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Tumor regression mechanisms by IL‐13 receptor–targeted cancer therapy involve apoptotic pathways
Author(s) -
Kawakami Mariko,
Kawakami Koji,
Puri Raj K.
Publication year - 2002
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10778
Subject(s) - apoptosis , biology , in vivo , programmed cell death , cancer research , pseudomonas exotoxin , cytochrome c , in vitro , caspase , microbiology and biotechnology , biochemistry , cytotoxicity , genetics
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. © 2002 Wiley‐Liss, Inc.