title: NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells.
abstract: The proteasome has been successfully targeted for the treatment of multiple myeloma and mantle cell lymphoma; however, in other hematologic malignancies, bortezomib has been less effective as a single agent. Here, we describe effects of NPI-0052, a novel proteasome inhibitor, in leukemia model systems. In cell lines, NPI-0052 inhibits all 3 proteolytic activities associated with the proteasome: chymotrypsin-, trypsin-, and caspase-like. NPI-0052 also induces DNA fragmentation in leukemia lines and in mononuclear cells from a Ph + acute lymphoblastic leukemia (ALL) patient. Caspase-3 activation by NPI-0052 was seen in wild-type Jurkat cells, but was significantly lessened in Fas-associated death domain (FADD)-deficient or caspase-8-deficient counterparts. NPI-0052-induced apoptosis was further probed using caspase-8 inhibitors, which were more protective than caspase-9 inhibitors. N-acetyl cysteine (NAC) also conferred protection against NPI-0052-induced apoptosis, indicating a role for oxidative stress by NPI-0052. In support of the drug's in vitro activities, biweekly treatment with NPI-0052 lessened total white blood cell (WBC) burden over 35 days in leukemic mice. Interestingly, combining NPI-0052 with either MS-275 or valproic acid (VPA) induced greater levels of cell death than the combination of bortezomib with these histone deacetylase inhibitors (HDACi). These effects of NPI-0052, alone and in combination with HDACi, warrant further testing to determine the compound's clinical efficacy in leukemia.
authors.affiliation: Department of Pediatrics Research, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Miller
authors.forename: Kechen
authors.initials: K
authors.lastname: Ban
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Dujka
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
authors.forename: Mark
authors.initials: M
authors.lastname: Munsell
authors.forename: Michael
authors.initials: M
authors.lastname: Palladino
authors.forename: Joya
authors.initials: J
authors.lastname: Chandra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D018384:Oxidative Stress; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D056572:Histone Deacetylase Inhibitors; D007783:Lactones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011758:Pyrroles; D017382:Reactive Oxygen Species; C475865:marizomib; D053181:Caspase 8