Abstract A9: The HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) inhibits vascular endothelial growth factor C-induced lymphangiogenesis

Abstract The lymphatic system plays an important role in tissue fluid homeostasis, immune surveillance, and fat absorption and also is involved in various pathological situations. Recent studies showed that lymphangiogenesis is not only important for physiological regulations but also associated with the metastatic spread of cancer. The histone deacetylase (HDAC) inhibitor SAHA has been reported to inhibit tumor cell proliferation, induce apoptosis and reduce angiogenesis in different cancer types. In this study, prox1-overexpressing endothelial cell line EA.hy926-Prox1 with the characteristics of lymphatic endothelial is used to evaluate the anti-lymphangiogenic and anti-cancer activity of SAHA. SAHA at low concentrations inhibits growth of EA.hy926-Prox1 endothelial cells via induction of G2/M arrest. Multiple G2/M cell cycle regulators are changed by SAHA. At high concentrations, SAHA causes significant cell death. SAHA at non-cytotoxic concentrations prevents vascular endothelial growth factor C (VEGF-C)-stimulated sprouting and capillary-like structure of EA.hy926-Prox1 cells. In addition, we find that SAHA treatment can inhibit the expression and secretion of VEGF-C in breast cancer cells. Our results provide evidence that SAHA can inhibit lymphagiogenic through (A) regulating the proliferation, apoptosis, sprouting and tube formation in lypmphatic endothelial cells and (B) reducing the expression and secretion of VEGF-C in cancer cells. Thus, SAHA may function as a therapeutic agent for the treatment or prevention of tumor-induced lymphangiogensis. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A9.