The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo

Mi Ae Lyu, Deepak Rai, Kwang Seok Ahn, Bokyung Sung, Lawrence H. Cheung, John W. Marks, Bharat B. Aggarwal, Ricardo C.T. Aguiar, Varsha Gandhi, Michael G. Rosenblum

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL) and accounts for 30% to 40% of NHL. Molecules targeting nuclear factor-κB (NF-κB) are expected to be of therapeutic value in those tumors where NF-κB seems to play a unique survival role such as activated B-cell (ABC)-subtype DLBCL. We previously generated a rGel/BLyS fusion toxin for receptor-mediated delivery of the rGel toxin specifically to malignant B cells. In this study, we examined this fusion toxin for its ability to suppress DLBCL growth in vitro and in vivo. rGel/BLyS was specifically cytotoxic to DLBCL lines expressing all three BLyS receptors and constitutively active NF-κB. Treatment with rGel/BLyS induced down-regulation of the phosphorylation of inhibitory subunit of NF-κB (IκB-α), inhibition of NF-κB DNA-binding activity, and accumulation of IκB-α. In agreement with these results, we additionally found that rGel/BLyS downregulated levels of several NF-κB targets including Bcl-xL, Mcl-1, survivin, and x-chromosome linked inhibitor-of-apoptosis. Treatment also induced up-regulation of Bax and apoptosis through caspase-3 activation and poly ADP-ribose polymerase cleavage. Importantly, rGel/BLyS significantly inhibited tumor growth (P < .05) in a DLBCL xenograft model. Thus, our results indicate that rGel/BLyS is an excellent candidate for the treatment of aggressive NHLs that are both dependent on NF-κB and are resistant to conventional chemotherapeutic regimens.

Original languageEnglish (US)
Pages (from-to)366-375
Number of pages10
JournalNeoplasia
Volume12
Issue number5
DOIs
StatePublished - May 2010

ASJC Scopus subject areas

  • Cancer Research

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    Lyu, M. A., Rai, D., Ahn, K. S., Sung, B., Cheung, L. H., Marks, J. W., Aggarwal, B. B., Aguiar, R. C. T., Gandhi, V., & Rosenblum, M. G. (2010). The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo. Neoplasia, 12(5), 366-375. https://doi.org/10.1593/neo.91960