Inhibiting Angiogenesis

(The Angiogenesis Foundation, 2013)

Naturally occurring negative inducers angiostatin, endostatin, interferon-alpha, interferon-beta, and PEX (chemopexin domain of matrix metalloproteinase II) (Jansen et al, 2004).

Angiogstatin binds many proteins, binding angiomotin, endothelial surface ATP synthase and integrin C annexin-II, c-MET receptor, No2-protoglyclans, and CD26 (O'Reilly et al, 1994). This binding capability inhibits endothelial migration, proliferation, and apoptosis (Sharma et al, 2004). Treatment using angiostatin showed: decreased vascularity, and reduced VEGF mRNA expression (Choudhury et al, 2010).

The second naturally occurring negative inducer, Endostatin targets integrin α_vβ₃ (Yokoyama et al, 2004) inhibiting endothelial cell proliferation and migration, inducing apoptosis in proliferating endothelial cells (Fuetal et al, 2009). Through its association with integrin α_vβ₃ and the proteolytic plasminogen activator system, the adhesion of endothelial cells to the extracellular matrix is affected (Rabbani et al, 2001).

IFN-α and IFN-β exert anti-angiogenic properties by suppressing bFGF expression and decreasing endothelial cell migration (Greenberg et al, 2005). IFN-α and IFN-β presented anti-glioblatoma activity by a mechanism involving central tumor necrosis followed by neovascularization or blood vessel death (Choudhury et al, 2010).

The final negative inducer, PEX, presents significant antimitotic, anti-invasive, and anti-angiogenic properties against GBM (Bello et al, 2001). Originally MMP-2 and integrin α_vβ₃ binding promotes endothelial cell invasion. PEX binds to this integrin, inhibiting the binding of MMP-2, decreasing endothelial cell proliferation (Choudhury et al, 2010).

Alongside naturally occurring negative inducers, clinical trials have used physiological factors to inhibit certain factors in angiogenesis.

Figure 2: Physiological Factors for the Inhibition of Angiogenic Receptors (Choudhury et al b, 2010)

Physiological Factors for the Inhibition of Angiogenic Receptors
Target of the Inhibitor	Inhibitors
EGFR	Gefitinib Erlotinib OSI-774 ZD1839 Tyrophostin AG1478 Lapantinib (EGFR, ErbB-2 inhibitor) AEE788 (EGFR, VEGFR inhibitor) ZD6474 (EGFR, VEGFR inhibitor) EKB569 (erbB1, erBb2 inhibitor) Cetuzimab (anti-EGFR monoclonal antibody)
VEGFR	Valatanib (PTK787) (PDGFR, VEGFR inhibitor) Sorafenib (VEGFR, PDGFR, Raf kinase inhibitor) AZD2171 (VEGFR2 inhibitor) ZD674 (VEGFR, EGFR inhibitor) SU5416 (VEGFR2 selective inhibitor) SU6668 (VEGFR2, PDGFR, FGF inhibitor) CEP 7055 SNS-032 (VEGF, CDK2,7,9 inhibitor) AA481 (VEGFR2 and Raf inhibitor) Pazopanib
PDGFR	Imatinib mesylate PTK787 (PDGFR, VEGFR inhibitor) SU011248 (PDGFR, VEGFR, c-KIT, FLT3 inhibitor) Sorafenib (PDGFRβ, VEGFR1, VEGFR2 inhibitor)
PI3K/Akt Pathway	LY294002 Perifosine PI-103
Integrin	Cliengitide (αvβ3 + αvβ5 inhibitor)