The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia

Mol Cancer Ther. 2006 Jul;5(7):1836-43. doi: 10.1158/1535-7163.MCT-06-0066.


Proteasome inhibitors are potent inducers of apoptosis in isolated lymphocytes from patients with chronic lymphocytic leukemia (CLL). However, the reversible proteasome inhibitor bortezomib (PS-341; Velcade) did not display substantial antitumor activity in CLL patients. Here, we compared the effects of bortezomib and a new irreversible proteasome inhibitor (NPI-0052) on 20S chymotryptic proteasome activity and apoptosis in isolated CLL cells in vitro. Although their steady-state (3 hours) IC(50)s as proteasome inhibitors were similar, NPI-0052 exerted its effects more rapidly than bortezomib, and drug washout experiments showed that short exposures to NPI-0052 resulted in sustained (> or =24 hours) 20S proteasome inhibition, whereas 20S activity recovered in cells exposed to even 10-fold higher concentrations of bortezomib. Thus, brief (15 minutes) pulses of NPI-0052 were sufficient to induce substantial apoptosis in CLL cells, whereas longer exposure times (> or =8 hours) were required for commitment to apoptosis in cells exposed to equivalent concentrations of bortezomib. Commitment to apoptosis seemed to be related to caspase-4 activation, in that cells exposed to bortezomib or NPI-0052 could be saved from death by addition of a selective caspase-4 inhibitor up to 8 hours after drug exposure. Our results show that NPI-0052 is a more effective proapoptotic agent than bortezomib in isolated CLL cells and suggest that the chemical properties of NPI-0052 might also make it an effective therapeutic agent in CLL patients.

Publication types

  • Comparative Study

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Humans
  • Lactones / pharmacology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / enzymology*
  • Lymphocytes / drug effects
  • Lymphocytes / enzymology
  • Protease Inhibitors / pharmacology*
  • Proteasome Inhibitors*
  • Pyrazines / pharmacology*
  • Pyrroles / pharmacology*


  • Antineoplastic Agents
  • Boronic Acids
  • Lactones
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Pyrazines
  • Pyrroles
  • Bortezomib
  • marizomib