title: Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity.
abstract: The proteasome inhibitor, bortezomib, and the histone deacetylase inhibitor, depsipeptide (FK228), up-regulate tumor death receptors. Therefore, we investigated whether pretreatment of malignant cells with these agents would potentiate natural killer (NK)-mediated tumor killing. NK cells isolated from healthy donors and patients with cancer were expanded in vitro and then tested for cytotoxicity against tumor cell lines before and after exposure to bortezomib or depsipeptide. In 11 of 13 (85%) renal cell carcinoma cell lines and in 16 of 37 (43%) other cancer cell lines, exposure to these drugs significantly increased NK cell-mediated tumor lysis compared with untreated tumor controls (P < 0.001). Furthermore, NK cells expanded from patients with metastatic renal cell carcinoma were significantly more cytotoxic against autologous tumor cells when pretreated with either bortezomib or depsipeptide compared with untreated tumors. Tumors sensitized to NK cell cytotoxicity showed a significant increase in surface expression of DR5 [tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-R2; P < 0.05]; in contrast, surface expression of MHC class I, MIC-A/B, DR4 (TRAIL-R1), and Fas (CD95) did not change. The enhanced susceptibility to NK cell killing was completely abolished by blocking TRAIL on NK cells, and partially abolished by blocking DR5 on tumor cells. These findings show that drug-induced sensitization to TRAIL could be used as a novel strategy to potentiate the anticancer effects of adoptively infused NK cells in patients with cancer.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, Laboratory of Tumor Immunology and Biology, and Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1202, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lundqvist
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
authors.forename: David S
authors.initials: DS
authors.lastname: Schrump
authors.forename: Gauri
authors.initials: G
authors.lastname: Alvarez
authors.forename: Dante
authors.initials: D
authors.lastname: Suffredini
authors.forename: Maria
authors.initials: M
authors.lastname: Berg
authors.forename: Richard
authors.initials: R
authors.lastname: Childs
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib