TY - JOUR
T1 - The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo
AU - Lyu, Mi Ae
AU - Rai, Deepak
AU - Ahn, Kwang Seok
AU - Sung, Bokyung
AU - Cheung, Lawrence H.
AU - Marks, John W.
AU - Aggarwal, Bharat B.
AU - Aguiar, Ricardo C.T.
AU - Gandhi, Varsha
AU - Rosenblum, Michael G.
N1 - Funding Information:
Abbreviations: rGel/BLyS, a fusion toxin containing rGel at the N-terminus followed by a G4S peptide tethered to the BLyS molecule; G4S, glycine-glycine-glycine-glycine-serine; ABC-DLBCL, activated B-cell–like diffuse large B-cell lymphoma; GC-DLBCL, germinal center–like diffuse large B-cell lymphoma; NHL, non–Hodgkin lymphoma; NF-κB, nuclear factor-κB; BLyS, B-lymphocyte stimulator; IκB, inhibitory subunit of NF-κB; IAP, inhibitor-of-apoptosis protein; x-IAP, x-chromosome linked inhibitor-of-apoptosis; EMSA, electrophoretic mobility shift assay; PVDF, polyvinylidene difluoride; PARP, poly ADP-ribose polymerase; TUNEL, terminal deoxynucleotidyl transferase–mediated nick end labeling Address all correspondence to: Michael G. Rosenblum, PhD, Immunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0044, Houston, TX 77030. E-mail: [email protected] 1This research was conducted, in part, by the Clayton Foundation for Research (M.G.R.), a Translational Research award (LLS 6234-07) by the Leukemia and Lymphoma Society (V.G. and M.G.R.), and Lymphoma SPORE CA136411, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Received 1 December 2009; Revised 1 February 2010; Accepted 2 February 2010 Copyright © 2010 Neoplasia Press, Inc. All rights reserved 1522-8002/10/$25.00 DOI 10.1593/neo.91960
PY - 2010/5
Y1 - 2010/5
N2 - 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.
AB - 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.
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U2 - 10.1593/neo.91960
DO - 10.1593/neo.91960
M3 - Article
C2 - 20454508
AN - SCOPUS:77951694051
SN - 1522-8002
VL - 12
SP - 366
EP - 375
JO - Neoplasia
JF - Neoplasia
IS - 5
ER -