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Blood, 1 July 2007, Vol. 110, No. 1, pp. 267-277.
Prepublished online as a Blood First Edition Paper on March 13, 2007; DOI 10.1182/blood-2006-03-013128.
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Submitted March 28, 2006
Accepted February 16, 2007
NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells
Claudia P Miller, Kechen Ban, Melanie E Dujka, David J McConkey, Mark Munsell, Michael Palladino, and Joya Chandra*
Department of Pediatrics Research, M.D. Anderson Cancer Center, Houston, TX
Department of Cancer Biology, M.D. Anderson Cancer Center, Houston, TX
Division of Quantitative Sciences, M.D. Anderson Cancer Center, Houston, TX
Nereus Pharmaceuticals, San Diego, CA
* Corresponding author; email: jchandra{at}mdanderson.org.
The proteasome has been successfully targeted for the treatment of multiple myeloma and mantle cell lymphoma, however, in other hematological 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 three 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+ ALL patient. Caspase-3 activation by NPI-0052 was seen in wild-type Jurkat cells, but was significantly lessened in 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 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 HDAC inhibitors. These effects of NPI-0052, alone and in combination with HDAC inhibitors, warrant further testing to determine the compound's clinical efficacy in leukemia.
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