title: The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP.
abstract: Because of the pivotal role the proteasome plays in apoptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synergy between proteasome inhibition and other apoptosis-inducing agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. In overnight assays, combinations of PS-341 and TRAIL were much more effective than either agent alone in promoting apoptosis of a murine myeloid leukemia, C1498, and a murine renal cancer, Renca. For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of nuclear factor kappaB (NF-kappaB) nor the levels of most antiapoptotic proteins. However, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells. Treatment of normal bone marrow mixed with C1498 tumor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the tumor cells. Upon transfer to irradiated syngeneic recipient mice, mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-term tumor-free survival of mice. These data therefore support the targeting of apoptotic pathways in tumor cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to preferentially promote tumor cell apoptosis.
authors.affiliation: Basic Sciences Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute/NIH, Bldg 560, Rm 31-30, Frederick, MD 21702-1201, USA. sayers@mail.ncifcrf.gov
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sayers
authors.forename: Alan D
authors.initials: AD
authors.lastname: Brooks
authors.forename: Crystal Y
authors.initials: CY
authors.lastname: Koh
authors.forename: Weihong
authors.initials: W
authors.lastname: Ma
authors.forename: Naoko
authors.initials: N
authors.lastname: Seki
authors.forename: Arati
authors.initials: A
authors.lastname: Raziuddin
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Elliott
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D016465:Bone Marrow Purging; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000032:analysis / Q000187:drug effects*; D018572:Disease-Free Survival; D004357:Drug Synergism; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand; D014185:Transplantation, Isogeneic; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib