Статья

The rGel/BLyS Fusion Toxin Inhibits Diffuse Large B-cell Lymphoma Growth In Vitro and In Vivo

Mi-Ae LyuImmunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USADeepak RaiDepartment of Medicine, The University of Texas Health Science Center, San Antonio, TX, USAKwang Seok AhnDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USABokyung SungDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USALawrence H. CheungImmunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USAJohn W. MarksImmunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USABharat B. AggarwalDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USARicardo C.T. AguiarDepartment of Medicine, The University of Texas Health Science Center, San Antonio, TX, USAVarsha GandhiDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USAMichael G. RosenblumImmunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2010en

ABI

Аннотация

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.

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Идентификаторы

DOI: 10.1593/neo.91960

Цитирования и источники

Цитирований: 2Использованных источников: 0

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