Journal
BLOOD
Volume 113, Issue 19, Pages 4656-4666Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-09-175430
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Funding
- CLL Global Research Foundation (Houston, TX) [NCI (P01 CA081534)]
- American Cancer Society (Atlanta, GA
- Institutional Research Grant)
- Samuel Waxman Cancer Research Foundation (New York, NY)
- Leukemia & Lymphoma Society (White Plains, NY)
- Warren Brown Foundation (Columbus, OH)
- National Cooperative Drug Discovery Group [CA52956, CA125066]
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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 LC(50) (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 E mu-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. (Blood. 2009;113:4656-4666)
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