Combination bortezomib and rituximab treatment affects multiple survival and death pathways to promote apoptosis in mantle cell lymphoma.
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.
Alinari
Lapo
L
Department of Internal Medicine, Division of Hematology & Oncology, Ohio State University, Columbus, Ohio 43210, USA.
White
Valerie L
VL
Earl
Christian T
CT
Ryan
Timothy P
TP
Johnston
Jeffrey S
JS
Dalton
James T
JT
Ferketich
Amy K
AK
Lai
Raymond
R
Lucas
David M
DM
Porcu
Pierluigi
P
Blum
Kristie A
KA
Byrd
John C
JC
Baiocchi
Robert A
RA
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
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