Limits...
Lonafarnib is a potential inhibitor for neovascularization.

Sun L, Xie S, Peng G, Wang J, Li Y, Qin J, Zhong D - PLoS ONE (2015)

Bottom Line: In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner.In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation.Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity.

View Article: PubMed Central - PubMed

Affiliation: Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.

ABSTRACT
Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.

No MeSH data available.


Related in: MedlinePlus

The effect of lonafarnib on the proliferation of endothelial cells.(A) HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, and SRB assay was performed to measure cell proliferation. (B)HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, stained with the DNA dye DAPI and cell cycle progression was examined by flow cytometric analysis of cellular DNA content. The amplitude of curves corresponds to the cell number. The peak on the left represents cells in G1 phase of cell cycle, while the right peak represents cells in G2/M phase. (C) Experiments were performed as in (B), and the percentage of cells in G1, S, and G2/M phases was analyzed. (D) HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, and cell death was evaluated by Annexin V/PI- staining assay.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4390146&req=5

pone.0122830.g003: The effect of lonafarnib on the proliferation of endothelial cells.(A) HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, and SRB assay was performed to measure cell proliferation. (B)HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, stained with the DNA dye DAPI and cell cycle progression was examined by flow cytometric analysis of cellular DNA content. The amplitude of curves corresponds to the cell number. The peak on the left represents cells in G1 phase of cell cycle, while the right peak represents cells in G2/M phase. (C) Experiments were performed as in (B), and the percentage of cells in G1, S, and G2/M phases was analyzed. (D) HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, and cell death was evaluated by Annexin V/PI- staining assay.

Mentions: The impaired neovascularization by lonafarnib could also result from its effect on cell proliferation, in addition to the inhibition of cell motility. To investigate the possibility, HUVECs were treated with DMSO or 10 μM lonafarnib for 24 hours and sulforhodamine B (SRB) assay was performed to measure cell proliferation. As shown in Fig 3A, lonafarnib had little effect on endothelial cell proliferation. By flow cytometric analysis of cellular DNA content, we evaluated the effect of lonafarnib on cell cycle. As shown in Fig 3B and 3C, lonafarnib treatment (10 μM) for 24 hours led to a slight increase in the number of G1 phase cells, suggesting that it might halt cell cycle progression and induced growth arrest upon prolonged treatment (see S1 Fig). We also examined the effect of lonafarnib on cell death with Annexin V/PI-staining assay. As shown in Fig 3D, we found that lonafarnib did not significantly affect cell death. Collectively, these results demonstrated that lonafarnib inhibits neovascularization via its effect on the motility, but not on the proliferation of endothelial cells.


Lonafarnib is a potential inhibitor for neovascularization.

Sun L, Xie S, Peng G, Wang J, Li Y, Qin J, Zhong D - PLoS ONE (2015)

The effect of lonafarnib on the proliferation of endothelial cells.(A) HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, and SRB assay was performed to measure cell proliferation. (B)HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, stained with the DNA dye DAPI and cell cycle progression was examined by flow cytometric analysis of cellular DNA content. The amplitude of curves corresponds to the cell number. The peak on the left represents cells in G1 phase of cell cycle, while the right peak represents cells in G2/M phase. (C) Experiments were performed as in (B), and the percentage of cells in G1, S, and G2/M phases was analyzed. (D) HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, and cell death was evaluated by Annexin V/PI- staining assay.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390146&req=5

pone.0122830.g003: The effect of lonafarnib on the proliferation of endothelial cells.(A) HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, and SRB assay was performed to measure cell proliferation. (B)HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, stained with the DNA dye DAPI and cell cycle progression was examined by flow cytometric analysis of cellular DNA content. The amplitude of curves corresponds to the cell number. The peak on the left represents cells in G1 phase of cell cycle, while the right peak represents cells in G2/M phase. (C) Experiments were performed as in (B), and the percentage of cells in G1, S, and G2/M phases was analyzed. (D) HUVECs were treated with DMSO or 10μM lonafarnib for 24 hours, and cell death was evaluated by Annexin V/PI- staining assay.
Mentions: The impaired neovascularization by lonafarnib could also result from its effect on cell proliferation, in addition to the inhibition of cell motility. To investigate the possibility, HUVECs were treated with DMSO or 10 μM lonafarnib for 24 hours and sulforhodamine B (SRB) assay was performed to measure cell proliferation. As shown in Fig 3A, lonafarnib had little effect on endothelial cell proliferation. By flow cytometric analysis of cellular DNA content, we evaluated the effect of lonafarnib on cell cycle. As shown in Fig 3B and 3C, lonafarnib treatment (10 μM) for 24 hours led to a slight increase in the number of G1 phase cells, suggesting that it might halt cell cycle progression and induced growth arrest upon prolonged treatment (see S1 Fig). We also examined the effect of lonafarnib on cell death with Annexin V/PI-staining assay. As shown in Fig 3D, we found that lonafarnib did not significantly affect cell death. Collectively, these results demonstrated that lonafarnib inhibits neovascularization via its effect on the motility, but not on the proliferation of endothelial cells.

Bottom Line: In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner.In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation.Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity.

View Article: PubMed Central - PubMed

Affiliation: Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.

ABSTRACT
Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.

No MeSH data available.


Related in: MedlinePlus