This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kawakami, M. Articles by Puri, R. K. Search for Related Content PubMed PubMed Citation Articles by Kawakami, M. Articles by Puri, R. K.

Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

Apoptosis is not only essential for homeostasis in normal cells but also in cancer cells, in which it is associated with cell death mechanisms caused by novel therapeutics. We have previously reported that interleukin-13 receptors (IL-13R) are constitutively overexpressed on a majority of human malignant glioma cell lines and primary cell cultures. In addition, we have reported that IL-13 cytotoxin, comprised of human IL-13 and a mutated form of Pseudomonas exotoxin, is highly and specifically cytotoxic to these cells and can lead to pronounced antitumor activity in malignant glioma tumors in animal models. However, the molecular mechanisms of tumor cytotoxicity induced by IL-13 cytotoxin are poorly understood. In this study, we demonstrate that glioma tumors undergo apoptotic cell death on intratumoral administration of IL-13 cytotoxin. This conclusion was made based on (a) time-dependent induction of several proapoptotic molecules, such as caspases (caspase-3, -8, and -9) in tumors; (b) cleavage of procaspase-3 and poly(ADP-ribose) polymerase (PARP); and (c) the release of cytochrome c from mitochondria to the cytosol on injection of IL-13 cytotoxin in U251 glioblastoma tumors established in immunodeficient animals. These indicators of two major pathways of apoptosis were detected in tumors even though IL-13 cytotoxin was no longer present in tumors. In addition, we found that inducible nitric oxide was expressed in tumors in a time-dependent manner with primary localization in infiltrating phagocytes after treatment with IL-13 cytotoxin. These studies demonstrate that IL-13 cytotoxin mediates apoptotic death of glioma cells, resulting in regression of established tumors. Our studies will help unravel the molecular pathways of cell death associated with tumor regression and provide additional insight and define apoptosis as possible surrogate marker of tumor response.

This article has been cited by other articles:

				J. S. Jarboe, K. R. Johnson, Y. Choi, R. R. Lonser, and J. K. Park Expression of Interleukin-13 Receptor {alpha}2 in Glioblastoma Multiforme: Implications for Targeted Therapies Cancer Res., September 1, 2007; 67(17): 7983 - 7986. [Abstract] [Full Text] [PDF]

				A.B. Madhankumar, B. Slagle-Webb, A. Mintz, J. M. Sheehan, and J. R. Connor Interleukin-13 receptor-targeted nanovesicles are a potential therapy for glioblastoma multiforme Mol. Cancer Ther., December 1, 2006; 5(12): 3162 - 3169. [Abstract] [Full Text] [PDF]

				K. Kawakami, M. Terabe, M. Kioi, J. A. Berzofsky, and R. K. Puri Intratumoral Therapy with IL13-PE38 Results in Effective CTL-Mediated Suppression of IL-13R{alpha}2-Expressing Contralateral Tumors Clin. Cancer Res., August 1, 2006; 12(15): 4678 - 4686. [Abstract] [Full Text] [PDF]

				G. J.A. Murad, S. Walbridge, P. F. Morrison, K. Garmestani, J. W. Degen, M. W. Brechbiel, E. H. Oldfield, and R. R. Lonser Real-time, Image-Guided, Convection-Enhanced Delivery of Interleukin 13 Bound to Pseudomonas Exotoxin. Clin. Cancer Res., May 15, 2006; 12(10): 3145 - 3151. [Abstract] [Full Text] [PDF]

				K. Kawakami, M. Terabe, M. Kawakami, J. A. Berzofsky, and R. K. Puri Characterization of a Novel Human Tumor Antigen Interleukin-13 Receptor {alpha}2 Chain. Cancer Res., April 15, 2006; 66(8): 4434 - 4442. [Abstract] [Full Text] [PDF]

				C. E. Jenkins, A. Swiatoniowski, A. C. Issekutz, and T.-J. Lin Pseudomonas aeruginosa Exotoxin A Induces Human Mast Cell Apoptosis by a Caspase-8 and -3-dependent Mechanism J. Biol. Chem., August 27, 2004; 279(35): 37201 - 37207. [Abstract] [Full Text] [PDF]

				K. Kawakami, M. Kawakami, and R. K. Puri Nitric Oxide Accelerates Interleukin-13 Cytotoxin-Mediated Regression in Head and Neck Cancer Animal Model Clin. Cancer Res., August 1, 2004; 10(15): 5264 - 5270. [Abstract] [Full Text] [PDF]

				C. Jakubzick, E. S. Choi, K. J. Carpenter, S. L. Kunkel, H. Evanoff, F. J. Martinez, K. R. Flaherty, G. B. Toews, T. V. Colby, W. D. Travis, et al. Human Pulmonary Fibroblasts Exhibit Altered Interleukin-4 and Interleukin-13 Receptor Subunit Expression in Idiopathic Interstitial Pneumonia Am. J. Pathol., June 1, 2004; 164(6): 1989 - 2001. [Abstract] [Full Text] [PDF]

				K. Kawakami, M. Kawakami, and R. K. Puri Specifically targeted killing of interleukin-13 (IL-13) receptor-expressing breast cancer by IL-13 fusion cytotoxin in animal model of human disease Mol. Cancer Ther., February 1, 2004; 3(2): 137 - 147. [Abstract] [Full Text] [PDF]

				D. A. Todhunter, W. A. Hall, E. Rustamzadeh, Y. Shu, S. O. Doumbia, and D. A. Vallera A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model Protein Eng. Des. Sel., February 1, 2004; 17(2): 157 - 164. [Abstract] [Full Text] [PDF]

				S. R. Husain, K. Kawakami, M. Kawakami, and R. K. Puri Interleukin-4 Receptor-targeted Cytotoxin Therapy of Androgen-dependent and -independent Prostate Carcinoma in Xenograft Models Mol. Cancer Ther., March 1, 2003; 2(3): 245 - 254. [Abstract] [Full Text] [PDF]