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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 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 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 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. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA 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. Lucas1, Ryan B. Edwards1, Gerard Lozanski2, Derek A. West1, Jungook D. Shin1, Melissa A. Vargo1, Melanie E. Davis1, Darlene M. Rozewski1, Amy J. Johnson1, Bao-Ning Su3, Virginia M. Goettl1, Nyla A. Heerema2, Thomas S. Lin1, Amy Lehman4, Xiaoli Zhang4, David Jarjoura4, David J. Newman5, John C. Byrd1,3, A. Douglas Kinghorn3, and Michael R. Grever1 Departments of 1 Internal Medicine and 2 Pathology, 3 College of Pharmacy, and 4 Center for Biostatistics, The Ohio State University (OSU), Columbus; and 5 Natural Products Branch, National Cancer Institute (NCI), Frederick, MD Therapeutic options for advanced B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are limited. Available treatments can also deplete T lymphocytes, leaving patients at risk of life-threatening infections. In the National Cancer Institute 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 investigated silvestrol efficacy using primary human B-leukemia cells, established B-leukemia cell lines, and animal models. In CLL 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 in Eµ-Tcl-1 transgenic mice and significantly extends survival of 697 xenograft severe combined immunodeficient (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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