Document Detail

Galiximab signals B-NHL cells and inhibits the activities of NF-B-induced YY1 and Snail resistant factors: mechanism of sensitization to apoptosis by chemo-immunotherapeutic drugs.
MedLine Citation:
PMID:  22267549     Owner:  NLM     Status:  Publisher    
Galiximab (anti-CD80 mAb) is a primatized (human IgG1 constant regions and Cynomolgous macaque variable regions) mAb that is currently in clinical trials. Galiximab inhibits tumor cell proliferation through possibly cell signaling-mediated effects. Thus, we hypothesized that Galiximab may signal the tumor cells and modify intracellular survival/anti-apoptotic pathways such as the NF-B pathway. This hypothesis was tested using various CD80+ Burkitt B-NHL cell lines as models. Treatment of B-NHL cells with Galiximab (25-100 g/ml) resulted in significant inhibition of NF-B activity and its target resistant factors such as YY1, Snail, and Bcl-2/Bcl-XL. Treatment of B-NHL cells with Galiximab sensitized the tumor cells to both CDDP and TRAIL-induced apoptosis. The important roles of YY1 and Snail-induced inhibition by Galiximab in the sensitization to CCDP and TRAIL were corroborated following transfection of Raji cells with YY1 or Snail siRNA. The transfected cells were shown to become sensitive to both CCDP and TRAIL-induced apoptosis in the absence of Galiximab. Further, knockdown of YY1 or Snail inhibited Bcl-XL. The involvement of Bcl-XL inhibition in sensitization was corroborated by the use of the pan Bcl-2 inhibitor 2MAM-3 whereby the treated cells were sensitive to both CDDP and TRAIL-induced apoptosis. These findings demonstrate that Galiximab inhibits the NF-B/Snail/YY1/Bcl-XL circuit that regulates drug-resistance in B-NHL and in combination with cytotoxic drugs results in apoptosis. The findings also support the therapeutic application of the combination of Galiximab and cytotoxic drugs in the treatment of drug-resistant CD80 positive B cell malignancies.
Melisa Martinez-Paniagua; Mario I Vega; Sarah Huerta-Yepez; Stavroula Baritaki; Gabriel G Vega; Kandasamy Hariharan; Benjamin Bonavida
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-1-19
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  -     ISSN:  1538-8514     ISO Abbreviation:  -     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-1-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1Hospital de Infectologia, Unidad de Investigacion Medica en Immunologia e Infectologia.
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