NEMO-binding domain peptide inhibits constitutive NF-?B activity and reduces tumor burden in a canine model of relapsed, refractory diffuse large B-cell lymphoma.

ABSTRACT: Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive, poorly chemoresponsive lymphoid malignancy characterized by constitutive canonical NF-?B activity that promotes lymphomagenesis and chemotherapy resistance via overexpression of antiapoptotic NF-?B target genes. Inhibition of the canonical NF-?B pathway may therefore have therapeutic relevance in ABC-DLBCL. Here, we set out to determine whether dogs with spontaneous DLBCL have comparative aberrant constitutive NF-?B activity and to determine the therapeutic relevance of NF-?B inhibition in dogs with relapsed, resistant DLBCL.Canonical NF-?B activity was evaluated by electrophoretic mobility shift assays and immunoblot analyses, and NF-?B target gene expression was measured by quantitative real time PCR. Primary malignant canine B lymphocytes were treated with the selective IKK complex inhibitor NF-?B essential modulator-binding domain (NBD) peptide and evaluated for NF-?B activity and apoptosis. NBD peptide was administered intranodally to dogs with relapsed B-cell lymphoma and NF-?B target gene expression and tumor burden were evaluated pre- and post-treatment.Constitutive canonical NF-?B activity and increased NF-?B target gene expression were detected in primary DLBCL tissue. NBD peptide inhibited this activity and induced apoptosis of primary malignant B cells in vitro. Intratumoral injections of NBD peptide to dogs with relapsed DLBCL inhibited NF-?B target gene expression and reduced tumor burden.This work shows that dogs with spontaneous DLBCL represent a clinically relevant, spontaneous, large animal model for human ABC-DLBCL and shows the therapeutic relevance of NF-?B inhibition in the treatment of ABC-DLBCL. These results have important translational relevance for ABC-DLBCL treatment in human patients.

SUBMITTER: Gaurnier-Hausser A 

PROVIDER: S-EPMC3273413 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature