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| Content Provider | PubMed Central |
|---|---|
| Author | Miller, Claudia P. Ban, Kechen Dujka, Melanie E. Mcconkey, David J. Munsell, Mark Palladino, Michael Chandra, Joya |
| Copyright Year | 2007 |
| 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. |
| Related Links | http://dx.doi.org/10.1182/blood-2006-03-013128 |
| Ending Page | 277 |
| Page Count | 11 |
| Starting Page | 267 |
| File Format | |
| ISSN | 00064971 |
| e-ISSN | 15280020 |
| Journal | Blood |
| Issue Number | 1 |
| Volume Number | 110 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2007-07-01 |
| Access Restriction | Open |
| Rights Holder | American Society of Hematology |
| Subject Keyword | Immunology Cell Biology Biochemistry Hematology Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Hematology Biochemistry Immunology |
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