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Rituximab (Chimeric Anti-CD20 Monoclonal Antibody) Inhibits the Constitutive Nuclear Factor-B Signaling Pathway in Non-Hodgkin's Lymphoma B-Cell Lines: Role in Sensitization to Chemotherapeutic Drug-induced Apoptosis

¹ Department of Microbiology, Immunology, and Molecular Genetics and ² Molecular Biology Institute, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California and ³ Unidad de Investigacion Medica en Inmunologia e Infectologia, Hospital de Infectologia, "La Raza," CMN, Mexico City, Mexico

Requests for reprints: Benjamin Bonavida, Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, 10833 Le Conte Avenue, A2-060 CHS, Los Angeles, CA 90095-1747. Phone: 310-825-2233; Fax: 310-206-2791; E-mail: bbonavida{at}mednet.ucla.edu

The chimeric anti-CD20 antibody rituximab (Rituxan, IDEC-C2B8) is widely used in the clinical treatment of patients with non-Hodgkin's lymphoma (NHL). Rituximab sensitizes NHL B-cell lines to drug-induced apoptosis via down-regulation of Bcl-x_L expression. We hypothesized that the mechanism by which rituximab down-regulates Bcl-x_L may be, in part, due to inhibition of constitutive nuclear factor-B (NF-B) activity that regulates Bcl-x_L expression. This hypothesis was tested in CD20⁺ drug-resistant Ramos (Bcl-2^–/Bcl-x_L⁺) and Daudi (Bcl-2⁺/Bcl-x_L⁺) cell lines. Rituximab decreased the phosphorylation of NF-B-inducing kinase, IB kinase, and IB-, diminished IKK kinase activity, and decreased NF-B DNA binding activity. These events occurred with similar kinetics and were observed 3 to 6 hours post-rituximab treatment. Rituximab significantly up-regulated Raf-1 kinase inhibitor protein expression, thus interrupting the NF-B signaling pathway concomitant with Bcl-x_L and Bfl-1/A1 down-regulation. The role of NF-B in the regulation of Bcl-x_L transcription was shown using promoter reporter assays in which deletion of the two-tandem NF-B binding sites in the upstream promoter region significantly reduced the luciferase activity. This was further corroborated by using IB superrepressor cells and by NF-B–specific inhibitors. The direct role of Bcl-x_L in drug resistance was assessed by using Bcl-x_L–overexpressing cells, which exhibited higher drug resistance that was partially reversed by rituximab. Rituximab-mediated inhibition of the NF-B signaling pathway and chemosensitization was corroborated by the use of specific inhibitors. These findings reveal a novel pathway mediated by rituximab through Raf-1 kinase inhibitor protein induction that negatively regulates the constitutive NF-B pathway and chemosensitization of the NHL B-cells.

Key Words: non–Hodgkin's lymphoma • Rituximab • NF-B • Bcl-x_L • RKIP

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