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

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 Mmol/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]

High-throughput identification of small molecules that affect human embryonic vascular development

“…Overall, our results indicated that hESC-derived ECs mature under flow conditions, as shown by the up-regulation of the mechanosensory complex and their capacity to express HSPG. ) conditions can respond to compounds that interfere with EC activity, we cultured cells for 7 d in each condition, after which the culture medium was supplemented or not with terbinafine (0.1 and 1 μM), an antiangiogenic drug that suppresses EC proliferation and activates EC apoptosis (17,18), for an additional day. Our results indicated that the hESC-derived ECs are highly sensitive to terbinafine because the expression of inflammation (ICAM-1; E-SELECTIN), oxidative stress sensing (HO-1), and vasculature modulation (eNOS) genes was upregulated in cells cultured in flow conditions with terbinafine (SI Appendix, Fig.…”

Role of RhoA and its effectors ROCK and mDia1 in the modulation of deformation-induced FAK, ERK, p38, and MLC motogenic signals in human Caco-2 intestinal epithelial cells

“…RhoA is required for cell motility in response to some stimuli (3,26,65), including strain (98) in other cells, and RhoA-dependent, ROCK-dependent signaling is required for epithelial migration across nondeforming substrates (62,68,76), including intestinal IEC-6 and T84 cells (60). Others have also observed that inhibiting RhoA or ROCK can stimulate basal migration (15,40,58,77,86,89) while blocking the stimulation of migration by some other stimulus in other cells (36,39,94). In our hands, silencing mDia1 also enhanced basal migration across tissue fibronectin similarly to ROCK inhibition or reduction while preventing strain stimulation of migration.…”

Ferrous Citrate Up-Regulates the NOS2 through Nuclear Translocation of NFκB Induced by Free Radicals Generation in Mouse Cerebral Endothelial Cells

“…Western blot analysis was performed as described previously [27]. Briefly, cell lysates were prepared, electrotransferred, immunoblotted with antibodies, and then visualized by incubating with the enhanced chemiluminescence system (Amersham, Buckinghamshire, England).…”