Cotreatment with apicidin overcomes TRAIL resistance via inhibition of Bcr-Abl signaling pathway in K562 leukemia cells.
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.
Park
Soo-Jung
SJ
Department of Biochemistry, Pusan National University School of Medicine, Yangsan 622-770, South Korea.
Kim
Mi-Ju
MJ
Kim
Hak-Bong
HB
Sohn
Hee-Young
HY
Bae
Jae-Ho
JH
Kang
Chi-Dug
CD
Kim
Sun-Hee
SH
D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D016313:Genes, abl; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D010456:Peptides, Cyclic; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C102351:apicidin; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; D051058:Oncogene Protein v-akt; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8