Abstract
To identify small molecules that selectively control hematopoietic stem cell differentiation, we performed an unbiased screen using primary human CD34(+) cells. We identified a plant-derived natural product, euphohelioscopin A, capable of selectively differentiating CD34(+) cells down the granulocyte/monocytic lineage. Euphohelioscopin A also inhibits proliferation and induces differentiation of the myeloid leukemia cell lines THP-1 and HL-60. Mechanistic studies revealed that euphohelioscopin A is an activator of protein kinase C (PKC), and that the promonocytic effects of this natural product are mediated by PKC activation. In addition to shedding insights into normal hematopoiesis, this work may ultimately facilitate the application of stem cell therapies to a host of myeloid dysfunctions.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antigens, CD34 / metabolism
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Cell Differentiation / drug effects*
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Cell Lineage
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Cells, Cultured
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Diterpenes / chemistry
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Diterpenes / pharmacology*
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Granulocytes / cytology
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HEK293 Cells
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HL-60 Cells
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HeLa Cells
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / metabolism
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Humans
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Indoles / pharmacology
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Macrophages / cytology
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Macrophages / drug effects
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Maleimides / pharmacology
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Protein Kinase C / chemistry
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Protein Kinase C / metabolism*
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Tetradecanoylphorbol Acetate / analogs & derivatives
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Tetradecanoylphorbol Acetate / pharmacology
Substances
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2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide
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Antigens, CD34
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Diterpenes
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Indoles
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Maleimides
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euphohelioscopin A
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4-O-methyl-12-O-tetradecanoylphorbol 13-acetate
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Protein Kinase C
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Tetradecanoylphorbol Acetate