Tumor regression mechanisms by IL-13 receptor-targeted cancer therapy involve apoptotic pathways.

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.

• Authors: Mariko Kawakami, Koji Kawakami, Raj K Puri
• Journal: International journal of cancer (Int J Cancer) Vol. 103 Issue 1 Pg. 45-52 (Jan 01 2003) ISSN: 0020-7136 [Print] United States
• PMID: 12455052 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2002 Wiley-Liss, Inc.

Chemical References

• Bacterial Toxins
• Cytochrome c Group
• Exotoxins
• IL13RA1 protein, human
• Il13ra1 protein, mouse
• Interleukin-13
• Interleukin-13 Receptor alpha1 Subunit
• Receptors, Interleukin
• Receptors, Interleukin-13
• Recombinant Fusion Proteins
• Virulence Factors
• ADP Ribose Transferases
• Poly(ADP-ribose) Polymerases
• Pseudomonas aeruginosa exotoxin A
• Caspases

Topics

• ADP Ribose Transferases (genetics)
• Animals
• Apoptosis (drug effects)
• Bacterial Toxins (genetics)
• Carcinoma, Squamous Cell (drug therapy, metabolism, pathology)
• Caspases (metabolism)
• Cytochrome c Group (metabolism)
• Exotoxins (genetics)
• Head and Neck Neoplasms (drug therapy, metabolism, pathology)
• Humans
• In Situ Nick-End Labeling
• Interleukin-13 (pharmacology)
• Interleukin-13 Receptor alpha1 Subunit
• Male
• Mice
• Mice, Nude
• Mitochondria (metabolism)
• Neoplasm Transplantation
• Neoplasms, Experimental (metabolism, therapy)
• Poly(ADP-ribose) Polymerases (metabolism)
• Pseudomonas aeruginosa
• Receptors, Interleukin (metabolism)
• Receptors, Interleukin-13
• Recombinant Fusion Proteins (pharmacology)
• Subcellular Fractions
• Tumor Cells, Cultured
• Virulence Factors (genetics)