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Farnesyltransferase inhibitors target multiple endothelial cell functions in angiogenesis

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Abstract

Farnesyltransferase inhibitors (FTIs) are novel anticancer drugs that inhibit the secretion of pro-angiogenic factors by Ras-transformed cancer cells. FTIs also inhibit angiogenesis in a rat corneal model, suggesting that FTIs have anti-angiogenic properties that extend beyond targeting cancer cells. Our hypothesis was that FTIs may directly target endothelial cell functions in angiogenesis. We examined the effects of FTI treatment on a range of assays designed to pick apart the individual functions of endothelial cells during angiogenesis. We found that FTIs inhibit endothelial cell proliferation, causing a failure of mitosis and accumulation of binucleate cells. FTIs also block the directional migration of endothelial cells toward VEGF, the major pro-angiogenic factor in adult tissues. In a co-culture assay of angiogenesis, FTI treatment significantly inhibits tube formation, but has no effect on pre-existing structures. Defects in tube formation could be replicated by specific targeting of endothelial cell farnesyltransferase using RNA interference. Our data show that FTIs directly target endothelial cells in angiogenesis, explaining previous in vivo findings. Importantly, these results suggest that the therapeutic use of FTIs may extend beyond cancer to include the treatment of other diseases involving pathological angiogenesis.

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Acknowledgments

This study was supported by a British Heart Foundation Project Grant to HM and a Medical Research Council Infrastructure Award to the School of Medical Sciences Imaging Centre.

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Authors and Affiliations

  1. Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK

    Alice N. Scott, Clare Hetheridge, Vrinda Nayak & Harry Mellor

  2. Cell Adhesion and Disease Laboratory, Richard Dimbleby Department of Cancer Research/Cancer Research UK, St. Thomas’ Hospital, Lambeth Palace Road, London, SE1 7EH, UK

    Andrew R. Reynolds & Kairbaan Hodivala-Dilke

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  1. Alice N. Scott
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  2. Clare Hetheridge
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  4. Vrinda Nayak
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Corresponding author

Correspondence to Harry Mellor.

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10456_2008_9115_MOESM1_ESM.pdf

MOESM1 [FTI inhibits proliferation in a co-culture assay of angiogenesis. Assays were performed in the absence or presence of FTI for the periods indicated. Prior to fixation, cells were treated with BrdU for 2 h to label actively proliferating cells. Cells were then fixed and stained with DAPI (blue) to reveal endothelial cells and fibroblasts, and with PECAM-1 (green) to reveal the endothelial cells. Staining for BrdU incorporation is shown in the right-hand panels. In each case, areas containing both endothelial cells and fibroblasts were selected. In the right-hand panels, In the right-hand panels, the line marks the boundary between the two cell types. Active proliferation of endothelial cells was restricted to the first 4 days, whereas fibroblast proliferation continued throughout the assay. FTI treatment blocked the proliferation of endothelial cells. Scale bar represents 20 μm (PDF 345 kb)

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Scott, A.N., Hetheridge, C., Reynolds, A.R. et al. Farnesyltransferase inhibitors target multiple endothelial cell functions in angiogenesis. Angiogenesis 11, 337–346 (2008). https://doi.org/10.1007/s10456-008-9115-3

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  • DOI: https://doi.org/10.1007/s10456-008-9115-3

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