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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.
AuthorsClaudia P Miller, Kechen Ban, Melanie E Dujka, David J McConkey, Mark Munsell, Michael Palladino, Joya Chandra
JournalBlood (Blood) Vol. 110 Issue 1 Pg. 267-77 (Jul 01 2007) ISSN: 0006-4971 [Print] United States
PMID17356134 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Histone Deacetylase Inhibitors
  • Lactones
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Pyrroles
  • Reactive Oxygen Species
  • marizomib
  • Caspase 8
Topics
  • Animals
  • Apoptosis (drug effects)
  • Caspase 8 (metabolism)
  • Cell Line, Tumor
  • Histone Deacetylase Inhibitors
  • Humans
  • Lactones (administration & dosage, pharmacology)
  • Leukemia (drug therapy, pathology)
  • Mice
  • Oxidative Stress
  • Protease Inhibitors (administration & dosage, pharmacology)
  • Proteasome Inhibitors
  • Pyrroles (administration & dosage, pharmacology)
  • Reactive Oxygen Species (metabolism)
  • Tumor Burden (drug effects)
  • Tumor Cells, Cultured

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