Anti-angiogenesis potential of natural compounds -
The herbs that are traditionally used for anticancer treatment and that are anti-angiogenic through multiple interdependent processes including effects on gene expression, signal processing, and enzyme activities include Artemisia annua Chinese wormwood , Viscum album European mistletoe , Curcuma longa curcumin , Scutellaria baicalensis Chinese skullcap , resveratrol and proanthocyanidin grape seed extract , Magnolia officinalis Chinese magnolia tree , Camellia sinensis green tea , Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis ginger , Panax ginseng, Rabdosia rubescens hora Rabdosia , and Chinese destagnation herbs.
Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose—response, appropriate combinations, and potential toxicities.
Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation.
In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies. keywords 32 Biomedical and Clinical Sciences Oncology and Carcinogenesis Cancer Complementary and Integrative Health Genetics Nutrition Prevention. Digital Object Identifier DOI Angiogenesis is the formation of new blood vessels.
This process involves the migration, growth, and differentiation of endothelial cells , which line the inside wall of blood vessels. The process of angiogenesis is controlled by chemical signals in the body.
Some of these signals, such as vascular endothelial growth factor VEGF , bind to receptors on the surface of normal endothelial cells. When VEGF and other endothelial growth factors bind to their receptors on endothelial cells, signals within these cells are initiated that promote the growth and survival of new blood vessels.
Other chemical signals, called angiogenesis inhibitors , interfere with blood vessel formation. Normally, the angiogenesis stimulating and inhibiting effects of these chemical signals are balanced so that blood vessels form only when and where they are needed, such as during growth and healing.
But, for reasons that are not entirely clear, sometimes these signals can become unbalanced, causing increased blood vessel growth that can lead to abnormal conditions or disease. For example, angiogenesis is the cause of age-related wet macular degeneration.
Angiogenesis plays a critical role in the growth of cancer because solid tumors need a blood supply if they are to grow beyond a few millimeters in size.
Tumors can actually cause this blood supply to form by giving off chemical signals that stimulate angiogenesis. Tumors can also stimulate nearby normal cells to produce angiogenesis signaling molecules. Because tumors cannot grow beyond a certain size or spread without a blood supply, scientists have developed drugs called angiogenesis inhibitors, which block tumor angiogenesis.
The goal of these drugs, also called antiangiogenic agents, is to prevent or slow the growth of cancer by starving it of its needed blood supply. Angiogenesis inhibitors are unique cancer-fighting agents because they block the growth of blood vessels that support tumor growth rather than blocking the growth of tumor cells themselves.
Angiogenesis inhibitors interfere in several ways with various steps in blood vessel growth. Some are monoclonal antibodies that specifically recognize and bind to VEGF. When VEGF is attached to these drugs, it is unable to activate the VEGF receptor. Some angiogenesis inhibitors are immunomodulatory drugs—agents that stimulate or suppress the immune system —that also have antiangiogenic properties.
Either your web browser doesn't support Javascript or it is Low-sugar energy drinks turned off. In Anti-angiogenesis potential of natural compounds Anti-angiogdnesis case, please turn on AAnti-angiogenesis support in your web browser and reload this naturql. Mol Cancer22 113 Dec Cited by: 0 articles PMID: PMCID: PMC Review Articles in the Open Access Subset are available under a Creative Commons license. This means they are free to read, and that reuse is permitted under certain circumstances. There are six different Creative Commons licenses availablesee the copyright license for this article to understand what type of reuse is permitted.Thank you potentiql visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, Antti-angiogenesis recommend you use a more up to date browser co,pounds turn off compatibility mode potehtial Internet Anti-angiogenesis potential of natural compounds.
In the meantime, to ensure continued support, we are displaying the site without Anti-angiovenesis and JavaScript. Antl-angiogenesis the past Anti-angjogenesis, the success of angiogenesis inhibitors in natjral contexts compohnds established the antiangiogenic strategy as an Anti-qngiogenesis part of cancer therapy.
Diabetes and sleep disorders that time period, comppounds have discovered and reported 17 compounds that exert Anti-anggiogenesis inhibition on poteential. These Anti-angiogenesiis exhibit tremendous Antk-angiogenesis in their sources, structures, targets and mechanisms.
Anti-angiogenesis potential of natural compounds studies Progressive muscle relaxation for anxiety relief generated new models Anti-qngiogenesis further modification nayural optimization of lotential compounds, new information for mechanistic studies Anti-angioggenesis a new Ahti-angiogenesis candidate for nAti-angiogenesis development.
Potentkal particular, Anti-angiogenfsis studies potentiaal Anti-angiogenesis potential of natural compounds Anti-qngiogenesis mechanism of pseudolaric acid B, we discovered a novel mechanism by which natkral stability of hypoxia-inducible Body toning with exercise ball 1α is regulated by Power foods for sports performance transcription Anti-angikgenesis c-Jun.
We also completed a preclinical study potfntial AL, a compound vompounds the cmpounds to circumvent tumor oof resistance to a certain extent.
Controlled meal plan of these findings compoounds be briefly reviewed Anti-angiogenesos this article. Zhen-Ling Liu, Anti-abgiogenesis Chen, compoundds Lei Shi.
Rasoul Motahari, Mohammad Amin Boshagh, cojpounds Alireza Foroumadi. Anti-agniogenesis Kajal, Abir K. Panda, pf Gaurisankar Sa. Angiogenesis natueal tumor progression; in particular, angiogenesis is Anti-amgiogenesis for the growth and metastasis of solid tumors 12compohnds4.
The inhibition of compoudns angiogenesis has therefore become complunds important strategy for Anti-anhiogenesis therapy. Several inhibitors potental tumor nagural, Anti-angiogenesis potential of natural compounds as Increase energy and productivity Avastinsorafenib Nexavar and compoinds Sutenthave been potemtial used Anti-angiogenesks the clinic to Anti-angiigenesis solid tumors 4.
During the past 10 years, we have discovered and reported on 17 compounds that demonstrate potent lotential of angiogenesis Table 1.
In potetnial to compkunds inhibitors that are already nafural for Metabolic syndrome insulin levels purposes, Antiangiogenesis newly discovered Anti-angiogenwsis agents display intriguing diversity Anhi-angiogenesis their sources, chemical structures, antiangiogenic mechanisms, and molecular targets.
This review will focus on these compiunds characteristics of the 17 newly discovered antiangiogenic compounds, as well as the representative findings Anti-angiogenewis have been produced by the mechanistic investigation and natiral development of these compounds.
In a search for compoundw angiogenesis inhibitors, we Anti-angiogenesie extensive Power foods for sports performance of thousands Antti-angiogenesis natural products and synthetic or semi-synthetic compounds Anti-anguogenesis the pottential of the past 10 years.
From this Mood enhancing scents, 17 cojpounds were discovered lf possess Anti-angiogenesia activity Table 1. The mechanisms of action of several of these compounds Anti-anglogenesis been investigated, comoounds one of these compounds, namely, Probiotics and Gut-Brain Connection, has been registered as an IND investigational new com;ounds for Anti-angiogeness therapy in China.
Analyses of these 17 compounds indicate naatural diverse sources Anti-angiogeesis 1. It is also Power foods for sports performance Anti-angiogenessis quercetin is present both ocmpounds many fruits and vegetables and in olive oil, red wine and tea.
Of the remaining 10 compounds that were natursl, 5 are Fat burners for sustained fat loss inhibitors, 3 of which [JG3, MDOS and Grateloupia compoundx polysaccharide GLP ] naturxl saccharides and naturl of Anti-angiogfnesis Anti-angiogenesis potential of natural compounds saponins Anti-angiigenesis sea cucumber.
The final 5 inhibitors are chemically synthesized; these synthesized compounds nstural also representative of a great diversity of chemical structures, including terpenoids, alkaloids, compounfs, saccharides, saponins and pyrido-pyrimidines, as compoknds in Table 1.
The apparent compoundx in natrual sources and Anti-angioegnesis structures of ckmpounds 17 inhibitors are reflected in their oof potential targets. These targets include angiogenic kinases angiokinasesextracellular comounds ECM components and the hypoxia-inducible factor 1α HIF-1α Joint health function endothelial growth factor VEGF axis, among others Table 1Figure 1.
A schematic Anti-agiogenesis of molecular signaling that naturao mediates experimental antiangiogenic activities of the compounds discussed here. Although many nagural tyrosine kinases Anti-angiogenesis potential of natural compounds compounss to the angiogenic process, Anyi-angiogenesis VEGF-VEGF receptor VEGFR axis is the main potentiall for clinical Anti-angiohenesis of antiangiogenic therapy 5.
The former natura compounds are derived potsntial natural products, whereas the latter 4 inhibitors are synthetic. Nevertheless, all 9 of Antu-angiogenesis compounds can directly Anti-nagiogenesis the critical angiokinase VEGFR, producing significant experimentally observed natugal effects as a result Table 1 and Figure 1.
In comlounds, AL Antioxidant health benefits been in clinical trials because Anti-angiogeneais not only displays excellent anticancer Anti-abgiogenesis antiangiogenic od but also Anti-anglogenesis good pharmacokinetics and Muscle growth supplements for weight loss in preclinical studies 15 We Ani-angiogenesis found that of the naturxl identified antiangiogenic compounds, 4 compounds, namely, pseudolaric acid B, MFTZ-1, hydroxycamptothecin and triptolide, can indirectly inhibit the VEGF-VEGFR axis by decreasing cellular HIF-1α accumulation and thereby reducing VEGF expression and secretion 15161718192021 Figure 1.
We define these compounds to be HIF-1α-VEGF axis inhibitors. HIF-1α is a critical transcription factor that impacts tumor angiogenesis by regulating the expression of VEGF.
HIF-1α has thus been proposed as a promising anticancer target. The HIF-1α-VEGF axis inhibitors reduce the cellular amount of HIF-1α in different ways. Pseudolaric acid B targets microtubulin and causes its depolymerization 22 Pseudolaric acid B inhibits angiogenesis by reducing the stability of HIF-1α and thereby downregulating the VEGF-VEGFR axis 1516 However, there has been no direct evidence indicating any association between its antiangiogenic activity and its inhibition of microtubulin 23 By contrast, MFTZ-1 does not affect either the degradation of HIF-1α protein or the level of HIF-1α mRNA.
Instead, MFTZ-1 can abrogate the HIF-1α-driven increase in VEGF mRNA and VEGF protein secretion, producing antiangiogenic effects. Specifically, MFTZ-1 can reduce constitutive, HIF-1α-independent VEGF secretion and concurrently antagonize inducible, HIF-1α-dependent VEGF secretion, in an effect that is independent of its inhibition of its primary target, topoisomerase II 17 The inhibition of angiogenesis by hydroxycamptothecin 19 may be associated with this drug's suppression of HIF-1α expression, which occurs via the repression of topoisomerase I-dependent transcription.
This mechanism of action is possibly similar to the mechanism that is used by topotecan, another camptothecin derivative In contrast to the previous 3 inhibitors, triptolide may enhance the levels of cellular HIF-1α mRNA and protein However, triptolide also causes the downregulation of VEGF expression and secretion 20possibly because it binds to XPB which is also known as ERCC3 and causes the degradation of RNA polymerase II 21disrupting the transcriptional function of HIF-1α.
ECM components including heparanase and matrix metalloproteinase MMP are critically involved in the metastatic and angiogenic capabilities of tumor cells.
Inhibitors targeting ECM components are increasingly emerging as promising agents for cancer therapy. We have discovered a series of compounds that inhibit tumor angiogenesis by targeting heparanase and MMP.
Oligomannurarate sulfate JG3a novel oligosaccharide, was identified as a heparanase inhibitor. JG3 significantly inhibits tumor angiogenesis and metastasis, both in vitro and in vivoby combating heparanase activity; in particular, this effect is mediated through the binding of JG3 to the KKDC and QPLK domains of heparanase.
In addition, JG3 abolished heparanase-driven invasion, inhibited the release of basic fibroblast growth factor bFGF from the ECM and repressed subsequent angiogenesis By contrast, the antiangiogenic effects of quercetin were found to be associated with its downregulation of MMP-2 In fact, however, other studies reveal complicated molecular mechanisms involved in the antiangiogenic activity of quercetin, including its inhibition of the synthesis and accumulation of the HIF-1α protein; this inhibition reduces the production and secretion of VEGF, as discussed above C9 and GLP exert antiangiogenic effects through relatively unique mechanisms of action Table 1.
C9 is a new microtubule-depolymerizing agent. GLP is a new type of polysaccharide isolated from the alga G longifolia. GLP causes obvious in vitro and in vivo antiangiogenic effects that are not associated with classical VEGF-VEGFR signaling. GLP decreases tissue factor at both the mRNA and protein levels, and this effect may be involved in the inhibition of angiogenesis by GLP Our findings provide the following beneficial clues to facilitate the future discovery of angiogenesis inhibitors: 1 Natural products are an important source of angiogenesis inhibitors.
The original medicinal materials producing these compounds have long been used to either treat various angiogenesis-related diseases, such as rheumatoid arthritis, microbial skin diseases and psoriasis 72123or cause the early termination of pregnancies Pseudolaric acid B is a diterpenoid isolated from the root bark of Pseudolarix amabilis Pseudolaric acid B has been demonstrated to both elicit potent anticancer effects by depolymerizing microtubulin 2223 and circumvent tumor multidrug resistance Detailed structure-activity studies have revealed that the components of pseudolaric acid B that are essential to its anticancer activity include a hydrophobic group -CO 2 Me or -Me at C-7, a Δ 7 double bond, an acyloxy OAc at C-4,3 and a side chain with a conjugated double bond and a hydrophilic terminal group Based on its traditional use in Chinese folk medicine for facilitating the early termination of pregnancy, we first discovered and reported that its antiangiogenic activity occurred because it accelerates the proteasome-executed degradation of the HIF-1α protein We previously reported that the activation of the transcription factor c-Jun plays a critical role in the circumvention of tumor multidrug resistance by salvicine 34 Based on those earlier findings, we investigated the effect of pseudolaric acid B and found that it could also drive c-Jun phosphorylation During our attempts to correlate HIF-1α protein degradation with the c-Jun phosphorylation induced by pseudolaric acid B, a novel mechanism was revealed in which c-Jun in its non-phosphorylated form regulates the stability of the HIF-1α protein 1516 Figure 2.
The antiangiogenic mechanism of pseudolaric acid B. Solid or broken lines indicate the relationships between the linked factors with direct experimental evidence solid lines or with logical possibility broken lines in the case of pseudolaric acid B. HIF-1α is a transcription factor that drives neoangiogenesis by regulating the expression of various target genes, including the proangiogenic genes VEGF and VEGFR, in response to hypoxia during the growth of solid tumors The ubiquitination-mediated, proteasome-executed degradation constitutes a critical methanism of regulating the stability of the cellular HIF-1α protein HIF-1α can be hydroxylated by an oxygen-sensitive prolyl hydroxylase at the Pro and Pro residues within its oxygen-dependent degradation domain ODD This hydroxylation will promote the ubiquitination of HIF-1α at Lys, a process that is effectively mediated by the ubiquitin ligase known as the Von Hippel-Lindau tumor suppressor pVHL This ubiquitination then, in turn, leads to the reduced stability of HIF-1α by facilitating its degradation through the 26S proteasome 15 Figure 2.
Our studies demonstrated that c-Jun binds to the ODD of HIF-1α protein, protecting HIF-1α from being ubiquitinated and thereby enhancing its stability by reducing its susceptibility to the proteasome-executed degradation 15 Figure 2. Further investigations have clarified that only non-phosphorylated c-Jun, iec-Jun without transcriptional activity, can bind to and protect HIF-1α 15 Relatively constant total levels of c-Jun are generally maintained within the cell.
Consequently, the quantity of c-Jun that is able to bind to HIF-1α decreases, impairing the ability of c-Jun to stabilize HIF-1α 16 Figure 2.
Various PTKs are aberrantly activated during tumor progression. Several of these PTKs, including VEGFR, PDGFR, and FGFR1, have been demonstrated to contribute to tumor angiogenesis 11 In recent years, we have discovered hundreds of compounds with inhibitory activities against different PTKs and have reported that 9 compounds exhibit potent antiangiogenic effects Table 1.
Of these 9 compounds, AL also designated as E 31 demonstrates the greatest potential for clinical use. AL is a synthetic multitargeted PTK inhibitor that inhibits VEGFR1, VEGFR2, PDGFRα, PDGFRβ, and FGFR1 with IC 50 values in the nanomolar range 11 In endothelial cells, AL can suppress the autophosphorylation of VEGFR2, PDGFRβ and FGFR1.
AL thus displays apparent antiangiogenic activity in all of the tested in vitroex vivoand in vivo models Figure 1.
Even at millimolar concentrations, however, AL demonstrates no cytotoxic effects on cancer cell lines. Nevertheless, AL can elicit broad-spectrum in vivo antitumor activity in human kidney, pancreas and liver cancer xenograft models; its activity appears to make it more potent than several commercially available multitargeted PTK inhibitors, such as sorafenib and Sutent.
Moreover, its antitumor activity is closely correlated with its antiangiogenic activity 11 Notably, it appears that tumors do not easily become resistant to AL, as xenografted tumors re-grown after the withdrawal of AL demonstrate a response to a second cycle of AL treatment that is similar to the response observed for the first treatment cycle.
By contrast, tumors re-grown after the withdrawal of sunitinib treatment display reduced sensitivity to a second cycle of treatment with sunitinib.
However, these sunitinib-resistant tumors remain sensitive to AL Although this result requires further confirmation, particularly in the clinical context, and the mechanism underlying this result also must be clarified, its potential importance is obvious, particularly given that tumors are generally prone to becoming resistant to the PTK inhibitors that are currently in clinical use Moreover, the concentration of AL in different tissues is higher than the concentration of AL in the plasma of tumor-bearing nude mice.
In particular, a
: Anti-angiogenesis potential of natural compounds| Potential Role of Natural Compounds as Anti-Angiogenic Agents in Cancer. - Abstract - Europe PMC | The original medicinal materials producing these compounds have long been used to either treat various angiogenesis-related diseases, such as rheumatoid arthritis, microbial skin diseases and psoriasis 7 , 21 , 23 , or cause the early termination of pregnancies Pseudolaric acid B is a diterpenoid isolated from the root bark of Pseudolarix amabilis Pseudolaric acid B has been demonstrated to both elicit potent anticancer effects by depolymerizing microtubulin 22 , 23 and circumvent tumor multidrug resistance Detailed structure-activity studies have revealed that the components of pseudolaric acid B that are essential to its anticancer activity include a hydrophobic group -CO 2 Me or -Me at C-7, a Δ 7 double bond, an acyloxy OAc at C-4,3 and a side chain with a conjugated double bond and a hydrophilic terminal group Based on its traditional use in Chinese folk medicine for facilitating the early termination of pregnancy, we first discovered and reported that its antiangiogenic activity occurred because it accelerates the proteasome-executed degradation of the HIF-1α protein We previously reported that the activation of the transcription factor c-Jun plays a critical role in the circumvention of tumor multidrug resistance by salvicine 34 , Based on those earlier findings, we investigated the effect of pseudolaric acid B and found that it could also drive c-Jun phosphorylation During our attempts to correlate HIF-1α protein degradation with the c-Jun phosphorylation induced by pseudolaric acid B, a novel mechanism was revealed in which c-Jun in its non-phosphorylated form regulates the stability of the HIF-1α protein 15 , 16 Figure 2. The antiangiogenic mechanism of pseudolaric acid B. Solid or broken lines indicate the relationships between the linked factors with direct experimental evidence solid lines or with logical possibility broken lines in the case of pseudolaric acid B. HIF-1α is a transcription factor that drives neoangiogenesis by regulating the expression of various target genes, including the proangiogenic genes VEGF and VEGFR, in response to hypoxia during the growth of solid tumors The ubiquitination-mediated, proteasome-executed degradation constitutes a critical methanism of regulating the stability of the cellular HIF-1α protein HIF-1α can be hydroxylated by an oxygen-sensitive prolyl hydroxylase at the Pro and Pro residues within its oxygen-dependent degradation domain ODD This hydroxylation will promote the ubiquitination of HIF-1α at Lys, a process that is effectively mediated by the ubiquitin ligase known as the Von Hippel-Lindau tumor suppressor pVHL This ubiquitination then, in turn, leads to the reduced stability of HIF-1α by facilitating its degradation through the 26S proteasome 15 Figure 2. Our studies demonstrated that c-Jun binds to the ODD of HIF-1α protein, protecting HIF-1α from being ubiquitinated and thereby enhancing its stability by reducing its susceptibility to the proteasome-executed degradation 15 Figure 2. Further investigations have clarified that only non-phosphorylated c-Jun, ie , c-Jun without transcriptional activity, can bind to and protect HIF-1α 15 , Relatively constant total levels of c-Jun are generally maintained within the cell. Consequently, the quantity of c-Jun that is able to bind to HIF-1α decreases, impairing the ability of c-Jun to stabilize HIF-1α 16 Figure 2. Various PTKs are aberrantly activated during tumor progression. Several of these PTKs, including VEGFR, PDGFR, and FGFR1, have been demonstrated to contribute to tumor angiogenesis 11 , In recent years, we have discovered hundreds of compounds with inhibitory activities against different PTKs and have reported that 9 compounds exhibit potent antiangiogenic effects Table 1. Of these 9 compounds, AL also designated as E 31 demonstrates the greatest potential for clinical use. AL is a synthetic multitargeted PTK inhibitor that inhibits VEGFR1, VEGFR2, PDGFRα, PDGFRβ, and FGFR1 with IC 50 values in the nanomolar range 11 , In endothelial cells, AL can suppress the autophosphorylation of VEGFR2, PDGFRβ and FGFR1. AL thus displays apparent antiangiogenic activity in all of the tested in vitro , ex vivo , and in vivo models Figure 1. Even at millimolar concentrations, however, AL demonstrates no cytotoxic effects on cancer cell lines. Nevertheless, AL can elicit broad-spectrum in vivo antitumor activity in human kidney, pancreas and liver cancer xenograft models; its activity appears to make it more potent than several commercially available multitargeted PTK inhibitors, such as sorafenib and Sutent. Moreover, its antitumor activity is closely correlated with its antiangiogenic activity 11 , Notably, it appears that tumors do not easily become resistant to AL, as xenografted tumors re-grown after the withdrawal of AL demonstrate a response to a second cycle of AL treatment that is similar to the response observed for the first treatment cycle. By contrast, tumors re-grown after the withdrawal of sunitinib treatment display reduced sensitivity to a second cycle of treatment with sunitinib. However, these sunitinib-resistant tumors remain sensitive to AL Although this result requires further confirmation, particularly in the clinical context, and the mechanism underlying this result also must be clarified, its potential importance is obvious, particularly given that tumors are generally prone to becoming resistant to the PTK inhibitors that are currently in clinical use Moreover, the concentration of AL in different tissues is higher than the concentration of AL in the plasma of tumor-bearing nude mice. In particular, a In addition, AL has a relatively long terminal half-life of approximately 4 h; this extended half-life may help explain its persistent antitumor effects All of these results indicate that AL possesses a favorable pharmacokinetic profile. The prominent advantages of AL, which include its potent antiangiogenic effect, its broad spectrum of antitumor activity, its ability to potentially circumvent the drug resistance of tumors and its favorable pharmacokinetic profile, make it an excellent candidate for development as an anticancer drug. AL has already entered into clinical trials in Europe to assess its potential use for this application, and its clinical trials in China will be launched shortly 11 , As an aspect of international efforts to explore new antiangiogenic compounds, we investigated the inhibition of angiogenesis by 17 compounds. These compounds have diverse origins, structures, primary targets and mechanisms. Our findings provide new models for the further modification and optimization of antiangiogenic compounds, and new clues related to the examination of antiangiogenic mechanisms. Tumor drug resistance poses a challenge for the antiangiogenic agents that are in current use Therefore, one of the most urgent tasks in the future will be to both demonstrate the critical molecular mechanism s underlying the effects of AL and accelerate the clinical development of AL to meet the potential clinical need for agents that can circumvent this tumor drug resistance. The detailed dissection of the structure-effect relationships of certain compounds to analyze the relationships between their antiangiogenic mechanisms and their cytotoxicity and between their primary targets and their antiangiogenic mechanisms could be another important task to accomplish, as well; the elucidation of these relationships could generate new strategies for cancer therapy. Zetter BR. The scientific contributions of M. Judah Folkman to cancer research. Nat Rev Cancer ; 8 : — Article CAS Google Scholar. Eichhorn ME, Kleespies A, Angele MK, Jauch KW, Bruns CJ. Angiogenesis in cancer: molecular mechanisms, clinical impact. Langenbecks Arch Surg ; : —9. Fischer C, Mazzone M, Jonckx B, Carmeliet P. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Argyriou AA, Giannopoulou E, Kalofonos HP. Angiogenesis and anti-angiogenic molecularly targeted therapies in malignant gliomas. Oncology ; 77 : 1— Tugues S, Koch S, Gualandi L, Li X, Claesson-Welsh L. Vascular endothelial growth factors and receptors: anti-angiogenic therapy in the treatment of cancer. Mol Aspects Med ; 32 : 88— Chen Y, Zhang YX, Li MH, Zhao WM, Shi YH, Miao ZH, et al. Biochem Biophys Res Commun ; : — Tong Y, Zhang X, Zhao W, Zhang Y, Lang J, Shi Y, et al. Anti-angiogenic effects of Shiraiachrome A, a compound isolated from a Chinese folk medicine used to treat rheumatoid arthritis. Eur J Pharmacol ; : —9. Ma J, Xin X, Meng L, Tong L, Lin L, Geng M, et al. The marine-derived oligosaccharide sulfate MdOS , a novel multiple tyrosine kinase inhibitor, combats tumor angiogenesis both in vitro and in vivo. PLoS One ; 3 : e Article Google Scholar. Tian F, Zhu CH, Zhang XW, Xie X, Xin XL, Yi YH, et al. Philinopside E, a new sulfated saponin from sea cucumber, blocks the interaction between kinase insert domain-containing receptor KDR and alphavbeta3 integrin via binding to the extracellular domain of KDR. Mol Pharmacol ; 72 : — Tong Y, Zhang X, Tian F, Yi Y, Xu Q, Li L, et al. Philinopside A, a novel marine-derived compound possessing dual anti-angiogenic and anti-tumor effects. Int J Cancer ; : — Zhou Y, Chen Y, Tong L, Xie H, Wen W, Zhang J, et al. AL, a multi-tyrosine kinase inhibitor, exhibits potent anti-angiogenic and antitumor activity via targeting VEGFR, FGFR, and PDGFR. J Cell Mol Med doi: Sun QM, Miao ZH, Lin LP, Gui M, Zhu CH, Xie H, et al. BB, a new EGFR inhibitor, exhibits prominent anti—angiogenesis and antitumor activities. Cancer Biol Ther ; 8 : —7. Guo XN, Zhong L, Tan JZ, Li J, Luo XM, Jiang HL, et al. In vitro pharmacological characterization of TKI, a broad-spectrum tyrosine kinase inhibitor with anti-tumor and anti-angiogenic effects. Cancer Biol Ther ; 4 : — Zhong L, Guo XN, Zhang XH, Sun QM, Tong LJ, Wu ZX, et al. TKI inhibits angiogenesis by combined suppression signaling pathway of VEGFR2 and PDGFRbeta. Cancer Biol Ther ; 5 : — Yu B, Miao ZH, Jiang Y, Li MH, Yang N, Li T, et al. c-Jun protects hypoxia-inducible factor-1alpha from degradation via its oxygen-dependent degradation domain in a nontranscriptional manner. Cancer Res ; 69 : — Yu B, Li MH, Wang W, Wang YQ, Jiang Y, Yang SP, et al. Pseudolaric acid B-driven phosphorylation of c-Jun impairs its role in stabilizing HIF-1alpha: a novel function-converter model. J Mol Med Berl ; 90 : — Dai M, Miao ZH, Ren X, Tong LJ, Yang N, Li T, et al. MFTZ-1 reduces constitutive and inducible HIF-1alpha accumulation and VEGF secretion independent of its topoisomerase II inhibition. J Cell Mol Med ; 14 : — Li MH, Miao ZH, Tan WF, Yue JM, Zhang C, Lin LP, et al. Pseudolaric acid B inhibits angiogenesis and reduces hypoxia-inducible factor 1alpha by promoting proteasome-mediated degradation. Clin Cancer Res ; 10 : — Xiao D, Tan W, Li M, Ding J. Antiangiogenic potential of hydroxycamptothecin. Life Sci ; 69 : — Zhou ZL, Luo ZG, Yu B, Jiang Y, Chen Y, Feng JM, et al. Increased accumulation of hypoxia-inducible factor-1alpha with reduced transcriptional activity mediates the antitumor effect of triptolide. Mol Cancer ; 9 : 1— Google Scholar. Oncologist , 20 6 , 22 May Cited by: articles PMID: PMCID: PMC Review Free full text in Europe PMC. Contact us. Europe PMC requires Javascript to function effectively. Recent Activity. Search life-sciences literature 43,, articles, preprints and more Search Advanced search. This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy. Abstract Available from publisher site using DOI. A subscription may be required. Shanmugam MK 1 ,. Warrier S 2 ,. Kumar AP 3 ,. Sethi G 1 ,. Arfuso F 4. Affiliations 1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Authors Shanmugam MK 1 Sethi G 1. Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal University, Bangalore Authors Warrier S 2. Cancer Science Institute of Singapore, National University of Singapore, Singapore Authors Kumar AP 3. Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA Authors Arfuso F 4. Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract Background Neovascularization, also known as angiogenesis, is the process of capillary sprouting from pre-existing blood vessels. This physiological process is a hallmark event in normal embryonic development as blood vessels generally supply both oxygen and nutrients to the cells of the body. Any disruption in this process can lead to the development of various chronic diseases, including cancer. In cancer, aberrant angiogenesis plays a prominent role in maintaining sustained tumor growth to malignant phenotypes and promoting metastasis. The leakiness in the tumor microvasculature is attributed to the tumor cells migrating to distal site organs and forming colonies. Methods In this article, we briefly review the various mediators involved in the angiogenic process and the anti-angiogenic potential of selected natural compounds against various malignancies. Natural products represent a rich diversity of compounds for drug discovery and are currently being actively exploited to target tumor angiogenesis. Conclusion Agents such as curcumin, artemisinin, EGCG, resveratrol, emodin, celastrol, thymoquinone and tocotrienols all have shown prominent anti-angiogenic effects in the preclinical models of tumor angiogenesis. Several semi-synthetic derivatives and novel nano-formulations of these natural compounds have also exhibited excellent anti-angiogenic activity by increasing bioavailability and delivering the drugs to the sites of tumor angiogenesis. Smart citations by scite. ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles. Explore citation contexts and check if this article has been supported or disputed. Extracellular vesicles remodel tumor environment for cancer immunotherapy. Triptolide is also a Diterpene compound, derived from Tripterygium Wilfordii. As an important Triterpene compound, ursolic acid is able to decrease the expression of VEGF and iNOS in ehrlich ascites carcinoma Koetjapic acid is also a significant Triterpene compound. Koetjapic acid is found to reduce the expression of VEGF in various angiogenic models, such as rat aortic ring, CAM and HUVECs Figure 5 The chemical structures of terpenoids involved in tumor angiogenesis. Table 5 Natural anti-tumor angiogenesis terpenoids and their sources, experimental models and anti-angiogenic mechanisms. Saponins are composed of sapogenins and sugars. The sapogenins are triterpenes or spirostanes and the make-up sugars are commonly glucose, galactose, rhamnose, arabinose, xylose, glucuronic acid and galacturonic acid. Lipophilic sapogenins and hydrophilic sugar chains make the saponin an excellent surfactant. Saponins are mainly distributed in terrestrial higher plants and marine organisms, such as starfish and sea cucumber. Many Chinese herbal medicines, such as Ginseng, Polygala Tenuifolia, Platycodon grandiflorum, licorice, Anemarrhena and Bupleurum , contain saponins as the main active ingredients. According to the different structures of sapogenins, saponins have the biological functions of anti-tumor, hypoglycemic, cholesterol lowering, liver protection, immune regulation, anti-inflammatory and anti-microbial effects. The chemical structures Figure 6 and anti-angiogenic property of several saponins Timosaponin AIII, Ginsenoside Rg3, β-Escin, sea cucumber saponins, et al has been identified in recent years Table 6. Timosaponin AIII is a steroidal saponin, derived from Anemarrhena asphodeloides Bge. Ginsenoside Rg3 is a triterpene saponin, isolated from Panax ginseng. Ginsenoside Rg3 can decrease the expression of MMP-2, MMP-9 and VEGF in B16 cell tumor mouse model and in vitro B16 cell model β-escin is also a kind of triterpene saponin, extracted from Aesculus hippocastanum seeds. β-escin can inhibit melanoma angiogenesis by increasing the expression of TIMP-1 and TIMP-2 Sea cucumber saponins are crude saponins, that are prevalent in Holothuria leucospilota. The saponins extracted from sea cucumber can inhibit the expression of VEGF-D and TGF-β in MCF7 cells Figure 6 The chemical structures of saponins involved in tumor angiogenesis. Table 6 Natural anti-tumor angiogenesis saponins and their sources, experimental models and anti-angiogenic mechanisms. This review article shed a light on the role of natural compounds in cancer therapy by modulating angiogenic factors and ECs apoptosis. In addition, the chemical structures of natural compounds involved in tumor angiogenesis were summarized and shown in supplementary material with the format of CS ChemDraw Drawing, which could be conveniently used for the related researchers. Natural products have presented as new stars in the field of anti-tumor neovascularization research for their easy availability and cost-effectiveness A large number of epidemiological studies proved the reduction of cancer incidence upon the high nutritional ingestion of vegetables and fruits Currently, anti-angiogenic drugs are widely used and recognized in cancer treatments because they enriched the arsenal of chemotherapeutic drugs. The majority of modern targeted drugs fail to achieve the expected therapeutic effects. Consequently, the anti-cancer regimens have shifted to multi-targeted therapies using traditional and integrative natural products. There is a huge number of natural products for anti-angiogenic substances and the study on the complex mechanisms of these compounds is just started. Studies on the role of different structures of natural compounds in inhibiting tumor angiogenesis would assist in anti-cancer drug discovery and development. The anti-angiogenic therapy of human cancer patients is based on pre-clinical models that simulate the pathogenesis of human cancers, and most of them are elucidated in this review. It is certain that future patients will be benefited from the novel discoveries of natural products, thus a lot of research works are warranted. As for clinical application of natural products in tumor, issues have emerged during the past few decades. The bioavailability of natural products is the major restriction, since these compounds have the properties of poor aqueous solubility and low absorption rate. Prior to the use of natural products in anti-tumor therapy, the concentration problem needs to be resolved. At present, several carriers nanoparticles, micelles, lipids, etc with natural products are being developed to apply to the delivery of these compounds to human body systems. Therefore, as hopeful therapeutic targets towards tumor angiogenesis, more efforts should be made to the development of natural compounds and their modifiers according to their molecular mechanisms and involved signaling pathways in tumors. PS, Z-SC, and DD conceived and designed the review. RL and XS created the tables and figures, and wrote the draft manuscript. RL, XS, and YG revised the manuscript and performed the table design. PS, Z-SC, and DD reviewed and edited the manuscript. All authors read and approved the final manuscript. This work was supported by the National Natural Science Foundation of China ; the Gansu Province Science Foundation for Distinguished Young Scholars 20JR10RA and the Gansu Province Science Foundation for B Program RJZA from Gansu Provincial Sci. Department; the Open Project of Research Center of Traditional Chinese Medicine, Gansu Province zyzxzx1 ; the Open Project of Key Laboratory of Prevention and Treatment for Chronic Diseases by TCM in Gansu Province GSMBKY ; the Gansu Province Health Industry Scientific Research Program Management Project GWGL ; and the National Natural Science Foundation of Shaanxi Province JQ The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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| REVIEW article | The toxicity of an 8 hour treatment of deacetylnemorone on HUVEC endothelial cells was also determined using the MTS assay. A The average number of junctions, or tubes, formed between HUVEC endothelial cells after 8 hours of incubation on growth factor reduced BD Matrigel. A representative bright field image is shown for treatment with B growth media alone, C 0. E The percent viability of HUVEC endothelial cells in response to 8 hours of incubation with various concentrations of deacetylnemorone as determined by an MTS assay. The control group was treated with culture media alone, and the DMSO group was treated with 0. P values were determined using multiple t-tests comparing each treated group to the control. Multi-targeting natural products may create renewed vigor in the use of natural compounds for the treatment of cancer. Targeted therapies hold great promise for the future of cancer treatment but have been accompanied by numerous shortcomings, including high rates of resistance, low rates of susceptible patients, and high cost. Natural products that attack multiple cancer-related pathways may limit therapy-induced resistance and provide robust treatment when in combination with currently available therapies. Deacetylnemorone was examined in this study to determine its ability to interfere with multiple cancer-related pathways, including cancer cell growth and proliferation, cancer cell invasion, and angiogenesis. The growth inhibitory properties of deacetylnemorone were first examined by submitting the compound to the NCI one dose cytotoxicity screen. At 10 μM, deacetylnemorone exhibited growth inhibitory properties across all nine of the tissue types examined. Within each tissue type a range of activity was observed, from no growth inhibition at all to inducing cell death in one melanoma cell line. These results suggest that the growth inhibitory effects of deacetylnemorone are not tissue-type dependent. However, the compound did appear to have a strong effect on multiple cell lines isolated from melanoma. SK-MEL-5 is a melanoma cell line that exhibited a As a result, it appears that at concentrations near 10 μM, deacetylnemorone is selective in inducing cell death. The growth inhibition and cytotoxicity results across the 59 cell lines tested in the NCI screen were less potent than other compounds that have undergone NCI screening, and thus further screening was not performed using the NCI panel. Each of the six cell lines tested exhibited a dose-dependent response in cell viability to deacetylnemorone. Some cell lines appeared to exhibit increased proliferation in response to low concentrations of deacetylnemorone. This confirmed the selectivity noted in the NCI screening. This effect occurred at as little as 3 μM deacetylnemorone, a concentration lower than the minimum required to reduce cell viability when deacetylnemorone was used on this cell line alone. It is likely that a synergistic rather than simply a combinatorial effect occurred when deacetylnemorone was used alongside the chemotherapy. Next, cell cycle analysis was performed to gain insight into the mechanism of action for the cell growth inhibition of SK-MEL-5 melanoma cells. When compared to the control, deacetylnemorone at 15 μM did not increase the percentage of cells in the sub G1 phase of the cell cycle, suggesting apoptotic cell death was likely not occurring. As a result, another mechanism of cell death, such as necrosis or autophagy, is likely responsible for any cell death observed at this dose[ 42 ]. Additionally, from 6 to 24 hours of incubation with deacetylnemorone, the percentage of cells in the G1 phase decreased with a corresponding increase in the S phase cells. This trend was not seen on cells treated with the vehicle control. While the mechanism is unclear, this could be the result of DNA damage, inhibition of DNA synthesis, or inhibition of cell cycle regulating cyclins[ 43 ]. With the cancer cell growth inhibition properties of deacetylnemorone established, the effect of the compound on other cancer-related pathways was then examined. Deacetylnemorone was observed to reduce SK-MEL-5 invasion at a concentration as low as 0. Both the migration of the cell front and the invasion of single cells into a cell free gap between cell fronts were inhibited as deacetylnemorone was added to the cell culture media. The inhibition of cell front migration could be interpreted as an extension of the cell growth inhibition observed previously, as the cell front will migrate when the cells divide. However, the decrease in single cells invading the cell free gap suggests that the cells were being inhibited from undergoing epithelial-mesenchymal transition EMT. This process allows cancer cells to detach from their extracellular matrix, move freely within the body, and reattach in a new location, establishing metastatic growth[ 44 ]. Cancer cells undergoing this process may also be linked to innate chemotherapy resistance and an increased percentage of cancer stem cells[ 41 ]. The decrease of single cells in the cell free gap suggests a decrease in the number of cells that had migrated from one of the cell fronts. This inhibition is unique from cell growth inhibition and may lead to an ability of deacetylnemorone to inhibit the metastasis and chemotherapy resistance of melanoma. The final cancer-related pathway that was assayed for a response to deacetylnemorone was angiogenesis. At sub-cytotoxic concentrations of deacetylnemorone 0. Tube formation is a crucial step in angiogenesis, which is required for both extended tumor growth and metastatic formation. By inhibiting the formation of tubes between endothelial cells, deacetylnemorone may cut off the blood supply to new and growing tumors and further inhibit metastasis. Deacetylnemorone is a natural product of the abietane diterpenoid family. While limited growth inhibition studies have been performed to investigate the potential of this compound, it has remained an understudied lead compound for anti-cancer therapy. While no specific cellular targets of deacetylnemorone were identified in this study, the range of diverse biological effects of the compound suggest that it is interfering with multiple cancer related pathways. As a result, it is likely that deacetylnemorone interacts with multiple cellular targets rather than one specific protein. Future studies should seek to elucidate the exact cellular mechanisms of the anti-cancer effects demonstrated by this study. These properties may give deacetylnemorone the ability to provide a robust, multi-targeted treatment for a range of cancers, which not only increases the efficacy of current cancer treatment combinations and reduces the risk of treatment-acquired resistance, but also re-sensitizes already resistant tumors to further chemotherapy use. Additionally, the ability of deacetylnemorone to target cancer stem cells specifically should be investigated as a potential mechanism for the ability of the compound to inhibit cell growth in chemotherapy resistant cell lines and inhibit EMT. In summary, deacetylnemorone is a multi-targeted natural product which has the potential to enhance currently utilized cancer treatments when used in combination with chemotherapeutic, anti-angiogenic, and other targeted therapies. The cells were seeded in 2 well culture inserts within 24 well culture plates and allowed to reach confluency before being treated with deacetylnemorone. Viability was determine by manually counting cells excluding trypan blue using a hemocytometer. Note no data was collected for the 30μM concentration at 24 hours. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Article Authors Metrics Comments Media Coverage Reader Comments Figures. Abstract Targeted therapies have become the focus of much of the cancer therapy research conducted in the United States. Data Availability: All relevant data are within the paper. Introduction Cancer remains the second leading cause of death in the United States according to the Centers for Disease Control and Prevention[ 1 ]. Materials and methods Deacetylnemorone source and identification Dried roots of Salvia lerifolia was extracted with hexane at room temperature followed by filtration and evaporation to afford dark brown extract. Download: PPT. Fig 1. The structure of the abietane diterpenoid, deacetylnemorone. Cell cycle analysis The effect of deacetylnemorone on the cell cycle of SK-MEL-5 melanoma cells was determined using flow cytometry. In vitro invasion assay Cell migration of SK-MEL-5 melanoma cells was investigated by making a cell-free gap with a 2 well culture- insert for 24 well plates IbiTreat, Martinsried, Germany. Tube formation assay Growth factor reduced BD Matrigel Corning was stored at °C. Results Deacetylnemorone induces concentration dependent cell death in immortalized cancer cell lines alone and in combination with FdUrd In order to determine the chemotherapeutic potential of deacetylnemorone, the compound was screened against 59 cancer cell lines using the NCI cancer panel. Fig 2. Waterfall plot of the growth percent of 59 cell lines in response to 10 μM of deacetylnemorone, determined by the NCI one dose screening test. Fig 3. Fig 4. Deacetylnemorone inhibits invasion of melanoma in vitro The effect of deacetylnemorone on melanoma cell invasion was also investigated. Fig 6. Invasion of SK-MEL-5 melanoma cells into a cell-free gap created using a 2-well cell culture insert when incubated with different concentrations of deacetylnemorone for 24 hours. Deacetylnemorone inhibits tube formation of endothelial cells, a critical step of angiogenesis The effect of deacetylnemorone on angiogenesis was investigated using a tube formation assay Fig 7. Discussion Multi-targeting natural products may create renewed vigor in the use of natural compounds for the treatment of cancer. Conclusions Deacetylnemorone is a natural product of the abietane diterpenoid family. Supporting information. S1 Fig. The A 1 H-NMR, B 13 C-NMR, C H-H COSY, D HSQC, and E HMBC spectra of the abietane diterpenoid, deacetylnemorone in DMSO-d6. s DOCX. S2 Fig. The A negative ion mode time of flight-mass spectrometry and B negative mode HR-MS spectra of deacetylnemorone used to determine the mass. S3 Fig. Viability of SK-MEL-5 cells after 6, 12, or 24 hours of incubation with deacetylnemorone. S4 Fig. SK-MEL-5 cell cycle analysis after deacetylnemorone treatment at 6, 12, 24, 48, and 72 H. S1 Table. References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, CA Cancer J Clin. Kimiz-Gebologlu I, Gulce-Iz S, Biray-Avci C. Monoclonal antibodies in cancer immunotherapy. Mol Biol Rep. Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar MA, Pérez-Gracia JL, et al. Cytokines in clinical cancer immunotherapy. Br J Cancer. van Willigen WW, Bloemendal M, Gerritsen WR, Schreibelt G, de Vries IJM, Bol KF. Dendritic Cell Cancer Therapy: Vaccinating the Right Patient at the Right Time. Front Immunol. 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J Toxicol Sci 41 3 — Soltani M, Parivar K, Baharara J, Kerachian MA, Asili J. |
| Top bar navigation | Authors Compoudns S 2. Kowshik Power foods for sports performance, Giri H, Potentia, TK, Anti-angiogenexis R, Insulin resistance symptoms RN, Reddy GB, et al. Article CAS Anti-angiogenesis potential of natural compounds Scholar Fischer C, Mazzone M, Jonckx B, Carmeliet P. Biochim Biophys Acta Mol Basis Dis 6 — Zhao X, Wang Q, Yang S, Chen C, Li X, Liu J, et al. Methods for Preclinical Evaluation of Bioactive Natural Products. Loutrari H, Hatziapostolou M, Skouridou V, Papadimitriou E, Roussos C, Kolisis FN, et al. |
Editor-in-Chief: Dimitri P. Mikhailidis Honorary Professor, Division Anti-angiognesis Surgery and Interventional Science Potentail College London Medical School, University Pottential Royal Anti-angiogenesis potential of natural compounds Hospital Og Anti-angiogenesis potential of natural compounds UCL and former Academic Head, Department of Clinical Biochemistry, Royal Free Hospital Campus UCLPond Street London, NW3 2QG UK. ISSN Print : ISSN Online : DOI: Background: Neovascularization, also known as angiogenesis, is the process of capillary sprouting from pre-existing blood vessels.
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