Alendronate suppresses tumor angiogenesis by inhibiting Rho activation of endothelial cells

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Abstract

We previously reported that alendronate inhibits intraperitoneal dissemination in an in vivo ovarian cancer model. Recently, nitrogen-containing bisphosphonates have been reported to have antiangiogenic activities. In this study, alendronate inhibited human umbilical vein endothelial cell (HUVEC) migration and capillary-like structure formation in vitro. These inhibitory effects were associated with reduced Rho activation and suppression of the formation of actin stress fibers and focal adhesions in HUVECs. Furthermore, the inhibition by alendronate was reversed by geranylgeraniol, which abrogated the inhibition of Rho geranylgeranylation. Next, we examined the effect of alendronate on angiogenesis in disseminated ovarian tumors of athymic immunodeficient mice. Alendronate treatment reduced the intra-tumor neoangiogenesis compared with that in the non-treated mice, although tumor-derived VEGF expression was not altered. In conclusion, the in vivo anti-tumor effect of alendronate might be derived, at least in part, from its direct antiangiogenic effects on intra-tumor endothelial cells by inhibiting Rho geranylgeranylation.

Section snippets

Materials and methods

Materials. We used alendronate (sodium hydrate) (TEIJIN LIMITED), which has already been marketed in Japan. Recombinant human VEGF was purchased from Wako (Osaka, Japan). BSA and collagen type I were purchased from Sigma (St. Louis, MO). Rat anti-mouse CD31 monoclonal antibody and growth factor reduced Matrigel were purchased from BD Biosciences (Bedford, MA). The Rho Activation Assay Kit and anti-paxillin monoclonal antibody were obtained from Upstate Biotechnology (Lake Placid, NY). Anti-RhoA

Alendronate inhibits VEGF-induced EC migration

Tumor-associated angiogenesis is known to play an important role in tumor growth and progression in vivo. Previously, we demonstrated that alendronate reduced the tumor burden and inhibited ascites accumulation [3]. In this study, we next examined the direct antiangiogenic effect of alendronate against ECs.

EC migration is an important factor in angiogenesis. We therefore investigated whether alendronate inhibits VEGF-enhanced EC migration. VEGF stimulated the cell migration of HUVECs as

Discussion

Clinical observations have confirmed that VEGF status is associated with the extent of neovascularization [12] and prognosis in many solid tumors [13]. There are some discrepancies among the previously reported effects of NBPs on tumor-derived VEGF expression. It was reported that non-cytotoxic concentrations of minodronate did not affect the production of VEGF by renal cell cancer [14]. On the other hand, NBPs were reported to reduce circulating VEGF in cancer patients [15]. Therefore, we

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    This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.

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