Angiogenesis inhibitor
An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (
While angiogenesis is a critical part of
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.
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
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
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.
Inhibitors | Mechanism |
---|---|
soluble NRP-1 |
|
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 |
ADAMTS1 and ADAMTS8 | |
inhibit cell migration of endothelial cells, downregulate bFGF | |
antithrombin III fragment |
inhibit cell proliferation of endothelial cells |
prolactin | 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[13] |
proliferin-related protein | mannose 6-phosphate binding lysosomal protein[14] |
A recent method for the delivery of anti-angiogenesis factors to tumor regions in cancer patients uses
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:
- Agaricus subrufescens mushrooms (contain the inhibitors sodium pyroglutamate and ergosterol)[18][19]
- Black raspberry (Rubus occidentalis) extract[20]
- TGF-beta)[21]
- Trametes versicolor mushrooms (Polysaccharide-K)[22][23][24]
- catechins)[28]
- glycyrrhizic acid)[29]
- Red wine (resveratrol)[29]
- Antiangiogenic phytochemicals and medicinal herbs[30]
- Royal Jelly (Queen bee acid)[31]
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
In addition to their use as anti-cancer drugs, angiogenesis inhibitors are being investigated for their use as
Overview
Inhibitors | Mechanism |
---|---|
bevacizumab (Avastin) | VEGF |
itraconazole | inhibits |
carboxyamidotriazole | Methionine aminopeptidase 2 inhibitors,[37] 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 | |
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 | 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 |
αVβ3 inhibitors |
induce apoptosis of endothelial cells |
linomide |
inhibit cell migration of endothelial cells |
ramucirumab | inhibition of VEGFR2[38] |
tasquinimod | Unknown[39] |
ranibizumab | VEGF[40] |
sorafenib (Nexavar) | inhibit kinases |
sunitinib (Sutent) | |
pazopanib (Votrient) | |
everolimus (Afinitor) |
Bevacizumab
Through binding to
After a series of
Thalidomide
Despite the therapeutic potential of anti-angiogenesis drugs, they can also be harmful when used inappropriately.
Cannabinoids
According to a study published in the August 15, 2004 issue of the journal Cancer Research,
General side effects of drugs
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.[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.[44]
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.[45][non-primary source needed]
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.[44]
See also
- Brain-specific angiogenesis inhibitor 1 (and others)
References
- PMID 19360048.
- ^ Fukumura, D., et al., Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol, 2018. 15(5): p. 325-340. doi: 10.1038/nrclinonc.2018.29
- ^ Huinen, Z., et al., Anti-angiogenic agents - overcoming tumor endothelial cell anergy and improving immunotherapy outcomes. Nat. Rev. Clin. Oncol., 2021. 18(8): p. 527-540. doi: 10.1038/s41571-021-00496-y
- ^ Dudley, A.C. & Griffioen, A.W., Pathological angiogenesis: mechanisms and therapeutic strategies. Angiogenesis, 2023. doi: 10.1007/s10456-023-09876-7
- ^ 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.
- PMID 15947805.
- ^ S2CID 10605205.
- ISBN 978-3-030-98950-7, retrieved 2022-07-13
- ^ PMID 11312106.
- PMID 17317817.
- ^ PMID 15899784.
- ^ Hugo H. Marti, "Vascular Endothelial Growth Factor", Madame Curie Bioscience Database, Landes Bioscience, retrieved January 25, 2012
- PMID 10625665.
- PMID 2963825.
- ^ 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.
- ^ 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.
- PMID 16969510.
- S2CID 7243576.
- PMID 11340091.
- PMID 15884816.
- PMID 15781230.
- PMID 12168863.
- S2CID 161680.
- PMID 7606203.
- PMID 19053855.
- PMID 18362935.
- PMID 18827365.
- S2CID 6846032.
- ^ a b 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.[unreliable medical source?]
- S2CID 968172.
- PMID 18955252.
- PMID 22258895.
- PMID 23642783.
- PMID 17432820.
- PMID 21896639.
- PMID 20176935.
- hdl:10044/1/102175.
- ^ Ramucirumab (Cyramza) package insert
- PMID 21717904. Retrieved 9 May 2022.
- PMID 17021318.
- ^ FDA News Release on Avastin, retrieved 2014-04-15
- PMID 21507989.
- S2CID 1357974.
- ^ PMID 22682133.
- PMID 19773379.
Further reading
- Milosevic, V., Edelmann, R.J., Fosse, J.H., Östman, A., Akslen, L.A. (2022). Molecular Phenotypes of Endothelial Cells in Malignant Tumors. In: Akslen, L.A., Watnick, R.S. (eds) Biomarkers of the Tumor Microenvironment. Springer, Cham. https://doi.org/10.1007/978-3-030-98950-7_3
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
- Angiogenesis+Inhibitors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)