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.
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Authors | Claudia P Miller, Kechen Ban, Melanie E Dujka, David J McConkey, Mark Munsell, Michael Palladino, Joya Chandra |
Journal | Blood
(Blood)
Vol. 110
Issue 1
Pg. 267-77
(Jul 01 2007)
ISSN: 0006-4971 [Print] United States |
PMID | 17356134
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Histone Deacetylase Inhibitors
- Lactones
- Protease Inhibitors
- Proteasome Inhibitors
- Pyrroles
- Reactive Oxygen Species
- marizomib
- Caspase 8
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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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