Abstract
Chronic myelogenous leukemia (CML) results from transformation of hematopoietic cells by the BCR/ABL gene. Although high rates of hematologic responses to imatinib therapy, the acquired resistance to imatinib has been recognized as a major problem in the treatment of CML Histone deacetylases (HDACs) and histone acetyltransferases (HATs) regulate gene expression and cell growth. Recently, HDAC inhibitors have known as a new class of anti-cancer drugs. One of the HDAC inhibitor, FK228 (FR901228, depsipeptide) is now doing the clinical trial for the treatment of patients, such as peripheral T-cell lymphoma, but there was not known to the CML. In this study, we used the TF-1 BCR-ABL cell line, which were transfected BCR/ABL gene to the leukemia cell line, TF-1. We show here that FK228 potently induced apoptosis of TF-1 BCR-ABL cells, compare to the parental cell line, TF-1, in a dose and time depend fashion. BCR-ABL, intracellular molecular chaperone, heat shock protein 90 (HSP90), and p53 which regulate cell cycle, were acetylated after FK228 treatment, but not glycogen synthase kinase-3 β(GSK-3β) and signal-transducing activators of transcription 5 (STAT5). Histone H4 is also acetylated after FK228 treatment. In a cell cycle analysis, TF-1 BCR-ABL cells were stopped at G2-M phase after FK228 treatment. The activity of MAPK and Src kinases were blocked after FK228 treatment in a time and dose depend fashion, but p38 was activated. Inhibitor of apoptosis proteins (c-IAPs) have prevented cell death by inhibiting effectors caspases. IAPs were inhibited by FK228 and caspase3, caspase9 and poly (ADP-ribose) polymerase (PARP) were activated in a time and dose depend manner. Histone acetylation and caspase activitation were not blocked by treatment of p38 inhibitor, SB203580. Our study supports the future clinical trial of FK228 in the management of CML patients.
Depletion of Pleckstrin Homology Domain Leucine-rich Repeat Protein Phosphatases 1 and 2 by Bcr-Abl Promotes Chronic Myelogenous Leukemia Cell Proliferation through Continuous Phosphorylation of Akt Isoforms
