title: Dual targeting of the proteasome regulates survival and homing in Waldenstrom macroglobulinemia.
abstract: Waldenström macroglobulinemia (WM) is an incurable low-grade B-cell lymphoma characterized by high protein turnover. We dissected the biologic role of the proteasome in WM using 2 proteasome inhibitors, NPI-0052 and bortezomib. We found that NPI-0052 inhibited proliferation and induced apoptosis in WM cells, and that the combination of NPI-0052 and bortezomib induced synergistic cytotoxicity in WM cells, leading to inhibition of nuclear translocation of p65NF-kappaB and synergistic induction of caspases-3, -8, and -9 and PARP cleavage. These 2 agents inhibited the canonical and noncanonical NF-kappaB pathways and acted synergistically through their differential effect on Akt activity and on chymotrypsin-like, caspaselike, and trypsinlike activities of the proteasome. We demonstrated that NPI-0052-induced cytotoxicity was completely abrogated in an Akt knockdown cell line, indicating that its major activity is mediated through the Akt pathway. Moreover, we demonstrated that NPI-0052 and bortezomib inhibited migration and adhesion in vitro and homing of WM cells in vivo, and overcame resistance induced by mesenchymal cells or by the addition of interleukin-6 in a coculture in vitro system. Theses studies enhance our understanding of the biologic role of the proteasome pathway in WM, and provide the preclinical basis for clinical trials of combinations of proteasome inhibitors in WM.
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.forename: Xavier
authors.initials: X
authors.lastname: Leleu
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Jia
authors.forename: Molly
authors.initials: M
authors.lastname: Melhem
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Moreau
authors.forename: Hai T
authors.initials: HT
authors.lastname: Ngo
authors.forename: Judith
authors.initials: J
authors.lastname: Runnels
authors.forename: Abdelkareem
authors.initials: A
authors.lastname: Azab
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.forename: Nicholas
authors.initials: N
authors.lastname: Burwick
authors.forename: Mena
authors.initials: M
authors.lastname: Farag
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.forename: Michael A
authors.initials: MA
authors.lastname: Palladino
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D004357:Drug Synergism; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: D001897:Boronic Acids; D007783:Lactones; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011758:Pyrroles; D000069286:Bortezomib; C475865:marizomib