a component of the nuclear factor (NF)-κB signaling pathway. We also found that SNX-2112 increased the expression of the differentiation transcription factors PU.1 and CCAATenhancer-binding protein-α. Thus, SNX-2112 induced KG-1a cell differentiation, cell cycle arrest and apoptosis via modulation of Akt and NF-κB signaling, suggesting that it is a promising therapeutic agent for the treatment of AML.
Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Proto-Oncogene Proteins c-akt/genetics , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , HSP90 Heat-Shock Proteins/genetics , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , NF-kappa B/genetics , Signal Transduction/drug effectsABSTRACT
<p><b>OBJECTIVE</b>To analyze the application of vertebral pedicle screw fixation in the treatment of burst fracture of thoracolumbar vertebrae.</p><p><b>METHODS</b>A total of 48 cases (31 males and 17 females, aged from 18-72 years, mean: 41.3 years) with thoracolumbar vertebrae burst fracture were treated by pedicle screw system since January 2004. According to the AO classification of thoracolumbar vertebrae fracture, there are 36 cases of Type A, 9 of Type B and 3 of Type C.</p><p><b>RESULTS</b>All patients were followed up for 6-25 months (average 12 months), no secondary nerve root injury, spinal cord injury, loosening or breakage of pedicle screw were observed. The nerve function of 29 patients with cauda equina nerve injury was restored to different degrees. The vertebral body height returned to normal level and posterior process angle was rectified after operation.</p><p><b>CONCLUSIONS</b>The vertebral pedicle screw internal fixation was technologically applicable, which can efficiently reposition and stabilize the bursting fractured vertebrae, indirectly decompress canalis spinalis, maintain spine stability, scatter stress of screw system, reduce the risk of loosening or breakage of screw and loss of vertebral height, and prevent the formation of posterior convex after operation.</p>