Anti-Angiogenetic and Anti-Lymphangiogenic Effects of a Novel 2-Aminobenzimidazole Derivative, MFB

Abstract

Background and PurposeBenzimidazoles have attracted much attention over the last few decades due to their broad-spectrum pharmacological properties. Increasing evidence is showing the potential use of benzimidazoles as anti-angiogenic agents, although the mechanisms that impact angiogenesis remain to be fully defined. In this study, we aim to investigate the anti-angiogenic mechanisms of MFB, a novel 2-aminobenzimidazole derivative, to develop a novel angiogenesis inhibitor.Experimental ApproachMTT, BrdU, migration and invasion assays, and immunoblotting were employed to examine MFB’s effects on vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration, invasion, as well as signaling molecules activation. The anti-angiogenic effects of MFB were analyzed by tube formation, aorta ring sprouting, and matrigel plug assays. We also used a mouse model of lung metastasis to determine the MFB’s anti-metastatic effects.Key ResultsMFB suppressed cell proliferation, migration, invasion, and endothelial tube formation of VEGF-A-stimulated human umbilical vascular endothelial cells (HUVECs) or VEGF-C-stimulated lymphatic endothelial cells (LECs). MFB suppressed VEGF-A and VEGF-C signaling in HUVECs or LECs. In addition, MFB reduced VEGF-A- or tumor cells-induced neovascularization in vivo. MFB also diminished B16F10 melanoma lung metastasis. The molecular docking results further showed that MFB may bind to VEGFR-2 rather than VEGF-A with high affinity.Conclusions and ImplicationsThese observations indicated that MFB may target VEGF/VEGFR signaling to suppress angiogenesis and lymphangiogenesis. It also supports the role of MFB as a potential lead in developing novel agents for the treatment of angiogenesis- or lymphangiogenesis-associated diseases and cancer.

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“…Western blot was performed as previously described [ 70 ]. Cells were lysed in an extraction buffer containing 0.5% NP-40, 2 mM phenylmethanesulfonylfluooride (PMSF), 140 mM NaCl, 10 mM Tris (pH 7.0), 0.2 mM leupeptin and 0.05 mM pepstatin A.…”

“…An 8 μm-pore-size transwell plate (Corning, NY, USA) was employed to perform the cell migration assay as described previously [ 70 ]. HCT116 cells were stimulated with IL-6/sIL-6R with or without PP2 for 72 h. After treatment, cells (2 × 10 4 cells per well) in 200 µL serum-free McCoy’s 5A medium were seeded in the top transwell chambers.…”

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“… 229 Additionally, various inhibitors targeting lymphangiogenesis have been documented, including rapamycin and a novel 2-aminobenzimidazole derivative called MFB, which effectively suppressed lymphangiogenesis by downregulating VEGFs. 230 , 231 Interestingly, Sasso et al demonstrated that the induction of lymphangiogenesis through VEGFC increased the efficacy of immunotherapy, thereby presenting a novel therapeutic strategy for cancer treatment targeting lymphangiogenesis. 232 …”

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“…Additionally, a mouse model of lung metastasis of melanoma confirmed that compound 8 showed an anti-tumor metastasis effect in vivo. Molecular docking experiments revealed that binding to VEGFR-2 might be the mechanism of compound 8 in inhibiting angiogenesis and lymphangiogenesis [ 55 ].…”