apicidin and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic cytokine that is capable of inducing apoptosis in a wide variety of cancer cells but not in normal cells. Although many cancer cells are sensitive to TRAIL-induced apoptosis, chronic myeloid leukemia (CML) develops resistance to TRAIL. In this study, we investigated whether apicidin, a novel histone deacetylase inhibitor, could overcome the TRAIL resistance in CML-derived K562 cells. Compared to treatment with apicidin or TRAIL alone, cotreatment with apicidin and TRAIL-induced apoptosis synergistically in K562 cells. This combination led to activation of caspase-8 and Bcl-2 interacting domain (Bid), resulting in the cytosolic accumulation of cytochrome c from mitochondria as well as an activation of caspase-3. Treatment with apicidin resulted in down-regulation of Bcr-Abl and inhibition of its downstream target, PI3K/AKT-NF-kappaB pathway. In addition, apicidin decreased the level of NF-kappaB-dependent Bcl-x(L), leading to caspase activation and Bid cleavage. These results suggest that apicidin may sensitize K562 cells to TRAIL-induced apoptosis through caspase-dependent mitochondrial pathway by regulating expression of Bcr-Abl and its related anti-apoptotic proteins. Therefore, the present study suggests that combination of apicidin and TRAIL may be an effective strategy for treating TRAIL-resistant Bcr-Abl expressing CML cells.

Topics: Apoptosis; Base Sequence; Caspase 3; Caspase 8; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Inhibitors; Fusion Proteins, bcr-abl; Genes, abl; Histone Deacetylase Inhibitors; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mitochondria; NF-kappa B; Oncogene Protein v-akt; Peptides, Cyclic; Phosphatidylinositol 3-Kinases; Recombinant Proteins; RNA, Small Interfering; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand

Apicidin, a histone deacetylase inhibitor, is a novel cyclic tetrapeptide with potent antiproliferative activity against various cancer cells. We examined whether apicidin potentiates the imatinib-induced apoptosis of Bcr-Abl-positive human leukaemia cells. In K562 cells, the co-administration of minimally toxic concentrations of imatinib and apicidin (imatinib/apicidin) for 48 h produced a marked increase in mitochondrial damage, processing of caspase cascades and apoptosis. Similar results were observed in leukaemic blasts obtained from patients with chronic myeloid leukaemia in blast crisis. Imatinib/apicidin co-treatment for 48 h resulted in a near complete loss of the full-length XIAP (X-linked inhibitor of apoptosis) protein, with a corresponding increase in the 29-kDa XIAP cleavage product. Both the degradation of XIAP and increased release of second mitochondria-derived activator of caspase/direct IAP-binding protein with low pI (Smac/DIABLO) into the cytosol were abrogated by pretreatment with the caspase-3 inhibitor DEVD-CHO. Imatinib/apicidin co-treatment for 48 h produced a prominent decrease in Bcr-Abl protein levels in a caspase-dependent manner. In summary, these data indicate that apicidin potentiates the imatinib-induced apoptosis of Bcr-Abl-positive leukaemia cells through the enhanced activation of the mitochondria-dependent caspase cascades, accompanied by caspase-dependent downregulation of Bcr-Abl and XIAP. These findings generate a rationale for further investigation of apicidin and imatinib as a potential therapeutic strategy in Bcr-Abl-positive leukaemias.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Blotting, Western; Caspases; Drug Synergism; Enzyme Inhibitors; Genes, abl; Histone Deacetylase Inhibitors; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mitochondria; Peptides, Cyclic; Piperazines; Pyrimidines