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Targeting c-kit receptor in neuroblastomas and colorectal cancers using stem cell factor (SCF)-based recombinant bacterial toxins
Swati Choudhary,
Published in Springer Verlag
2016
PMID: 26428235
Volume: 100
   
Issue: 1
Pages: 263 - 277
Abstract
Autocrine activation of c-kit (KIT receptor tyrosine kinase) has been postulated to be a potent oncogenic driver in small cell lung cancer, neuroblastoma (NB), and poorly differentiated colorectal carcinoma (CRC). Although targeted therapy involving tyrosine kinase inhibitors (TKIs) such as imatinib mesylate is highly effective for gastrointestinal stromal tumor carrying V560G c-kit mutation, it does not show much potential for targeting wild-type KIT (WT-KIT). Our study demonstrates the role of stem cell factor (SCF)-based toxin conjugates for targeting WT-KIT-overexpressing malignancies such as NBs and CRCs. We constructed SCF-based recombinant bacterial toxins by genetically fusing mutated form of natural ligand SCF to receptor binding deficient forms of Diphtheria toxin (DT) or Pseudomonas exotoxin A (ETA') and evaluated their efficacy in vitro. Efficient targeting was achieved in all receptor-positive neuroblastoma (IMR-32 and SHSY5Y) and colon cancer cell lines (COLO 320DM, HCT 116, and DLD-1) but not in receptor-negative breast carcinoma cell line (MCF-7) thereby proving specificity. While dose- and time-dependent cytotoxicity was observed in both neuroblastoma cell lines, COLO 320DM and HCT 116 cells, only an anti-proliferative effect was observed in DLD-1 cells. We prove that these novel targeting agents have promising potential as KIT receptor tyrosine kinase targeting system. © 2015, Springer-Verlag Berlin Heidelberg.
About the journal
JournalData powered by TypesetApplied Microbiology and Biotechnology
PublisherData powered by TypesetSpringer Verlag
ISSN01757598
Open AccessNo
Concepts (82)
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    Amino acids
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    Cell culture
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    Cytology
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    Diseases
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    Enzymes
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    Metabolites
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    Stem cells
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    Toxic materials
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    ANTIPROLIFERATIVE EFFECT
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    GASTROINTESTINAL STROMAL TUMORS
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    NEUROBLASTOMA CELL LINES
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    PROTEIN FUSION
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    RECEPTOR TYROSINE KINASE
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    Stem cell factor
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    Targeting
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    TYROSINE KINASE INHIBITOR
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    Cells
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    CHIMERIC PROTEIN
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    Diphtheria toxin
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    PSEUDOMONAS EXOTOXIN
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    PSEUDOMONAS EXOTOXIN A
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    Stem cell factor receptor
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    Unclassified drug
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    Antineoplastic agent
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    BACTERIAL TOXIN
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    Cancer
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    Inhibitor
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    Microbial activity
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    Protein
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    Toxicity
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    Toxin
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    Tumor
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    AFFINITY CHROMATOGRAPHY
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    Antiproliferative activity
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    Apoptosis
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    Article
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    Cancer cell line
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    CODON USAGE
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    Colorectal cancer
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    Controlled study
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    Cytotoxicity
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    Escherichia coli
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    EXPRESSION VECTOR
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    Flow cytometry
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    Gene expression profiling
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    HCT116 CELL LINE
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    Human
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    Human cell
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    Immunofluorescence
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    In vitro study
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    Mcf 7 cell line
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    Molecular cloning
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    Neuroblastoma
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    NEUROBLASTOMA CELL LINE
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    Protein binding
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    Protein expression
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    Protein purification
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    Protein targeting
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    Receptor binding
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    Western blotting
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    Antagonists and inhibitors
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    Cell proliferation
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    Cell survival
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    COLORECTAL TUMOR
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    Dose response
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    Drug delivery system
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    Drug effects
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    Genetics
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    Metabolism
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    Procedures
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    Tumor cell line
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    Bacteria (microorganisms)
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    CITRUS MACROPHYLLA
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    PSEUDOMONAS EXOTOXIN
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    Antineoplastic agents
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    Bacterial toxins
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    Cell line, tumor
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    COLORECTAL NEOPLASMS
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    Dose-response relationship, drug
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    Drug delivery systems
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    Humans
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    Proto-oncogene proteins c-kit