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

Ming-Jen Hsu; Han-Kun Chen; Cheng-Yu Chen; Jin-Cherng Lien; Jing-Yan Gao; Yu-Han Huang; Justin Bo-Kai Hsu; Gilbert Aaron Lee; Shiu-Wen Huang

doi:10.3389/fonc.2022.862326

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

Front Oncol. 2022 Jun 20:12:862326. doi: 10.3389/fonc.2022.862326. eCollection 2022.

Authors

Ming-Jen Hsu^{1

2

3}, Han-Kun Chen⁴, Cheng-Yu Chen^{5

6

7

8

9}, Jin-Cherng Lien^{10

11}, Jing-Yan Gao^{10

11}, Yu-Han Huang^{12

13}, Justin Bo-Kai Hsu^{5

14}, Gilbert Aaron Lee^{5

14

15}, Shiu-Wen Huang^{1

2

5

14

16}

Affiliations

¹ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
² Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
³ Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
⁴ Department of General Surgery, Chi Mei Medical Center, Tainan, Taiwan.
⁵ Translational Imaging Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
⁶ Department of Radiology, National Defense Medical Center, Taipei, Taiwan.
⁷ Research Center for Artificial Intelligence in Medicine, Taipei Medical University, Taipei, Taiwan.
⁸ Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan.
⁹ Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
¹⁰ School of Pharmacy, China Medical University, Taichung, Taiwan.
¹¹ Department of Medical Research, Hospital of China Medical University, Taichung, Taiwan.
¹² Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States.
¹³ The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, United States.
¹⁴ Department of Medical Research; Research Center of Thoracic Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
¹⁵ Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
¹⁶ Research Center of Thoracic Medicine, Taipei Medical University Hospital, Taipei, Taiwan.

Abstract

Background and purpose: Benzimidazoles 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 approach: MTT, 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 results: MFB 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 implications: These 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.

Keywords: aminobenzimidazole; angiogenesis; human umbilical vascular endothelial cells (HUVECs); lymphatic endothelial cells (LECs); vascular endothelial growth factor (VEGF).