An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through drugs or diet.
Angiogenesis inhibitors were once thought to have potential as a "silver bullet" treatment applicable to many types of cancer, but the limitations of anti-angiogenic therapy have been shown in practice.[1] Nonetheless, inhibitors are used to effectively treat cancer, macular degeneration in the eye, and other diseases that involve a proliferation of blood vessels.[2][3]
Contents
- 1 Mechanism of action
- 2 Endogenous regulation
- 3 Exogenous regulation
- 4 References
- 5 External links
Mechanism of action
When solid cancers are small, they are supplied with oxygen and nutrients by diffusion from nearby blood vessels. In order for a tumor to grow and metastasize, it must become vascularized through the action of angiogenesis promoters such as VEGF. Drugs that interrupt that process show promise in treating cancer.[4]
Endogenous regulation
Main article: 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.[5]
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.[6] 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.[7] However, the use of endogenous inhibitors has its disadvantages. In animal studies, high doses of inhibitors were required to prevent tumor growth and the use of endogenous inhibitors would likely be long-term.[8]
| Inhibitors |
Mechanism |
| soluble VEGFR-1 and NRP-1 |
decoy receptors[9] 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 (a fragment of COL4A2) |
inhibits endothelial cell migration, induces apoptosis[10] |
| proliferin-related protein |
mannose 6-phosphate binding lysosomal protein[11] |
Exogenous regulation
Main article: Exogenous
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.[citation needed]
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 was approved by the FDA, becoming the first commercially available anti-angiogenesis drug. FDA approval of Avastin for breast cancer treatment was later revoked on November 18, 2011.[12]
Despite the therapeutic potential of anti-angiogenesis drugs, they can also be harmful when used inappropriately. Pharmaceutical thalidomide is one such 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.[13]
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.[14]
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).[15]
| 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.[16][17][18] |
| carboxyamidotriazole |
|
inhibit cell proliferation and cell migration of endothelial cells |
| TNP-470 (an analog of fumagillin) |
|
| 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[19] |
|
|
|
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:
- Soy products such as tofu and tempeh, (which contain the inhibitor "genistein")[20]
- Agaricus subrufescens mushrooms (contain the inhibitors sodium pyroglutamate and ergosterol)[21][22]
- Black raspberry (Rubus occidentalis) extract[23]
- Reishi mushrooms (via inhibition of VEGF and TGF-beta)[24]
- Trametes versicolor mushrooms (Polysaccharide-K).[25][26][27]
- Maitake mushrooms (via inhibition of VEGF)[28]
- Phellinus linteus mushrooms[29](via active substance Interfungins A inhibition of glycation).[30]
- Green tea (catechins)[31]
- Liquorice (glycyrrhizic acid)[32]
- Red wine (resveratrol)[32]
- Antiangiogenic phytochemicals and medicinal herbs.[33]
- Royal Jelly(Queen bee acid) [34]
References
- ^ Hayden, Erika C. (2009-04-08). "Cutting off cancer's supply lines". Nature 458 (7239): 686–687. doi:10.1038/458686b. PMID 19360048.
- ^ 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
- ^ Eugene W. M. Ng & Anthony P. Adamis (June 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.
- ^ , PMID 12516034 http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm280536.htm, retrieved 2014-04-15
- ^ Nyberg P, Xie L, Kalluri R (May 2005). "Endogenous inhibitors of angiogenesis". Cancer Res. 65 (10): 3967–79. doi:10.1158/0008-5472.CAN-04-2427. PMID 15899784.
- ^ Nyberg P, Xie L, Kalluri R (May 2005). "Endogenous inhibitors of angiogenesis". Cancer Res. 65 (10): 3967–79. doi:10.1158/0008-5472.CAN-04-2427. PMID 15899784.
- ^ Folkman J (2004). "Endogenous angiogenesis inhibitors". APMIS 112 (7-8): 496–507. doi:10.1111/j.1600-0463.2004.apm11207-0809.x. PMID 15563312.
- ^ Cao Y (April 2001). "Endogenous angiogenesis inhibitors and their therapeutic implications". Int. J. Biochem. Cell Biol. 33 (4): 357–69. PMID 11312106.
- ^ Hugo H. Marti, "Vascular Endothelial Growth Factor", Madame Curie Bioscience Database (Landes Bioscience), retrieved January 25, 2012
- ^ J Biol Chem 275 (2): 1209–15. January 2000. doi:10.1371/journal.pone.0066721. PMID 10625665.
- ^ J Biol Chem 263 (7): 3521–7. March 1988. PMID 2963825.
- ^ http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm280536.htm, retrieved 2014-04-15
- ^ 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.
- ^ Bruemmer, D. (2012). "Targeting Angiogenesis as Treatment for Obesity". Arteriosclerosis, Thrombosis, and Vascular Biology 32 (2): 161–162. doi:10.1161/ATVBAHA.111.241992. ISSN 1079-5642.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Evolving Therapeutic Paradigms for Advanced Prostate Cancer. 2011.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Fisher, M. Y. (May 2002). "Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy". Anticancer research 22 (3): 1737–1754. ISSN 0250-7005. PMID 12168863. edit
- ^ Oba K, Teramukai S, Kobayashi M, Matsui T, Kodera Y, Sakamoto J (June 2007), "Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curative resections of gastric cancer", Cancer Immunol Immunother 56 (6): 905–11, doi:10.1007/s00262-006-0248-1, PMID 17106715
- ^ ref>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.
- ^ 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.
- ^ 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.
- ^ Lee YS, Kang YH, Jung JY, et al. (October 2008). "Protein glycation inhibitors from the fruiting body of Phellinus linteus" ([dead link]). Biological & Pharmaceutical Bulletin 31 (10): 1968–72. doi:10.1248/bpb.31.1968. PMID 18827365.
- ^ 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.
- ^ a b Smith, Roderick. Antiangiogenic Substances in Blackberries, Licorice May Aid Cancer Prevention. The Angiogenesis Foundation. 6 May 2009.[unreliable medical source?]
- ^ 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.
- ^ 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.
External links
- The idea of antiangiogenesis was pioneered by Dr. Judah Folkman. See [1] and [2]
- Angiogenesis Inhibitors for Cancer - from The Angiogenesis Foundation, 23 June 2009
- Angiogenesis Inhibitors for Eye Disease - from The Angiogenesis Foundation, 23 June 2009
- Angiogenesis Inhibitors in the Treatment of Cancer - from the National Cancer Institute
- New Scientist on their use as fat-reducing drugs - from New Scientist, 10 April 2004
- Angiogenesis Inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)
|
Antiangiogenics
|
|
| Endogenous Regulation |
- Angiopoietin 2
- angiostatin
- canstatin
- calreticulin
- endostatin
- IFN-α
- IFN-β
- IFN-γ
- CXCL10
- IL-4
- IL-12
- IL-18
- maspin
- Meth-1
- Meth-2
- osteopontin
- platelet factor-4
- prolactin
- proliferin-related protein
- prothrombin (kringle domain-2)
- antithrombin III fragment
- SPARC
- Thrombospondin 1
- TIMP
- vasostatin
- VEGI
- soluble VEGFR-1
- NRP-1
- CDAI
|
|
| Exogenous Regulation |
- 2-methoxyestradiol
- αVβ3 inhibitors
- angiostatic steroids
- heparin
- angiostatin
- bevacizumab
- carboxyamidotriazole
- Cartilage-Derived Angiogenesis Inhibitory Factor
- CM101
- endostatin
- IFN-α
- IL-12
- itraconazole
- linomide
- matrix metalloproteinase inhibitors
- platelet factor-4
- prolactin
- SU5416
- suramin
- tasquinimod
- tecogalan
- tetrathiomolybdate
- thalidomide
- thrombospondin
- thrombospondin
- TNP-470
- VEGFR antagonists
|
|
| See also |
- Angiogenesis
- Angiogenesis inhibitors
|
|
