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Research Articles: Therapeutics, Targets, and Development

Terbinafine inhibits endothelial cell migration through suppression of the Rho-mediated pathway

Graduate Institutes of ¹ Cell and Molecular Biology, ² Biomedical Technology, ³ Medical Sciences, and ⁴ Neuroscience and ⁵ Department of Physiology, School of Medicine, Taipei Medical University, Taipei, Taiwan

Requests for reprints: Wen-Sen Lee, Graduate Institute of Medical Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan. Phone: 886-2-27361661, ext. 3103; Fax: 886-2-27391775. E-mail: wslee{at}tmu.edu.tw

Abstract

We showed previously that terbinafine, an allylamine with fungicidal activity, could inhibit angiogenesis by suppressing the endothelial cell proliferation. In the present study, we further showed that terbinafine (0–120 µmol/L) dose dependently inhibited the adhesion and migration of human umbilical vascular endothelial cells (HUVEC). Western blot analysis showed that terbinafine decreased the levels of Ras protein and membrane-bound RhoA protein. Moreover, the terbinafine-induced migration inhibition in HUVEC was prevented by pretreatment with farnesol or geranylgeraniol. Pretreatment of HUVEC with Ras inhibitor peptide or a ROCK (a kinase associated with RhoA for transducing RhoA signaling) inhibitor, Y27632, abolished the farnesol- or geranylgeraniol-induced prevention effect on the terbinafine-induced migration inhibition, respectively. These data suggest that the consuming or depletion of geranylgeranyl pyrophosphate and consequent suppression of protein geranylgeranylation and farnesylation, which is essential for activation of Rho GTPases and Ras, respectively, might account for the terbinafine-induced inhibition of HUVEC migration. The levels of phosphorylated focal adhesion kinase and paxillin protein and the mRNA levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 were also decreased by terbinafine treatment. Taken together, these results indicate that suppression of Rho-mediated pathway might be involved in the signal transduction leading to the inhibition of cell migration caused by terbinafine in HUVEC. [Mol Cancer Ther 2006;5(12):3130–8]

Grant support: National Science Council of the Republic of China grants NSC 93-2320-B-038-018 and NSC 94-2320-B-038-005 and Topnotch Stroke Research Center Grant, Ministry of Education.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/ 2/06; revised 9/12/06; accepted 10/20/06.