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Angiogenesis inhibitor

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Anangiogenesis inhibitoris a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors areendogenousand a normal part of the body's control and others are obtainedexogenouslythroughpharmaceutical drugsordiet.

While angiogenesis is a critical part ofwound healingand other favorable processes, certain types of angiogenesis are associated with the growth ofmalignanttumors.Thus angiogenesis inhibitors have been closely studied for possiblecancertreatment. 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]Currently, angiogenesis inhibitors are recognized for their improvement of cancer immunotherapy[2][3]by overcomingendothelial cell anergy.Angiogenesis inhibitors are also used to effectively treatmacular degenerationin the eye, and other diseases that involve a proliferation of blood vessels.[4][5][6]

Mechanism of action

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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.[7]Specifically,tumorcells release various pro-angiogenicparacrinefactors (includingangiogenin,vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and transforming growth factor-β (TGF-β). These stimulateendothelial cellproliferation, migration and invasion resulting in new vascular structures sprouting from nearby blood vessels.[8]Cell adhesion molecules,such asintegrins,are critical to the attachment and migration of endothelial cells to theextracellular matrix.[7]

VEGF pathway inhibition

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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 includeantibodiesdirected against VEGF or VEGFR, soluble VEGFR/VEGFR hybrids, andtyrosine kinase inhibitors.[7][9]The most widely used VEGF pathway inhibitor on the market today isBevacizumab.[10][11][12]Bevacizumab binds to VEGF and inhibits it from binding to VEGF receptors.[13]

Endogenous regulation

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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 withendothelial cellformation and migration, endothelial tubemorphogenesis,anddown-regulationof 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.[14]Endogenous inhibitors are attractive targets forcancer therapybecause they are less toxic and less likely to lead to drug resistance than some exogenous inhibitors.[7][9]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.[14]

Inhibitors Mechanism
solubleVEGFR-1andNRP-1 decoy receptors[15]forVEGF-B andPIGF
Angiopoietin 2 antagonist ofangiopoietin 1
TSP-1andTSP-2 inhibitcell migration,cell proliferation,cell adhesionand survival ofendothelial cells
angiostatinand related molecules inhibit cell proliferation and induceapoptosisof 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 ofbFGFandVEGF
TIMPandCDAI inhibit cell migration of endothelial cells
ADAMTS1andADAMTS8
IFN-α,-βand-γ,CXCL10,IL-4,-12and-18 inhibit cell migration of endothelial cells, downregulate bFGF
prothrombin(kringle domain-2),antithrombin IIIfragment inhibit cell proliferation of endothelial cells
prolactin VEGF
VEGI affects cell proliferation of endothelial cells
SPARC inhibit binding and activity ofVEGF
osteopontin inhibitintegrinsignalling
maspin inhibitsproteases
canstatin (a fragment ofCOL4A2) inhibits endothelial cell migration, induces apoptosis[16]
proliferin-related protein mannose 6-phosphatebinding lysosomal protein[17]

A recent method for the delivery of anti-angiogenesis factors to tumor regions in cancer patients usesgenetically modified bacteriathat are able to colonize solid tumorsin vivo,such asClostridium,BifidobacteriaandSalmonellaby adding genes for anti-angiogenic factors such asendostatinor IP10chemokineand 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.[18]This method has been shown to work both in vitro and in vivo in mice models, with very promising results.[19]It is expected that this method will become commonplace for treatment of various cancer types in humans in the future.[citation needed]

Exogenous regulation

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Diet

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

Drugs

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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 thusmetastasize.

In addition to their use as anti-cancer drugs, angiogenesis inhibitors are being investigated for their use asanti-obesityagents, as blood vessels inadipose tissuenever fully mature, and are thus destroyed by angiogenesis inhibitors.[35]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 thevitreous humorof the eye.[36]

Overview

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Inhibitors Mechanism
bevacizumab(Avastin) VEGF
itraconazole inhibitsVEGFRphosphorylation,glycosylation,mTORsignaling, endothelial cell proliferation, cell migration,lumenformation, and tumor associated angiogenesis.[37][38][39]
carboxyamidotriazole Methionine aminopeptidase 2inhibitors,[40]inhibit cell proliferation and cell migration of endothelial cells
TNP-470(an analog offumagillin)
CM101 activateimmune 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
SU5416
thrombospondin
VEGFR antagonists
angiostatic steroids +heparin inhibitbasement membranedegradation
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 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 VEGF
αVβ3inhibitors induce apoptosis of endothelial cells
linomide inhibit cell migration of endothelial cells
ramucirumab inhibition of VEGFR2[41]
tasquinimod Unknown[42]
ranibizumab VEGF[43]
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

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Through binding toVEGFRand other VEGF receptors in endothelial cells, VEGF can trigger multiple cellular responses like promoting cell survival, preventing apoptosis, and remodelingcytoskeleton,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.[14]

After a series ofclinical trialsin 2004,Avastinwas 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.[44]

Thalidomide

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Despite the therapeutic potential of anti-angiogenesis drugs, they can also be harmful when used inappropriately.Thalidomideis 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 withdeformities,most notablyphocomelia,as a consequence of thalidomide use.[45]

Cannabinoids

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According to a study published in the August 15, 2004 issue of the journalCancer Research,cannabinoids,the active ingredients inmarijuana,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).[46]

General side effects of drugs

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Bleeding

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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.[citation needed]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.[47]

Increased blood pressure

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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.[48][non-primary source needed]

Less common side effects

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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.[47]

See also

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References

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Further reading

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