The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo.
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-kappaB (NF-kappaB) are expected to be of therapeutic value in those tumors where NF-kappaB 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-kappaB. Treatment with rGel/BLyS induced down-regulation of the phosphorylation of inhibitory subunit of NF-kappaB (IkappaB-alpha), inhibition of NF-kappaB DNA-binding activity, and accumulation of IkappaB-alpha. In agreement with these results, we additionally found that rGel/BLyS downregulated levels of several NF-kappaB 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-kappaB and are resistant to conventional chemotherapeutic regimens.
Lyu
Mi-Ae
MA
Immunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Rai
Deepak
D
Ahn
Kwang Seok
KS
Sung
Bokyung
B
Cheung
Lawrence H
LH
Marks
John W
JW
Aggarwal
Bharat B
BB
Aguiar
Ricardo C T
RC
Gandhi
Varsha
V
Rosenblum
Michael G
MG
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D053264:B-Cell Activating Factor / Q000008:administration & dosage* / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D016503:Drug Delivery Systems / Q000379:methods*; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics; D054789:Ribosome Inactivating Proteins, Type 1 / Q000008:administration & dosage / Q000235:genetics; D014118:Toxins, Biological / Q000008:administration & dosage* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D053264:B-Cell Activating Factor; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D014118:Toxins, Biological; C025674:GEL protein, Gelonium multiflorum
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