title: The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia.
abstract: 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.
authors.affiliation: Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Box 173, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Ruiz
authors.forename: Yelena
authors.initials: Y
authors.lastname: Krupnik
authors.forename: Michael
authors.initials: M
authors.lastname: Keating
authors.forename: Joya
authors.initials: J
authors.lastname: Chandra
authors.forename: Michael
authors.initials: M
authors.lastname: Palladino
authors.forename: David
authors.initials: D
authors.lastname: McConkey
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology*; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D007783:Lactones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011758:Pyrroles; D000069286:Bortezomib; C475865:marizomib