The critical role of angiogenesis in tumor development has long been considered for the development of effective therapeutical antiangiogenic drugs. It has been shown that different inhibitors of the sterol biosynthesis pathway affect the angiogenic process. For instance the antifungal drugs terbinafine and itraconazole, two inhibitors of the late steps of cholesterol biosynthesis, inhibit the proliferation and differentiation of endothelial cells (EC) acting downstream the formation of prenyl intermediates, suggesting a mechanism different from that of the HMGCoA reductase inhibitors statins. Therefore different steps of sterol biosynthesis could be targeted to obtain antiangiogenic drugs. Here we present the antiangiogenic activity of four different sterol biosynthetic pathway enzyme inhibitors, namely Ro48-8071, policosanol, naftifine and itraconazole, which target oxidosqualene cyclase, HMGCoA reductase, squalene epoxidase and C14 demethylase enzymes, respectively. All the compounds were able to inhibit the migration, differentiation, adhesion of EC in vitro and the vessel network pattern ex vivo experimental models. Compared to the other inhibitors, Ro48-8071 was the most potent inhibitor of VEGF-A-mediated EC migration and adhesion on fibronectin. Besides, the compound was the most efficient in inhibiting the vessel network formation on matrigel and in the presence of cholesterol its antiangiogenic acivity was completely abrogated. Ro48-8071 did not affect the expression and activation of the small GTPase Rho, rather it was able to decrease the phosphorylation of AKT, but not ERK, in a time-dependent manner, thus suggesting its specificity for the mTOR pathway, an important regulator of cell growth and proliferation. Taken together these data indicate that the inhibition of the oxidosqualene cyclase enzyme, by sensing the membrane sterol content, exerts an effect on vessel formation conferring to Ro-8071 a role as a potential new antiangiogenic drug.
Effect of inhibiting the sterol biosynthesis pathway and the cholesterol content in the regulation of angiogenesis in vitro and in vivo
MEDA, CLAUDIA MARIA;OLIARO BOSSO, Simonetta;BUSSOLINO, Federico;BALLIANO, Gianni;VIOLA, Franca Cecilia;GIRAUDO, Enrico
2011-01-01
Abstract
The critical role of angiogenesis in tumor development has long been considered for the development of effective therapeutical antiangiogenic drugs. It has been shown that different inhibitors of the sterol biosynthesis pathway affect the angiogenic process. For instance the antifungal drugs terbinafine and itraconazole, two inhibitors of the late steps of cholesterol biosynthesis, inhibit the proliferation and differentiation of endothelial cells (EC) acting downstream the formation of prenyl intermediates, suggesting a mechanism different from that of the HMGCoA reductase inhibitors statins. Therefore different steps of sterol biosynthesis could be targeted to obtain antiangiogenic drugs. Here we present the antiangiogenic activity of four different sterol biosynthetic pathway enzyme inhibitors, namely Ro48-8071, policosanol, naftifine and itraconazole, which target oxidosqualene cyclase, HMGCoA reductase, squalene epoxidase and C14 demethylase enzymes, respectively. All the compounds were able to inhibit the migration, differentiation, adhesion of EC in vitro and the vessel network pattern ex vivo experimental models. Compared to the other inhibitors, Ro48-8071 was the most potent inhibitor of VEGF-A-mediated EC migration and adhesion on fibronectin. Besides, the compound was the most efficient in inhibiting the vessel network formation on matrigel and in the presence of cholesterol its antiangiogenic acivity was completely abrogated. Ro48-8071 did not affect the expression and activation of the small GTPase Rho, rather it was able to decrease the phosphorylation of AKT, but not ERK, in a time-dependent manner, thus suggesting its specificity for the mTOR pathway, an important regulator of cell growth and proliferation. Taken together these data indicate that the inhibition of the oxidosqualene cyclase enzyme, by sensing the membrane sterol content, exerts an effect on vessel formation conferring to Ro-8071 a role as a potential new antiangiogenic drug.
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