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Published on: May 8, 2017
SI-27, a novel inhibitor of matrix metalloproteinases with antiangiogenic activity: detection with a
Daizo Yoshida1, Masahiro Noha, Kunihiro Watanabe
1Department of Neurosurgery, Nippon Medical School, Tokyo, Japan. dyoshida@nms.ac.jp
Objective:
Degradation of basement membrane is one the of crucial steps in tumor angiogenesis and is performed by matrix metalloproteinases (MMPs). This study was designed to investigate the suppression of tumor angiogenesis by SI-27, an MMP inhibitor.
Methods:
SI-27 was applied at noncytotoxic concentrations (1-100 micromol/L), and its effect on nonmitogenic vascular endothelial growth factor (VEGF)-enhanced cell motility and in vitro angiogenesis by human umbilical vein endothelial cells was determined. The activity of MMP-1, MMP-2, and tissue inhibitor of metalloproteinase 1 was determined by enzyme-linked immunosorbent assay. The effect of SI-27 on in vitro angiogenesis stimulated by supernatants of human glioma cell lines (U87MG, U251MG, and U373MG) also was examined. Angiogenesis was detected with variable vacuum scanning electron microscopy.
Results:
Cell motility and in vitro angiogenesis by human umbilical vein endothelial cells were significantly increased by VEGF. The maximal effect on cell motility by VEGF was noted at 5 ng/ml (P < 0.001), and the maximal effect on the capillary network was observed at 10 ng/ml (P < 0.001), along with elevated MMP-1 and MMP-2 activity. Whereas SI-27 significantly suppressed VEGF-mediated in vitro angiogenesis (50 micromol/L; P < 0.001) and inactivated both MMP-1 and MMP-2, the expression of tissue inhibitor of metalloproteinase 1 and VEGF-mediated cell motility were not affected by SI-27. The angiogenesis promoted by glioma supernatants showed a significant reduction in the presence of SI-27 (10 micromol/L; U87MG, P < 0.01; U251MG, P < 0.01; U373MG, P < 0.01).
Conclusion:
SI-27 inhibited in vitro tumor angiogenesis by suppression of MMP. This agent may be anticipated to prevent tumor growth through an angiosuppressive effect.
Insights
SI-27, a matrix metalloproteinase (MMP) inhibitor, effectively suppressed tumor angiogenesis in vitro by inhibiting MMP-1 and MMP-2 activity. This suggests SI-27 may prevent tumor growth by reducing blood vessel formation.
Area of Science:
- Oncology
- Biochemistry
- Cell Biology
Background:
- Tumor angiogenesis, crucial for growth, involves basement membrane degradation by matrix metalloproteinases (MMPs).
- Vascular Endothelial Growth Factor (VEGF) stimulates endothelial cell motility and angiogenesis.
Purpose of the Study:
- To investigate the anti-angiogenic potential of SI-27, a novel MMP inhibitor.
- To determine SI-27's effect on VEGF-induced endothelial cell behavior and glioma-associated angiogenesis.
Main Methods:
- Human umbilical vein endothelial cells (HUVECs) were treated with SI-27 (1-100 µmol/L) and VEGF.
- MMP-1, MMP-2, and tissue inhibitor of metalloproteinase 1 (TIMP-1) activity were measured using ELISA.
- In vitro angiogenesis and cell motility were assessed.
- Glioma cell line supernatants (U87MG, U251MG, U373MG) were used to stimulate angiogenesis, with and without SI-27.
Main Results:
- VEGF significantly enhanced HUVEC motility and in vitro angiogenesis, increasing MMP-1 and MMP-2 activity.
- SI-27 (50 µmol/L) significantly suppressed VEGF-mediated angiogenesis and inactivated MMP-1 and MMP-2, without affecting cell motility or TIMP-1.
- SI-27 (10 µmol/L) significantly reduced angiogenesis stimulated by glioma cell supernatants.
Conclusions:
- SI-27 demonstrates potent in vitro anti-angiogenic activity through MMP inhibition.
- SI-27 holds promise as a therapeutic agent to prevent tumor growth via an angiosuppressive mechanism.
