title: The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis.
abstract: Interactions between inhibitors of the proteasome and histone deacetylases have been examined in human T-leukemia/lymphoma cells both in vitro and in vivo. Co-exposure of cells to bortezomib and suberoylanilide hydroxamic acid (SAHA) synergistically induces T-leukemia/lymphoma cells to undergo apoptosis, consistent with a significant increase in mitochondrial injury and caspase activation. These events are accompanied by inhibition of cyto-protective signaling pathways, including the nuclear factor (NF)-kappaB, Raf-1/mitogen-induced extracellular kinase (MEK)/extracellular signal-related kinase (ERK) and AKT pathways, and activation of stress-related cascades, including the stress-activated kinases c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK). Moreover, bortezomib in conjunction with SAHA efficiently induces apoptosis of primary T-leukemia/lymphoma cells and inhibits tumor growth in a murine xenograft model established with subcutaneous injection of Jurkat cells. Taken together, these findings confirm the synergistic anti-tumor effect of the proteasome and histone deacetylase inhibitors, and provide an insight into the future clinical applications of bortezomib-SAHA combining regimen in treating T-cell malignancies.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Q-L
authors.initials: QL
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: Y-W
authors.initials: YW
authors.lastname: Zhang
authors.forename: X-X
authors.initials: XX
authors.lastname: Jiang
authors.forename: F
authors.initials: F
authors.lastname: Yang
authors.forename: W-L
authors.initials: WL
authors.lastname: Wu
authors.forename: A
authors.initials: A
authors.lastname: Janin
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: Z-X
authors.initials: ZX
authors.lastname: Shen
authors.forename: S-J
authors.initials: SJ
authors.lastname: Chen
authors.forename: W-L
authors.initials: WL
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D019169:Jurkat Cells / Q000187:drug effects / Q000201:enzymology / Q000637:transplantation; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011494:Protein Kinases / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000077337:Vorinostat; D000069286:Bortezomib; D011494:Protein Kinases