Abstract 2992: Zoledronic acid inhibits angiogenesis through Rac1 inactivation in ovarian cancer

Background Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a complex and crucial process for tumor growth and development of metastasis. Rac1, a member of the Rho GTPase family, plays a central role in angiogenesis through regulation of endothelial cell migration, tube formation, adhesion, invasion, and proliferation. In this study we hypothesized that zoledronic acid (ZA) inhibits ovarian cancer angiogenesis through the inactivation of Rac1. Methods We treated HeyA8 MDR and Ovcar-5 cells with ZA to assess its effects on cell invasion, proliferation, expression of matrix metalloproteinases (MMPs; Milliplex assay) and angiogenic factors. We also determined Rac1 activation by pull-down assay. HeyA8 MDR and Ovcar-5 orthotopic murine models of ovarian cancer were assessed for expression of CD31 and Ki-67, Rac1 activation, and apoptosis by immunohistochemistry after treatment with ZA, nanoparticle, albumin-bound paclitaxel (nab-paclitaxel), or a combination. Results In vitro, we observed inhibition of HeyA8 MDR and Ovcar-5 cell invasion and proliferation by ZA. Moreover, ZA decreased the secretion of MMP-7 and vascular endothelial growth factor C (VEGF-C) in HeyA8 MDR cells and MMP-9, MMP-10, VEGF-C, granulocyte-colony stimulating factor, endothelin-1, follistatin, interleukin-8, placenta growth factor, fibroblast growth factor-1, and hepatocyte growth factor in Ovcar-5 cells. Furthermore, ZA inactivated Rac1 in both cells lines. In vivo, ZA decreased the number of nodules and tumor weight, inhibited angiogenesis and cell proliferation, and increased apoptosis in both HeyA8 MDR and Ovcar-5 animal models. These in vivo antitumor effects were enhanced in both models when ZA was combined with nab-paclitaxel. Conclusion ZA inhibits ovarian cancer angiogenesis through the inactivation of Rac1, suggesting that ZA combined with paclitaxel could be a novel therapeutic approach to ovarian cancer angiogenesis. Citation Format: Viany Gonzalez-Villasana, Cristian Rodriguez-Aguayo, Enrique Fuentes-Mattei, Sunila Pradeep, Cristina Ivan, Anil K. Sood, Gabriel Lopez-Berestein. Zoledronic acid inhibits angiogenesis through Rac1 inactivation in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2992. doi:10.1158/1538-7445.AM2014-2992