title: Combination bortezomib and rituximab treatment affects multiple survival and death pathways to promote apoptosis in mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) is a distinct histologic subtype of B cell non-Hodgkins lymphoma (NHL) associated with an aggressive clinical course. Inhibition of the ubiquitin-proteasome pathway modulates survival and proliferation signals in MCL and has shown clinical benefit in this disease. This has provided rationale for exploring combination regimens with B-cell selective immunotherapies such as rituximab. In this study, we examined the effects of combined treatment with bortezomib and rituximab on patient-derived MCL cell lines (Jeko, Mino, SP53) and tumor samples from patients with MCL where we validate reversible proteasome inhibition concurrent with cell cycle arrest and additive induction of apoptosis. When MCL cells were exposed to single agent bortezomib or combination bortezomib/rituximab, caspase dependent and independent apoptosis was observed. Single agent bortezomib or rituximab treatment of Mino and Jeko cell lines and patient samples resulted in decreased levels of nuclear NFkappaB complex(es) capable of binding p65 consensus oligonucleotides, and this decrease was enhanced by the combination. Constitutive activation of the Akt pathway was also diminished with bortezomib alone or in combination with rituximab. On the basis of in vitro data demonstrating additive apoptosis and enhanced NFkappaB and phosphorylated Akt depletion in MCL with combination bortezomib plus rituximab, a phase II trial of bortezomib-rituximab in patients with relapsed/refractory MCL is underway.
authors.affiliation: Department of Internal Medicine, Division of Hematology & Oncology, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Lapo
authors.initials: L
authors.lastname: Alinari
authors.forename: Valerie L
authors.initials: VL
authors.lastname: White
authors.forename: Christian T
authors.initials: CT
authors.lastname: Earl
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Ryan
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Johnston
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Amy K
authors.initials: AK
authors.lastname: Ferketich
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Porcu
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baiocchi
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000201:enzymology; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D000069283:Rituximab; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069283:Rituximab; D000069286:Bortezomib