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| [[canstatin]] || inhibits endothelial cell migration, induces apoptosis<ref>{{cite journal |journal=J Biol Chem |volume=275 |issue=2|pages=1209-15 |year=2000 |month=January |pmid=10625665 |doi= 10.1371/journal.pone.0066721|url=}}</ref>
| [[canstatin]] || inhibits endothelial cell migration, induces apoptosis<ref>{{cite journal |journal=J Biol Chem |volume=275 |issue=2|pages=1209-15 |year=2000 |month=January |pmid=10625665 |doi= 10.1371/journal.pone.0066721|url=}}</ref>
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| [[proliferin-related protein]] || [[mannose 6-phosphate]] binding lysosomal protein<ref>{{cite journal |journal=J Biol Chem |volume=263 |issue=7|pages=3521-7 |year=1988|month=March |pmid= 2963825 |</ref>
| [[proliferin-related protein]] ||
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Revision as of 01:03, 19 March 2014

An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are a normal part of the body's control, some are administered as drugs, and some come from diet.

Angiogenesis inhibitors were once thought to have potential as a "silver bullet" treatment applicable to many types of cancer, but this has not been the case in practice.[1] Nonetheless, inhibitors are used to treat cancer, macular degeneration in the eye, and other diseases that involve a proliferation of blood vessels [2]

When solid cancers are small, they are supplied with nutrients by diffusion from nearby blood vessels. In order to grow larger, they need their own blood vessels, which are created by the action of angiogenesis promoters such as VEGF. Drugs that interrupt that process show promise in treating cancer. However, when one angiogenesis promoter is blocked, cancers eventually grow blood vessels using another angiogenesis promoter.

Angiogenesis inhibitors are also used to treat age-related macular degeneration, in which the blood vessels of the retina of the eye become overgrown and damage vision.[3]

Endogenous

Angiogenesis is regulated by the activity of endogenous stimulators and inhibitors. Unlike exogenous inhibitors, endogenous inhibitors are found in the body naturally and involved in the day-to-day process of regulating blood vessel formation. Endogenous inhibitors are often derived from the extracellular matrix or basement membrane proteins and function by interfering with endothelial cell formation and migration, endothelial tube morphogenesis, and down-regulation of genes expressed in endothelial cells. [4] During tumor growth, the action of angiogenesis stimulators surpasses the control of angiogenesis inhibitors, allowing for unregulated or less regulated blood vessel growth and formation. [5] Endogenous inhibitors are attractive targets for cancer therapy because they are less toxic and less likely to lead to drug resistance than some exogenous inhibitors. [6]

However, the use of endogenous inhibitors has its disadvantages as well. In animal studies, high doses of inhibitors were required to prevent tumor growth and the use of endogenous inhibitors would likely be long-term. [7]

Inhibitors Mechanism
soluble VEGFR-1 and NRP-1 decoy receptors[8] for VEGF-B and PIGF
Angiopoietin 2 antagonist of angiopoietin 1
TSP-1 and TSP-2 inhibit cell migration, cell proliferation, cell adhesion and survival of endothelial cells
angiostatin and related molecules inhibit cell proliferation and induce apoptosis of endothelial cells
endostatin inhibit cell migration, cell proliferation and survival of endothelial cells
vasostatin, calreticulin inhibit cell proliferation of endothelial cells
platelet factor-4 inhibits binding of bFGF and VEGF
TIMP and CDAI inhibit cell migration of endothelial cells
Meth-1 and Meth-2
IFN-α, -β and -γ, CXCL10, IL-4, -12 and -18 inhibit cell migration of endothelial cells, downregulate bFGF
prothrombin (kringle domain-2), antithrombin III fragment inhibit cell proliferation of endothelial cells
prolactin inhibit bFGF and VEGF
VEGI affects cell proliferation of endothelial cells
SPARC inhibit binding and activity of VEGF
osteopontin inhibit integrin signalling
maspin inhibits proteases
canstatin inhibits endothelial cell migration, induces apoptosis[9]
proliferin-related protein mannose 6-phosphate binding lysosomal protein[10]
restin

Exogenous

Exogenous angiogenesis inhibitors may be drugs or a dietary components. Some of them are endogenous as well.

Drugs

Known inhibitors include the drug bevacizumab (brand name Avastin), a kind of humanized mouse monoclonal antibody against vascular endothelial growth factor (VEGF)

Through binding to VEGFR and other VEGF receptors in endothelial cells, VEGF can trigger multiple cellular responses like promoting cell survival, preventing apoptosis, and remodeling cytoskeleton, all of which promote angiogenesis.

Because it traps VEGF in the blood, bevacizumab is an anti-angiogenesis factor. Lowering the concentration of VEGF results in reduced activation of the angiogenesis pathway, thus inhibiting new blood vessel formation in tumors.

Research and development in this field has been driven largely by the desire to find better cancer treatments. Tumors cannot grow larger than 2mm without angiogenesis. By stopping the growth of blood vessels, scientists hope to cut the means by which tumors can nourish themselves and thus metastasize. After a series of clinical trials in 2004, Avastin got approval from the FDA, becoming the first commercially available anti-angiogenesis drug. FDA approval for breast cancer was later revoked on November 18, 2011. [citation needed]

Despite the therapeutic potential of anti-angiogenesis drugs, they can also be harmful when used inappropriately. Pharmaceutical thalidomide is one such an antiangiogenic agent. Thalidomide was given to pregnant women to treat nausea. However, when pregnant women take an antiangiogenic agent, the developing fetus will not form blood vessels properly, thereby preventing the proper development of fetal limbs and circulatory systems. In the late 1950s and early 1960s, thousands of children were born with deformities, most notably phocomelia, as a consequence of thalidomide use.[11]


In addition to their use as anti-cancer drugs, angiogenesis inhibitors are being investigated for their use as anti-obesity agents, as blood vessels in adipose tissue never fully mature, and are thus destroyed by angiogenesis inhibitors.

According to a study published in the August 15, 2004 issue of the journal Cancer Research, cannabinoids, the active ingredients in marijuana, restrict the sprouting of blood vessels to brain tumors by inhibiting the expression of genes needed for the production of vascular endothelial growth factor (VEGF).[12]

Summary

Overview table
Inhibitors Antiangiogenic
use in		 Mechanism
bevacizumab Cancer binds VEGF
itraconazole Cancer inhibits VEGFR phosphorylation, glycosylation, mTOR signaling, endothelial cell proliferation, cell migration, lumen formation, and tumor associated angiogenesis.[13][14][15]
carboxyamidotriazole inhibit cell proliferation and cell migration of endothelial cells
TNP-470
CM101 activate immune system
IFN-α downregulate angiogenesis stimulators and inhibit cell migration of endothelial cells
IL-12 stimulate angiogenesis inhibitor formation
platelet factor-4 inhibits binding of angiogenesis stimulators
suramin prostate cancer
SU5416
thrombospondin
VEGFR antagonists
angiostatic steroids + heparin inhibit basement membrane degradation
Cartilage-Derived Angiogenesis Inhibitory Factor
matrix metalloproteinase inhibitors
angiostatin inhibit cell proliferation and induce apoptosis of endothelial cells
endostatin inhibit cell migration, cell proliferation and survival of endothelial cells
2-methoxyestradiol inhibit cell proliferation and cell migration and induce apoptosis of endothelial cells
tecogalan inhibit cell proliferation of endothelial cells
tetrathiomolybdate Cancer copper chelation which inhibits blood vessel growth
thalidomide inhibit cell proliferation of endothelial cells
thrombospondin inhibit cell migration, cell proliferation, cell adhesion and survival of endothelial cells
prolactin inhibit bFGF and VEGF
αVβ3 inhibitors induce apoptosis of endothelial cells
linomide inhibit cell migration of endothelial cells
tasquinimod prostate cancer Unknown[16]

Diet

Some common components of human diets also act as mild angiogenesis inhibitors and have therefore been proposed for angioprevention, the prevention of metastasis through the inhibition of angiogenesis. In particular, the following foodstuffs contain significant inhibitors and have been suggested as part of a healthy diet for this and other benefits:

References

  1. ^ Hayden, Erika C. (2009-04-08). "Cutting off cancer's supply lines". Nature. 458 (7239): 686–687. doi:10.1038/458686b. PMID 19360048.
  2. ^ Cancer.com [homepage on the Internet]. National Cancer Institute at the National Institutes of Health; 2011 [cited 18 March 2014]. Available from: http://www.cancer.gov/cancertopics/factsheet/Therapy/angiogenesis-inhibitors
  3. ^ Eugene W. M. Ng & Anthony P. Adamis (2005). "Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration". Canadian journal of ophthalmology. Journal canadien d'ophtalmologie. 40 (3): 352–368. doi:10.1016/S0008-4182(05)80078-X. PMID 15947805. {{cite journal}}: Unknown parameter |month= ignored (help)
  4. ^ Nyberg P, Xie L, Kalluri R (2005). "Endogenous inhibitors of angiogenesis". Cancer Res. 65 (10): 3967–79. doi:10.1158/0008-5472.CAN-04-2427. PMID 15899784. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Nyberg P, Xie L, Kalluri R (2005). "Endogenous inhibitors of angiogenesis". Cancer Res. 65 (10): 3967–79. doi:10.1158/0008-5472.CAN-04-2427. PMID 15899784. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Folkman J (2004). "Endogenous angiogenesis inhibitors". APMIS. 112 (7–8): 496–507. doi:10.1111/j.1600-0463.2004.apm11207-0809.x. PMID 15563312.
  7. ^ Cao Y (2001). "Endogenous angiogenesis inhibitors and their therapeutic implications". Int. J. Biochem. Cell Biol. 33 (4): 357–69. PMID 11312106. {{cite journal}}: Unknown parameter |month= ignored (help)
  8. ^ Hugo H. Marti, "Vascular Endothelial Growth Factor", Madame Curie Bioscience Database, Landes Bioscience, retrieved January 25, 2012
  9. ^ J Biol Chem. 275 (2): 1209–15. 2000. doi:10.1371/journal.pone.0066721. PMID 10625665. {{cite journal}}: Missing or empty |title= (help); Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)
  10. ^ {{cite journal |journal=J Biol Chem |volume=263 |issue=7|pages=3521-7 |year=1988|month=March |pmid= 2963825 |
  11. ^ Kim, J. H.; Scialli, A. R. (2011). "Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease". Toxicological Sciences. 122 (1): 1–6. doi:10.1093/toxsci/kfr088. ISSN 1096-6080.
  12. ^ Cristina Blázquez, Luis González-Feria, Luis Álvarez, Amador Haro, M. Llanos Casanova, and Manuel Guzmán (August 15, 2004). "Cannabinoids Inhibit the Vascular Endothelial Growth Factor Pathway in Gliomas". Cancer Research. 64 (16): 5617–5623. doi:10.1158/0008-5472.CAN-03-3927. PMID 15313899.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Chong, Curtis R.; Xu, Jing; Lu, Jun; Bhat, Shridhar; Sullivan, David J.; Liu, Jun O. (2007). "Inhibition of Angiogenesis by the Antifungal Drug Itraconazole". ACS Chemical Biology. 2 (4): 263–70. doi:10.1021/cb600362d. PMID 17432820.
  14. ^ Aftab, B. T.; Dobromilskaya, I.; Liu, J. O.; Rudin, C. M. (2011). "Itraconazole Inhibits Angiogenesis and Tumor Growth in Non-Small Cell Lung Cancer". Cancer Research. 71 (21): 6764–72. doi:10.1158/0008-5472.CAN-11-0691. PMC 3206167. PMID 21896639.
  15. ^ Xu, J.; Dang, Y.; Ren, Y. R.; Liu, J. O. (2010). "Cholesterol trafficking is required for mTOR activation in endothelial cells". Proceedings of the National Academy of Sciences. 107 (10): 4764–9. doi:10.1073/pnas.0910872107. PMC 2842052. PMID 20176935.
  16. ^ "Evolving Therapeutic Paradigms for Advanced Prostate Cancer". 2011. {{cite journal}}: Cite journal requires |journal= (help)
  17. ^ Farina HG, Pomies M, Alonso DF, Gomez DE (October 2006). "Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer". Oncol. Rep. 16 (4): 885–91. PMID 16969510.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Takaku T, Kimura Y, Okuda H (May 2001). "Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action". J. Nutr. 131 (5): 1409–13. PMID 11340091.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Kimura, Y; Kido, T; Takaku, T; Sumiyoshi, M; Baba, K (2004). "Isolation of an anti-angiogenic substance from Agaricus blazei Murill: its antitumor and antimetastatic actions". Cancer Sci. 95 (9): 758–764. doi:10.1111/j.1349-7006.2004.tb03258.x. PMID 15471563.
  20. ^ Liu, Zhijun.; Schwimer, Joshua.; Liu, Dong.; Greenway, Frank L.; Anthony, Catherine T.; Woltering, Eugene A. Black Raspberry Extract and Fractions Contain Angiogenesis Inhibitors. ACS Publications.
  21. ^ Stanley, Gwenaelle; Harvey, Kevin; Slivova, Veronika; Jiang, Jiahua; Sliva, Daniel (2005). "Ganoderma lucidum suppresses angiogenesis through the inhibition of secretion of VEGF and TGF-β1 from prostate cancer cells". Biochemical and Biophysical Research Communications. 330 (1): 46–52. doi:10.1016/j.bbrc.2005.02.116. PMID 15781230.
  22. ^ Kobayashi, H; Matsunaga, K; Oguchi, Y (1995). "Antimetastatic effects of PSK (Krestin), a protein-bound polysaccharide obtained from basidiomycetes: An overview". Cancer epidemiology, biomarkers & prevention. 4 (3): 275–81. PMID 7606203.
  23. ^ Lee, Jong-Suk; Park, Byung Chul; Ko, Yu Jin; Choi, Mi Kyoung; Choi, Han Gon; Yong, Chul Soon; Lee, Jae-Sung; Kim, Jung-Ae (2008). "Grifola frondosa(Maitake Mushroom) Water Extract Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis Through Inhibition of Reactive Oxygen Species and Extracellular Signal-Regulated Kinase Phosphorylation". Journal of Medicinal Food. 11 (4): 643–51. doi:10.1089/jmf.2007.0629. PMID 19053855.
  24. ^ Sliva, D, Jedinak, A, Kawasaki, J, Harvey, K, Slivova, V (2008). "Phellinus linteus suppresses growth, angiogenesis and invasive behaviour of breast cancer cells through the inhibition of AKT signalling". British Journal of Cancer. 98 (8): 1348–1356. doi:10.1038/sj.bjc.6604319. PMC 2361714. PMID 18362935.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Rodriguez, Shaun K.; Guo, Weimin; Liu, Liping; Band, Michael A.; Paulson, Eric K.; Meydani, Mohsen (2006). "Green tea catechin, epigallocatechin-3-gallate, inhibits vascular endothelial growth factor angiogenic signaling by disrupting the formation of a receptor complex". International Journal of Cancer. 118 (7): 1635–44. doi:10.1002/ijc.21545.
  26. ^ a b Smith, Roderick. Antiangiogenic Substances in Blackberries, Licorice May Aid Cancer Prevention. The Angiogenesis Foundation. 6 May 2009.[unreliable medical source?]
  27. ^ Jeong, Soo-Jin; Koh, Wonil; Lee, Eun-Ok; Lee, Hyo-Jung; Lee, Hyo-Jeong; Bae, Hyunsu; Lü, Junxuan; Kim, Sung-Hoon (2011). "Antiangiogenic phytochemicals and medicinal herbs". Phytotherapy Research. 25 (1): 1–10. doi:10.1002/ptr.3224. PMID 20564543.
  28. ^ Izuta, Hiroshi; Chikaraishi, Yuichi; Shimazawa, Masamitsu; Mishima, Satoshi; Hara, Hideaki (2009). "10-Hydroxy-2-decenoic Acid, a Major Fatty Acid from Royal Jelly, Inhibits VEGF-Induced Angiogenesis in Human Umbilical Vein Endothelial Cells". Evidence-Based Complementary and Alternative Medicine. 6 (4): 489–94. doi:10.1093/ecam/nem152. PMC 2781774. PMID 18955252.
  29. ^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427174/
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