Abstract
Aberrant angiogenesis is essential for the progression of solid tumors and hematological malignancies. Thus, antiangiogenic therapy is one of the most promising approaches to control cancer. In the present work, we examined the ability of perillyl alcohol (POH), a dietary monoterpene with well-established tumor chemopreventive and chemotherapeutic activity, to interfere with the process of angiogenesis. POH remarkably prevented new blood vessel growth in the in vivo chicken embryo chorioallantoic membrane assay and proved to be effective in inhibiting the morphogenic differentiation of cultured endothelial cells into capillary-like networks both in collagen gel and Matrigel models. In addition, POH reduced the cell number in a proliferation assay and induced apoptosis of endothelial cells as indicated by the POH-mediated increase of caspase-3 activity and DNA fragmentation. Consistent with the observed antisurvival effect, POH treatment resulted in a significant inhibition of Akt phosphorylation in endothelial cells. Finally, POH was able to differentially modulate the release of two important angiogenic regulators: vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2). POH decreased the release of VEGF from cancer cells but stimulated the expression of Ang2 by endothelial cells, indicating that it might suppress neovascularization and induce vessel regression. Overall, these data underscore the antiangiogenic potential of POH and suggest that POH, in addition to its anticancer activity, may be an effective agent in the treatment of angiogenesis-dependent diseases.
Footnotes
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This study was supported in part by a grant from The Chios Gum Mastic Growers Association and by funds from the Thorax Foundation.
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doi:10.1124/jpet.104.070516.
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ABBREVIATIONS: POH, perillyl alcohol; VEGF, vascular endothelial growth factor; Ang, angiopoietin; CAM, chorioallantoic membrane; BLMVEC, bovine lung microvascular endothelial cell; HUVEC, human umbilical vein endothelial cell; PMA, phorbol 12-myristate 13-acetate; ELISA, enzyme-linked immunosorbent assay.
- Received April 23, 2004.
- Accepted June 15, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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