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angiogenesis, which include cytokines and chemokines such as tumor necrosis
factor-a (TNF- a) [27], interleukin-8 (IL-8) [28]; oncogenes such as Ras [29]; as
well as angiogenin [30], angiopoietin-1 [31], prostaglandins E1 and E2 [32, 33].
In 1980, interferon a was reported as the first angiogenesis inhibitor [34–36]. Since
then, many more endogenous angiogenesis inhibitors have been described, which can
be divided into two categories: matrix-derived which are fragments of naturally occur-
ring basement membrane and ECM proteins and nonmatrix-derived. Matrix-derived
inhibitors including endostatin [37], a fragment of collagen XVIII; arresten [38], a
fragment of the noncollagenous (NC1) domain of the a1 chain of type IV collagen;
canstatin [39], a fragment of the NC1 domain of the a2 chain of type IV collagen;
endorepellin [40], a peptide derived from the carboxy terminus of perlecan; fibulins
[41], fragments released by elastases and cathepsins-mediated digestion of basement
membrane; thrombospondin-1 [42], an ECM adhesive glycoprotein; and tumstatin
[43, 44], a peptide derived from the a3 chain of type IV collagen NC1 domain. Non-
matrix-derived inhibitors including angiostatin [45], which is an internal fragment of
plasminogen; truncated antithrombin III [46]; interferons [36]; interleukin-12 [47];
2-methoxyestradiol [48]; pigment epithelial-derived factor (PEDF) [49, 50]; platelet
factor 4 [51]; prolactin fragment [52]; tissue inhibitors of matrix metalloproteinase-2
(TIMP-2) [53]; troponin I (Tn 1) [54]; and vasostatin [55].
These inhibitors suppress angiogenesis by inhibiting endothelial cell prolif-
eration, adhesion, migration, and tube formation and promoting apoptosis and
cell cycle arrest in endothelial cells through common and distinct signaling
mechanisms. How they function together to inhibit angiogenesis is not fully
understood.

5.1.3 Therapeutic Angiogenesis Inhibitors

Several angiogenesis inhibitors have been approved for the use in treating cancer
and many others are currently in clinical trials. Bevacizumab (Avastin), a
monoclonal antibody against VEGF, is the first angiogenesis inhibitor approved by
FDA [56]. It is currently used to treat various cancers, including metastatic colorec-
tal, nonsmall-cell lung, and breast cancer. In addition to VEGF, other targets of
angiogenesis inhibitors include VEGF receptor (VEGFR), epidermal growth factor
receptor (EGFR), mammalian target of rapamycin (mTOR), and MMPs. Cetuximab
(Erbitux) is a chimeric monoclonal antibody directed against EGFR and inhibits
EGFR signaling, thereby inhibiting angiogenesis and cell proliferation [57]. There
are several receptor tyrosine kinase inhibitors developed against angiogenesis,
including sorafenib (Nexavar), a dual-function tyrosine kinase inhibitor of VEGFR
and Raf kinase that exhibits antiproliferative and anti-angiogenic activities [58];
sunitinib (Sutent), an inhibitor of VEGFR and PDGFR [59]; and erlotinib (Tarveca),
an inhibitor of EGFR [60]. Other inhibitors include temsirolimus (Torisel), a small
molecule inhibitor of mTOR [61]; bortezomib (Velcade), a proteasome inhibitor
that inhibits cancer cell survival and angiogenesis [62]; thalidomide (Thalomid),