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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2745-2754. Prepublished online as a Blood First Edition Paper on June 27, 2006; DOI 10.1182/blood-2006-04-020263. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2006-04-020263v1 108/8/2745    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ng, P. P. Articles by Penichet, M. L. Search for Related Content PubMed PubMed Citation Articles by Ng, P. P. Articles by Penichet, M. L. Related Collections Immunobiology Neoplasia Apoptosis Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Molecular events contributing to cell death in malignant human hematopoietic cells elicited by an IgG3-avidin fusion protein targeting the transferrin receptor Patrick P. Ng, Gustavo Helguera, Tracy R. Daniels, Simon Z. Lomas, Jose A. Rodriguez, Gary Schiller, Benjamin Bonavida, Sherie L. Morrison, and Manuel L. Penichet From the Department of Microbiology, Immunology, and Molecular Genetics, the Division of Surgical Oncology, the Department of Surgery, the Division of Hematology and Oncology, the Department of Medicine, and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles. We have previously reported that an anti-human transferrin receptor IgG3-avidin fusion protein (anti-hTfR IgG3-Av) inhibits the proliferation of an erythroleukemia-cell line. We have now found that anti-hTfR IgG3-Av also inhibits the proliferation of additional human malignant B and plasma cells. Anti-hTfR IgG3-Av induces internalization and rapid degradation of the TfR. These events can be reproduced in cells treated with anti-hTfR IgG3 cross-linked with a secondary Ab, suggesting that they result from increased TfR cross-linking. Confocal microscopy of cells treated with anti-hTfR IgG3-Av shows that the TfR is directed to an intracellular compartment expressing the lysosomal marker LAMP-1. The degradation of TfR is partially blocked by cysteine protease inhibitors. Furthermore, cells treated with anti-hTfR IgG3-Av exhibit mitochondrial depolarization and activation of caspases 9, 8, and 3. The mitochondrial damage and cell death can be prevented by iron supplementation, but cannot be fully blocked by a pan-caspase inhibitor. These results suggest that anti-hTfR IgG3-Av induces lethal iron deprivation, but the resulting cell death does not solely depend on caspase activation. This report provides insights into the mechanism of cell death induced by anti-TfR Abs such as anti-hTfR IgG3-Av, a molecule that may be useful in the treatment of B-cell malignancies such as multiple myeloma. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. R. Daniels, P. P. Ng, T. Delgado, M. R. Lynch, G. Schiller, G. Helguera, and M. L. Penichet Conjugation of an anti transferrin receptor IgG3-avidin fusion protein with biotinylated saporin results in significant enhancement of its cytotoxicity against malignant hematopoietic cells Mol. Cancer Ther., November 1, 2007; 6(11): 2995 - 3008. [Abstract] [Full Text] [PDF]

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