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Blood, 15 December 2006, Vol. 108, No. 13, pp. 4126-4135. Prepublished online as a Blood First Edition Paper on August 29, 2006; DOI 10.1182/blood-2006-04-017046. This Article Full Text Full Text (PDF) Supplemental Table and Video All Versions of this Article: blood-2006-04-017046v1 108/13/4126    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ge, Y. Articles by Gardner, K. Search for Related Content PubMed PubMed Citation Articles by Ge, Y. Articles by Gardner, K. Related Collections Neoplasia Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Selective leukemic-cell killing by a novel functional class of thalidomide analogs Yun Ge, Idalia Montano, Gabriella Rustici, Wendy J. Freebern, Cynthia M. Haggerty, Wenwu Cui, Damaris Ponciano-Jackson, G. V. R. Chandramouli, Erin R. Gardner, William D. Figg, Mones Abu-Asab, Maria Tsokos, Sharon H. Jackson, and Kevin Gardner The Advanced Technology Center, Laboratory of Receptor Biology and Gene Expression, National Cancer Institute (NCI), National Institutes of Health (NIH) Bethesda, MD; Clinical Pharmacology Research Core, SAIC-Frederick Inc, NCI-Frederick, Frederick, MD; Molecular Pharmacology Section, Cancer Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD; Laboratory of Pathology, NCI, Bethesda, MD; and Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD. Using a novel cell-based assay to profile transcriptional pathway targeting, we have identified a new functional class of thalidomide analogs with distinct and selective antileukemic activity. These agents activate nuclear factor of activated T cells (NFAT) transcriptional pathways while simultaneously repressing nuclear factor-B (NF-B) via a rapid intracellular amplification of reactive oxygen species (ROS). The elevated ROS is associated with increased intracellular free calcium, rapid dissipation of the mitochondrial membrane potential, disrupted mitochondrial structure, and caspase-independent cell death. This cytotoxicity is highly selective for transformed lymphoid cells, is reversed by free radical scavengers, synergizes with the antileukemic activity of other redox-directed compounds, and preferentially targets cells in the S phase of the cell cycle. Live-cell imaging reveals a rapid drug-induced burst of ROS originating in the endoplasmic reticulum and associated mitochondria just prior to spreading throughout the cell. As members of a novel functional class of "redoxreactive" thalidomides, these compounds provide a new tool through which selective cellular properties of redox status and intracellular bioactivation can be leveraged by rational combinatorial therapeutic strategies and appropriate drug design to exploit cell-specific vulnerabilities for maximum drug efficacy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2006 by American Society of Hematology         Online ISSN: 1528-0020