Abstract
IL-13 cytotoxin, composed of IL-13 and a truncated form of Pseudomonas exotoxin, targets IL-13R-overexpressing tumor cell lines in vitro and in vivo. To reveal the molecular mechanism of IL-13 cytotoxin-induced cell death in vivo, we demonstrate activation of apoptotic pathways in 2 s.c. growing human SCCHN tumor models in immunodeficient mice after i.t. administration of IL-13 cytotoxin. Treatment of HN12 tumor bearing mice with i.p. or i.t. administration of IL-13 cytotoxin mediated marked regression of established tumors with complete remission. Interestingly, after a single i.t. administration, IL-13 cytotoxin disappeared within 6 hr but accumulation of caspase-3, -8 and -9 and cleavage of procaspase-3 and PARP continued within the tumors for a prolonged period. We further demonstrate that IL-13 cytotoxin also utilizes an alternate pathway of cell death via the release of cytochrome c from mitochondria to the cytosol. Our results indicate that IL-13 cytotoxin induces 2 major pathways of apoptosis, which may play a role in tumor regression. In addition, apoptotic molecules may serve as surrogate molecular markers of tumor response to IL-13R-directed cytotoxin therapy.
Copyright 2002 Wiley-Liss, Inc.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ADP Ribose Transferases / genetics
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Animals
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Apoptosis / drug effects*
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Bacterial Toxins / genetics
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Caspases / metabolism
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Cytochrome c Group / metabolism
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Exotoxins / genetics
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Head and Neck Neoplasms / drug therapy*
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Head and Neck Neoplasms / metabolism
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Head and Neck Neoplasms / pathology
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Humans
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In Situ Nick-End Labeling
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Interleukin-13 / pharmacology*
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Interleukin-13 Receptor alpha1 Subunit
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Male
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Mice
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Mice, Nude
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Mitochondria / metabolism
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Neoplasm Transplantation
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / therapy*
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Poly(ADP-ribose) Polymerases / metabolism
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Pseudomonas aeruginosa
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Pseudomonas aeruginosa Exotoxin A
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Receptors, Interleukin / metabolism
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Receptors, Interleukin-13
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Recombinant Fusion Proteins / pharmacology*
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Subcellular Fractions
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Tumor Cells, Cultured
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Virulence Factors / genetics
Substances
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Bacterial Toxins
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Cytochrome c Group
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Exotoxins
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IL13RA1 protein, human
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Il13ra1 protein, mouse
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Interleukin-13
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Interleukin-13 Receptor alpha1 Subunit
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Receptors, Interleukin
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Receptors, Interleukin-13
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Recombinant Fusion Proteins
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Virulence Factors
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ADP Ribose Transferases
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Poly(ADP-ribose) Polymerases
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Caspases