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rdf:type |
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lifeskim:mentions |
umls-concept:C0021467,
umls-concept:C0021469,
umls-concept:C0205314,
umls-concept:C0205369,
umls-concept:C0332256,
umls-concept:C0441655,
umls-concept:C0521447,
umls-concept:C0598002,
umls-concept:C0679622,
umls-concept:C1880022,
umls-concept:C2603343,
umls-concept:C2827421
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pubmed:issue |
10
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pubmed:dateCreated |
2010-10-7
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pubmed:abstractText |
The transcription factor nuclear factor-?B (NF-?B) is a central mediator of growth and homeostasis for both normal and neoplastic cells. I?B? is the natural intracellular inhibitor of NF-?B and can effectively complex with and thereby inhibit the biologic activity and translocation of NF-?B to the nucleus. We designed a fusion protein designated I?B?/scFvMEL composing of human I?B? and the single-chain antibody scFvMEL, targets melanoma gp240 antigen. Cells treated with I?B?/scFvMEL before irradiation showed specifically inhibition of both constitutive and radiation-induced NF-?B activity on gp240 antigen-positive A375M cells. Pretreatment of A375M cells with I?B?/scFvMEL significantly sensitized melanoma cells to ionizing radiation assessed using a clonogenic survival assay. Mechanistic studies showed that I?B?/scFvMEL, when exogenously added to A375M cells, could be coimmunoprecipitated with the p65 subunit of NF-?B. I?B?/scFvMEL inhibited in a time and/or dose-dependent manner of tumor necrosis factor ?- or radiation-induced NF-?B activity in vitro. I?B?/scFvMEL was also shown to specifically inhibit the translocation of the NF-?B p65 subunit to the cell nucleus and NF-?B-mediated gene transcription. Further, initial studies showed that mice bearing well-established A375M xenografts were treated (intravenously) with I?B?/scFvMEL and showed a significant suppression of tumor growth. We also observed a decrease in levels of Bcl-2 and Bcl-XL signaling events downstream of NF-?B in the tumor model. These studies demonstrate for the first time that tumor cell-targeted delivery of I?B? may be beneficial for the treatment of melanoma when combined with standard anticancer therapies such as radiation.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/I-kappa B Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappaB inhibitor alpha,
http://linkedlifedata.com/resource/pubmed/chemical/Proteoglycans,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Radiation-Sensitizing Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Rela protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Single-Chain Antibodies,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor RelA,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/gp240 glycoprotein, human
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1476-5586
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
12
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
766-77
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pubmed:meshHeading |
pubmed-meshheading:20927315-Animals,
pubmed-meshheading:20927315-Apoptosis,
pubmed-meshheading:20927315-Blotting, Western,
pubmed-meshheading:20927315-Cell Nucleus,
pubmed-meshheading:20927315-Dose-Response Relationship, Drug,
pubmed-meshheading:20927315-Electrophoretic Mobility Shift Assay,
pubmed-meshheading:20927315-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:20927315-Flow Cytometry,
pubmed-meshheading:20927315-Humans,
pubmed-meshheading:20927315-I-kappa B Proteins,
pubmed-meshheading:20927315-Immunoenzyme Techniques,
pubmed-meshheading:20927315-Melanoma, Experimental,
pubmed-meshheading:20927315-Mice,
pubmed-meshheading:20927315-Mice, Nude,
pubmed-meshheading:20927315-NF-kappa B,
pubmed-meshheading:20927315-Phosphorylation,
pubmed-meshheading:20927315-Protein Transport,
pubmed-meshheading:20927315-Proteoglycans,
pubmed-meshheading:20927315-RNA, Messenger,
pubmed-meshheading:20927315-Radiation, Ionizing,
pubmed-meshheading:20927315-Radiation-Sensitizing Agents,
pubmed-meshheading:20927315-Recombinant Fusion Proteins,
pubmed-meshheading:20927315-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:20927315-Signal Transduction,
pubmed-meshheading:20927315-Single-Chain Antibodies,
pubmed-meshheading:20927315-Transcription Factor RelA,
pubmed-meshheading:20927315-Tumor Necrosis Factor-alpha
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pubmed:year |
2010
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pubmed:articleTitle |
Characterization and mechanistic studies of a novel melanoma-targeting construct containing I?Ba for specific inhibition of nuclear factor-?B activity.
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pubmed:affiliation |
Immunopharmacology & Targeted Therapy Laboratory, Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX 77030,USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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