Angiogenesis inhibitor

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 pharmaceutical drugs or diet.

While angiogenesis is a critical part of wound healing and other favorable processes, certain types of angiogenesis are associated with the growth of malignant tumors. Thus angiogenesis inhibitors have been closely studied for possible cancer treatment. 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]

Mechanism of action

When a tumor stimulates the growth of new vessels, it is said to have undergone an 'angiogenic switch'. The principal stimulus for this angiogenic switch appears to be oxygen deprivation, although other stimuli such as inflammation, oncogenic mutations and mechanical stress may also play a role. The angiogenic switch leads to tumor expression of pro-angiogenic factors and increased tumor vascularization.[4] Specifically, tumor cells release various pro-angiogenic paracrine factors (including angiogenin, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and transforming growth factor-β (TGF-β). These stimulate endothelial cell proliferation, migration and invasion resulting in new vascular structures sprouting from nearby blood vessels.[5] Cell adhesion molecules, such as integrins, are critical to the attachment and migration of endothelial cells to the extracellular matrix.[4]

VEGF pathway inhibition

Inhibiting angiogenesis requires treatment with anti-angiogenic factors, or drugs which reduce the production of pro-angiogenic factors, prevent them binding to their receptors or block their actions. Inhibition of the VEGF pathway has become the focus of angiogenesis research, as approximately 60% of malignant tumors express high concentrations of VEGF. Strategies to inhibit the VEGF pathway include antibodies directed against VEGF or VEGFR, soluble VEGFR/VEGFR hybrids, and tyrosine kinase inhibitors.[4][6] The most widely used VEGF pathway inhibitor on the market today is Bevacizumab. Bevacizumab binds to VEGF and inhibits it from binding to VEGF receptors.[7]

Endogenous regulation

Angiogenesis is regulated by the activity of endogenous stimulators and inhibitors. Endogenous inhibitors, found in the body naturally, are 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.

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.[8] 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.[4][6] However, the therapeutic use of endogenous inhibitors has 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]

InhibitorsMechanism
soluble VEGFR-1 and NRP-1decoy receptors[9] for VEGF-B and PIGF
Angiopoietin 2antagonist of angiopoietin 1
TSP-1 and TSP-2inhibit cell migration, cell proliferation, cell adhesion and survival of endothelial cells
angiostatin and related moleculesinhibit cell proliferation and induce apoptosis of endothelial cells
endostatininhibit cell migration, cell proliferation and survival of endothelial cells
vasostatin, calreticulininhibit cell proliferation of endothelial cells
platelet factor-4inhibits binding of bFGF and VEGF
TIMP and CDAIinhibit cell migration of endothelial cells
Meth-1 and Meth-2
IFN-α, -β and -γ, CXCL10, IL-4, -12 and -18inhibit cell migration of endothelial cells, downregulate bFGF
prothrombin (kringle domain-2), antithrombin III fragmentinhibit cell proliferation of endothelial cells
prolactinVEGF
VEGIaffects cell proliferation of endothelial cells
SPARCinhibit binding and activity of VEGF
osteopontininhibit integrin signalling
maspininhibits proteases
canstatin (a fragment of COL4A2)inhibits endothelial cell migration, induces apoptosis[10]
proliferin-related proteinmannose 6-phosphate binding lysosomal protein[11]

A recent method for the delivery of anti-angiogenesis factors to tumor regions in cancer patients uses genetically modified bacteria that are able to colonize solid tumors in vivo, such as Clostridium, Bifidobacteria and Salmonella by adding genes for anti-angiogenic factors such as endostatin or IP10 chemokine and removing any harmful virulence genes. A target can also be added to the outside of the bacteria so that they are sent to the correct organ in the body. The bacteria can then be injected into the patient and they will locate themselves to the tumor site, where they release a continual supply of the desired drugs in the vicinity of a growing cancer mass, preventing it from being able to gain access to oxygen and ultimately starving the cancer cells.[12] This method has been shown to work both in vitro and in vivo in mice models, with very promising results.[13] It is expected that this method will become commonplace for treatment of various cancer types in humans in the future.

Exogenous regulation

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 foods contain significant inhibitors and have been suggested as part of a healthy diet for this and other benefits:

Drugs

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.

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.[29] Angiogenesis inhibitors are also used as treatment for the wet form of macular degeneration. By blocking VEGF, inhibitors can cause regression of the abnormal blood vessels in the retina and improve vision when injected directly into the vitreous humor of the eye.[30]

Overview
InhibitorsMechanism
bevacizumab (Avastin)VEGF
itraconazoleinhibits VEGFR phosphorylation, glycosylation, mTOR signaling, endothelial cell proliferation, cell migration, lumen formation, and tumor associated angiogenesis.[31][32][33]
carboxyamidotriazoleinhibit cell proliferation and cell migration of endothelial cells
TNP-470 (an analog of fumagillin)
CM101activate immune system
IFN-αdownregulate angiogenesis stimulators and inhibit cell migration of endothelial cells
IL-12stimulate angiogenesis inhibitor formation
platelet factor-4inhibits binding of angiogenesis stimulators
suramin
SU5416
thrombospondin
VEGFR antagonists
angiostatic steroids + heparininhibit basement membrane degradation
Cartilage-Derived Angiogenesis Inhibitory Factor
matrix metalloproteinase inhibitors
angiostatininhibit cell proliferation and induce apoptosis of endothelial cells
endostatininhibit cell migration, cell proliferation and survival of endothelial cells
2-methoxyestradiolinhibit cell proliferation and cell migration and induce apoptosis of endothelial cells
tecogalaninhibit cell proliferation of endothelial cells
tetrathiomolybdatecopper chelation which inhibits blood vessel growth
thalidomideinhibit cell proliferation of endothelial cells
thrombospondininhibit cell migration, cell proliferation, cell adhesion and survival of endothelial cells
prolactinVEGF
αVβ3 inhibitorsinduce apoptosis of endothelial cells
linomideinhibit cell migration of endothelial cells
ramucirumab inhibition of VEGFR2[34]
tasquinimodUnknown[35]
ranibizumabVEGF[36]
sorafenib (Nexavar)inhibit kinases
sunitinib (Sutent)
pazopanib (Votrient)
everolimus (Afinitor)
Mechanism of action of angiogenesis inhibitors. Bevacizumab binds to VEGF inhibiting its ability to bind to and activate VEGF receptors. Sunitinib and Sorafenib inhibit VEGF receptors. Sorafenib also acts downstream.

Bevacizumab

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. Bevacizumab (brand name Avastin) traps VEGF in the blood, lowering the binding of VEGF to its receptors. This results in reduced activation of the angiogenesis pathway, thus inhibiting new blood vessel formation in tumors.[8]

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.[37]

Thalidomide

Despite the therapeutic potential of anti-angiogenesis drugs, they can also be harmful when used inappropriately. 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.[38]

Cannabinoids

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 gliomas (brain tumors) implanted under the skin of mice, by inhibiting the expression of genes needed for the production of vascular endothelial growth factor (VEGF).[39]

Bleeding

Bleeding is one of the most difficult side effects to manage; this complication is somewhat inherent to the effectiveness of the drug. Bevacizumab has been shown to be the drug most likely to cause bleeding complications. While the mechanisms of bleeding induced by anti-VEGF agents are complicated and not yet totally understood, the most accepted hypothesis is that VEGF could promote endothelial cell survival and integrity in the adult vasculature and its inhibition may decrease capacity for renewal of damaged endothelial cells.[40]

Increased blood pressure

In a study done by ML Maitland, a mean blood pressure increase of 8.2 mm Hg systolic and 6.5 mm Hg diastolic was reported in the first 24 hours after the first treatment with sorafenib, a VEGF pathway inhibitor.[41]

Less common side effects

Because these drugs act on parts of the blood and blood vessels, they tend to have side effects that affect these processes. Aside from problems with hemorrhage and hypertension, less common side effects of these drugs include dry, itchy skin, hand-foot syndrome (tender, thickened areas on the skin, sometimes with blisters on palms and soles), diarrhea, fatigue, and low blood counts. Angiogenesis inhibitors can also interfere with wound healing and cause cuts to re-open or bleed. Rarely, perforations (holes) in the intestines can occur.[40]

See also
  • Brain-specific angiogenesis inhibitor 1 (and others)

References
  1. Hayden EC (April 2009). "Cutting off cancer's supply lines". Nature. 458 (7239): 686–7. 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: "Angiogenesis Inhibitors". Archived from the original on 2015-02-08. Retrieved 2022-05-09.
  3. Ng EW, Adamis AP (June 2005). "Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration". Canadian Journal of Ophthalmology. 40 (3): 352–68. doi:10.1016/S0008-4182(05)80078-X. PMID 15947805.
  4. Folkman J (2004). "Endogenous angiogenesis inhibitors". APMIS. 112 (7–8): 496–507. doi:10.1111/j.1600-0463.2004.apm11207-0809.x. PMID 15563312. S2CID 10605205.
  5. Milosevic, Vladan; Edelmann, Reidunn J.; Fosse, Johanna Hol; Östman, Arne; Akslen, Lars A. (2022), Akslen, Lars A.; Watnick, Randolph S. (eds.), "Molecular Phenotypes of Endothelial Cells in Malignant Tumors", Biomarkers of the Tumor Microenvironment, Cham: Springer International Publishing, pp. 31–52, doi:10.1007/978-3-030-98950-7_3, ISBN 978-3-030-98950-7, retrieved 2022-07-13
  6. Cao Y (April 2001). "Endogenous angiogenesis inhibitors and their therapeutic implications". The International Journal of Biochemistry & Cell Biology. 33 (4): 357–69. doi:10.1016/s1357-2725(01)00023-1. PMID 11312106.
  7. Rini BI (February 2007). "Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions". Clinical Cancer Research. 13 (4): 1098–106. doi:10.1158/1078-0432.CCR-06-1989. PMID 17317817.
  8. Nyberg P, Xie L, Kalluri R (May 2005). "Endogenous inhibitors of angiogenesis". Cancer Research. 65 (10): 3967–79. doi:10.1158/0008-5472.CAN-04-2427. PMID 15899784.
  9. Hugo H. Marti, "Vascular Endothelial Growth Factor", Madame Curie Bioscience Database, Landes Bioscience, retrieved January 25, 2012
  10. Kamphaus GD, Colorado PC, Panka DJ, Hopfer H, Ramchandran R, Torre A, Maeshima Y, Mier JW, Sukhatme VP, Kalluri R (January 2000). "Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth". The Journal of Biological Chemistry. 275 (2): 1209–15. doi:10.1074/jbc.275.2.1209. PMID 10625665.
  11. Lee SJ, Nathans D (March 1988). "Proliferin secreted by cultured cells binds to mannose 6-phosphate receptors". The Journal of Biological Chemistry. 263 (7): 3521–7. doi:10.1016/S0021-9258(18)69101-X. PMID 2963825.
  12. Gardlik, R., Behuliak, M., Palffy, R., Celec, P., & Li, C. J. (2011). Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy. Gene therapy, 18(5), 425-431.
  13. Xu, Y. F., Zhu, L. P., Hu, B., Fu, G. F., Zhang, H. Y., Wang, J. J., & Xu, G. X. (2007). A new expression plasmid in Bifidobacterium longum as a delivery system of endostatin for cancer gene therapy. Cancer gene therapy, 14(2), 151-157.
  14. 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". Oncology Reports. 16 (4): 885–91. doi:10.3892/or.16.4.885. PMID 16969510.
  15. Kimura Y, Kido T, Takaku T, Sumiyoshi M, Baba K (September 2004). "Isolation of an anti-angiogenic substance from Agaricus blazei Murill: its antitumor and antimetastatic actions". Cancer Science. 95 (9): 758–64. doi:10.1111/j.1349-7006.2004.tb03258.x. PMID 15471563. S2CID 7243576.
  16. Takaku T, Kimura Y, Okuda H (May 2001). "Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action". The Journal of Nutrition. 131 (5): 1409–13. doi:10.1093/jn/131.5.1409. PMID 11340091.
  17. Liu, Zhijun; Schwimer, Joshua; Liu, Dong; Greenway, Frank L.; Anthony, Catherine T.; Woltering, Eugene A. (2005). "Black Raspberry Extract and Fractions Contain Angiogenesis Inhibitors". Journal of Agricultural and Food Chemistry. 53 (10): 3909–3915. doi:10.1021/jf048585u. PMID 15884816.
  18. Stanley G, Harvey K, Slivova V, Jiang J, Sliva D (April 2005). "Ganoderma lucidum suppresses angiogenesis through the inhibition of secretion of VEGF and TGF-beta1 from prostate cancer cells". Biochemical and Biophysical Research Communications. 330 (1): 46–52. doi:10.1016/j.bbrc.2005.02.116. PMID 15781230.
  19. Fisher M, Yang LX (May 2002). "Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy". Anticancer Research. 22 (3): 1737–54. PMID 12168863.
  20. 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. S2CID 161680.
  21. 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.
  22. Lee JS, Park BC, Ko YJ, Choi MK, Choi HG, Yong CS, Lee JS, Kim JA (December 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.
  23. Sliva D, Jedinak A, Kawasaki J, Harvey K, Slivova V (April 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): 1348–56. doi:10.1038/sj.bjc.6604319. PMC 2361714. PMID 18362935.
  24. Lee YS, Kang YH, Jung JY, Lee S, Ohuchi K, Shin KH, Kang IJ, Park JH, Shin HK, Lim SS, et al. (October 2008). "Protein glycation inhibitors from the fruiting body of Phellinus linteus". Biological & Pharmaceutical Bulletin. 31 (10): 1968–72. doi:10.1248/bpb.31.1968. PMID 18827365.
  25. Rodriguez SK, Guo W, Liu L, Band MA, Paulson EK, Meydani M (April 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. PMID 16217757. S2CID 6846032.
  26. Smith, Roderick. Antiangiogenic Substances in Blackberries, Licorice May Aid Cancer Prevention. Archived 2010-02-14 at the Wayback Machine The Angiogenesis Foundation. 6 May 2009.
  27. Jeong SJ, Koh W, Lee EO, Lee HJ, Lee HJ, Bae H, Lü J, Kim SH (January 2011). "Antiangiogenic phytochemicals and medicinal herbs". Phytotherapy Research. 25 (1): 1–10. doi:10.1002/ptr.3224. PMID 20564543. S2CID 968172.
  28. Izuta H, Chikaraishi Y, Shimazawa M, Mishima S, Hara H (December 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. Bruemmer D (February 2012). "Targeting angiogenesis as treatment for obesity". Arteriosclerosis, Thrombosis, and Vascular Biology. 32 (2): 161–2. doi:10.1161/ATVBAHA.111.241992. PMID 22258895.
  30. Heier JS (May 2013). "Neovascular age-related macular degeneration: individualizing therapy in the era of anti-angiogenic treatments". Ophthalmology. 120 (5 Suppl): S23–5. doi:10.1016/j.ophtha.2013.01.059. PMID 23642783.
  31. Chong CR, Xu J, Lu J, Bhat S, Sullivan DJ, Liu JO (April 2007). "Inhibition of angiogenesis by the antifungal drug itraconazole". ACS Chemical Biology. 2 (4): 263–70. doi:10.1021/cb600362d. PMID 17432820.
  32. Aftab BT, Dobromilskaya I, Liu JO, Rudin CM (November 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.
  33. Xu J, Dang Y, Ren YR, Liu JO (March 2010). "Cholesterol trafficking is required for mTOR activation in endothelial cells". Proceedings of the National Academy of Sciences of the United States of America. 107 (10): 4764–9. doi:10.1073/pnas.0910872107. PMC 2842052. PMID 20176935.
  34. Ramucirumab (Cyramza) package insert
  35. Ruch, Joshua M.; Hussain, Maha H. (15 May 2011). "Evolving Therapeutic Paradigms for Advanced Prostate Cancer". Oncology. 25 (6). Retrieved 9 May 2022.
  36. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY (October 2006). "Ranibizumab for neovascular age-related macular degeneration". The New England Journal of Medicine. 355 (14): 1419–31. doi:10.1056/NEJMoa054481. PMID 17021318.
  37. FDA News Release on Avastin, retrieved 2014-04-15
  38. Kim JH, Scialli AR (July 2011). "Thalidomide: the tragedy of birth defects and the effective treatment of disease". Toxicological Sciences. 122 (1): 1–6. doi:10.1093/toxsci/kfr088. PMID 21507989.
  39. Blázquez C, González-Feria L, Alvarez L, Haro A, Casanova ML, Guzmán M (August 2004). "Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas". Cancer Research. 64 (16): 5617–23. doi:10.1158/0008-5472.CAN-03-3927. PMID 15313899.
  40. Elice F, Rodeghiero F (April 2012). "Side effects of anti-angiogenic drugs". Thrombosis Research. 129: S50–3. doi:10.1016/S0049-3848(12)70016-6. PMID 22682133.
  41. Maitland ML, Kasza KE, Karrison T, Moshier K, Sit L, Black HR, Undevia SD, Stadler WM, Elliott WJ, Ratain MJ (October 2009). "Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment". Clinical Cancer Research. 15 (19): 6250–7. doi:10.1158/1078-0432.CCR-09-0058. PMC 2756980. PMID 19773379.

Further reading
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.