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Blood, 7 May 2009, Vol. 113, No. 19, pp. 4656-4666. Prepublished online as a Blood First Edition Paper on February 3, 2009; DOI 10.1182/blood-2008-09-175430. This Article Full Text (PDF) All Versions of this Article: blood-2008-09-175430v1 113/19/4656    most recent Alert me when this article is cited Alert me if a correction is posted 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 Lucas, D. M. Articles by Grever, M. R. Search for Related Content PubMed PubMed Citation Articles by Lucas, D. M. Articles by Grever, M. R. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 8, 2008 Accepted January 27, 2009 The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo David M. Lucas*, Ryan B. Edwards, Gerard Lozanski, Derek A. West, Jungook D. Shin, Melissa A. Vargo, Melanie E. Davis, Darlene M. Rozewski, Amy J. Johnson, Bao-Ning Su, Virginia M. Goettl, Nyla A. Heerema, Thomas S. Lin, Amy Lehman, Xiaoli Zhang, David Jarjoura, David J. Newman, John C. Byrd, A. Douglas Kinghorn, and Michael R. Grever Department of Internal Medicine, The Ohio State University, Columbus, OH, United States Department of Pathology, The Ohio State University, Columbus, OH, United States College of Pharmacy, The Ohio State University, Columbus, OH, United States Center for Biostatistics, The Ohio State University, Columbus, OH, United States Natural Products Branch, National Cancer Institute, Frederick, MD, United States * Corresponding author; email: david.lucas{at}osumc.edu. Therapeutic options for advanced B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are limited. Currently available treatments can also deplete T-lymphocytes, leaving patients at risk of life-threatening infections. In the NCI cell-line screen, the structurally unique natural product silvestrol produces an unusual pattern of cytotoxicity that suggests activity in leukemia and selectivity for B-cells. We therefore assessed silvestrol efficacy using primary human B-leukemia cells, established B-leukemia cell lines, and animal models. In CLL patient cells, silvestrol LC50 (concentration lethal to 50%) is 6.9 nM at 72 hours. At this concentration, there is no difference in sensitivity of cells from patients with or without the del(17p13.1) abnormality. In isolated cells and whole blood, silvestrol is more cytotoxic toward B-cells than T-cells. Silvestrol causes early reduction in Mcl-1 expression due to translational inhibition with subsequent mitochondrial damage, as evidenced by reactive oxygen species generation and membrane depolarization. In vivo, silvestrol causes significant B-cell reduction relative to T-cells in Eµ-Tcl-1 transgenic mice and significantly extends survival of 697 xenograft SCID mice without discernible toxicity. These data indicate silvestrol has efficacy against B-cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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