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

Int J Cancer. 2003 Jan 1;103(1):45-52. doi: 10.1002/ijc.10778.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADP Ribose Transferases / genetics
  • Animals
  • Apoptosis / drug effects*
  • Bacterial Toxins / genetics
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Caspases / metabolism
  • Cytochrome c Group / metabolism
  • Exotoxins / genetics
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / 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
  • Neoplasms, Experimental / therapy*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Pseudomonas aeruginosa
  • Pseudomonas aeruginosa Exotoxin A
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-13
  • Recombinant Fusion Proteins / pharmacology*
  • Subcellular Fractions
  • Tumor Cells, Cultured
  • Virulence Factors / genetics

Substances

  • 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
  • Caspases