title: The novel proteasome inhibitor carfilzomib induces cell cycle arrest, apoptosis and potentiates the anti-tumour activity of chemotherapy in rituximab-resistant lymphoma.
abstract: Targeting the proteasome system with bortezomib (BTZ) results in anti-tumour activity and potentiates the effects of chemotherapy/biological agents in multiple myeloma and B-cell lymphoma. Carfilzomib (CFZ) is a more selective proteasome inhibitor that is structurally distinct from BTZ. In an attempt to characterize its biological activity, we evaluated CFZ in several lymphoma pre-clinical models. Rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL), and primary tumour cells derived from B-cell lymphoma patients were exposed to CFZ or BTZ. Cell viability and changes in cell cycle were determined. Western blots were performed to detect PARP-cleavage and/or changes in Bcl-2 (BCL2) family members. CFZ was 10 times more active than BTZ and exhibited dose- and time-dependent cytotoxicity. CFZ exposure induced apoptosis by upregulation of Bak (BAK1) and subsequent PARP cleavage in RSCL and RRCL; it was also partially caspase-dependent. CFZ induced G2/M phase cell cycle arrest in RSCL. CFZ demonstrated the ability to overcome resistance to chemotherapy in RRCL and potentiated the anti-tumour activity of chemotherapy agents. Our data suggest that CFZ is able to overcome resistance to chemotherapeutic agents, upregulate pro-apoptotic proteins to promote apoptosis, and induce G2/M cell cycle arrest in lymphoma cells. Our pre-clinical data supports future clinical evaluation of CFZ in B-cell lymphoma.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gu
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Hernandez-Ilizaliturri
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Kaufman
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Czuczman
authors.forename: Cory
authors.initials: C
authors.lastname: Mavis
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Skitzki
authors.forename: Myron S
authors.initials: MS
authors.lastname: Czuczman
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D000069283:Rituximab; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids; D061945:Caspase Inhibitors; D009363:Neoplasm Proteins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069283:Rituximab; D000069286:Bortezomib; C524865:carfilzomib; D020169:Caspases
keywords: B-cell lymphoma; bortezomib; carfilzomib; ubiquitin-proteasome system