|Blood vessel formation; Angiogenesis; Cancer biology;
Inhibitors; Natural products; Phytochemicals; Nutraceuticals; Targeted
|AADR: Acquired Drug Resistance; AITC: Allyl
Isothiocyanate; ANG2: Angiopoietin 2; AP-1: Activator Protein 1;
APN: Aminopeptidase N; ARE: Antioxidant Response Element; BAEC:
Bovine Aortic Endothelial Cells; BPGF-1: Bone-Derived Growth
Factor-1; bFGF: Basic Fibroblast Growth Factor; BRCA1: Breast
Cancer 1, early onset; CAM: Chicken Chorioallantoic Membrane;
CD31: Cluster of Differentiation 31; COX: Cyclooxygenase; CREB:
cAMP Response Element Binding; DHA: Docosahexenoic Acid;
EGCG: Epiallocatechin Gallate; EGF: Epidermal Growth Factor; EGFR:
Epidermal Growth Factor Receptor; EPA: Eicosapentaenoic Acid;
ERK: Extracellular Signal-Regulated Kinase; FAK: Focal Adhesion
Kinase; FGFR: Fibroblast Growth Factor Receptor; HER: Human
Epidermal Growth Factor Receptor; HGF: Hepatocyte Growth Factor;
HIF: Hypoxia-Inducible Factor; HUVEC: Human Umbilical Vein
Endothelial Cells; IκB: Inhibitor of Kappa B; IL: Interleukin; iNOS:
Inducible Nitric Oxide Synthase; JAK2: Janus Kinase 2; JNK: Janus
Kinase; KDR: Kinase Insert Domain Receptor; LOX: Lysyl Oxidase;
MAP-Kinase: Mitogen-Activated Protein Kinase; MCP-1: Monocyte
Chemoattractant Protein1; MIF: Migration Inhibitory Factor; MMP:
Matrix Metalloproteinase; MT1-MMP: Membrane-Type 1 Matrix
Metalloproteinase; MVD: Microvessel Density; NFκB: Nuclear Factor
Kappa B; NO: Nitric Oxide; NOS: Nitric Oxide Synthase; Nrf2: Nuclear
Factor (erythroid-derived 2)-like 2; PAI-1: Plasminogen Activator
Inhibitor-1; pAKT: Phosphorylated Akt; PAR: Protease Activated
Receptor; PDGF: Platelet-Derived Growth Factor; PEITC: Phenethyl
Isothiocyanate; PGC-1a: Peroxisome Proliferator- Activated Receptor
Coactivator-1a; PGE2: Prostaglandin E2; PGG: Penta-1,2,3,4,6-OGalloyl-
beta-d-Glucose; PI3: Phosphatidylinositide 3; PIGF: Platelet-
Inhibitor Growth Factor; PKC: Protein Kinase C; PTK: Protein Tyrosine
Kinase; RA: Rosmarinic Acid; ROS: Reactive Oxygen Species; RTK:
Receptor Tyrosine Kinase; RWPC: Red Wine Polyphenolic Compound;
SC: Shark Cartilage; SFN: Sulforaphane; Sirt1: Silent Information
Regulator 1; Src: V-Src Sarcoma; STAT-3: Signal Transducer And
Activator of Transcription 3; TGF: Transforming Growth Factor;
TIMP1: Tissue Inhibitor of MMP-1; TNF: Tumor Necrosis Factor;
uPAR: Urokinase-Type Plasminogen Activator Receptor; VEGF: Vascular Endothelial Growth Factor; VEGFR: Vascular Endothelial
Growth Factor Receptor; VSMC: Vascular Smooth Muscle Cell
|Angiogenesis is the growth of new blood vessels to ensure wound
healing, reproduction and development of cells. It is strictly regulated
and various inhibitors and stimulators play role to maintain it in
balance . Tumor growth and metastasis depend on angiogenesis
and stimulators are upregulated disrupting the angiogenesis balance
[1,2]. Tumor blood vessels have a different structure with irregular
branches and they are more heterogenous compared to normal blood
vessels . Various pathways such as VEGF, EGF, FGF and HGF ensure
the heterogeneity of tumor blood vessel structure and upregulated
|Secondary plant metabolites are valuable sources of small
molecules and various drugs were identified from plants. Combined
therapy approach targeting multiple components of angiogenesis with
phytochemicals might be promising to achieve an effective anti-cancer
|Therapy with phytochemicals
|Natural products from botanical sources (phytochemicals)
continue to attract interest for various applications including cancer
treatment with their effect on cancer-related biological pathways such
as angiogenesis [5,6]. Throughout nature in flora, marine wildlife and
microbial products might involve effective active principles which
contain a multitude of diverse molecular entities. For natural products from marine or microorganisms, three reviews are helpful in that
|Herbal ingredients have been used for more than 10000 years by
mankind to influence body functions and curing diseases . Indian
Ayurveda and Traditional Chinese Medicine are successful examples
for traditional therapeutic paradigms.
|Phytochemicals are mostly classified as secondary plant metabolites.
Various anti-angiogenic effects of phytochemicals including flavonoids,
sulphated carbohydrates, triterpenoids, catechols, tannins and aromatic
substances have been reported [9,10]. Wholesome herbal extracts
have been investigated in terms of anti-angiogenic activities 
identifying molecules targeting different pathways of angiogenesis.
Nitric oxide synthase (NOS) and VEGF are of special importance for
their interaction with well-known secondary plant metabolites from
different botanical sources .
|In vitro studies serve as the main source of evidence for antiangiogenic
activities of phytochemicals. Single steps of angiogenesis
such as apoptosis, proliferation, migration and protease production
in addition to complex cascades leading to neovascularization have
been investigated . Culturing of microvascular endothelium cells
can be difficult for such experiments . VEGF and MMPs are
prominent angiogenic effectors and the effect of phytochemicals on the
corresponding regulatory pathways can be screened via endothelial or
chicken embryo cell cultures .
|Various phytochemicals target the transcription factor Nrf2
(nuclear factor (erythroid-derived 2)- related factor), which triggers an
antioxidant defense response by ARE (antioxidant response element)-
mediated induction of Phase II detoxifying and antioxidant enzymes
[15,16]. Nrf2 can be activated by caloric restriction mimetic agents
and caloric restriction together with activation of enzymes playing role
in plasma membrane redox system. Thus, Nrf2 can be implicated in
the cancer protection induced by caloric restriction . Induction
of Nrf2 activation with caloric restriction can lead to prevention of
vascular aging by antioxidant defense activities of endothelial cells .
Antiangiogenic phytochemicals have been proven to be active in some
cases via mostly in vitro animal studies, human studies are rare.
|Plant phenolics are found in various botanical sources and they are
probably the best analyzed phytochemical category. More than 5000
flavanoids, which is the most important phenolics class in human diets,
are described in literature classified in 10 chemical groups . Various
effects such as anti-inflammation, inhibition of cell proliferation,
antioxidation, detoxification of mutagenic metabolites, apoptosis and
inhibition of angiogenesis are exerted on cancer-related biochemical
pathways by the phenolic phytochemicals . Some examples of
phenolics are mentioned below giving more importance to reported
mechanisms for angiogenesis control, resistance and side effects.
|Green Tea: Tea leaves are known for their relaxative and stimulative
effects for long time. They have been recently investigated for healthrelated
effects. Catechins such as epigallocatechin gallate (EGCG),
which is the most prominent phytochemical category in green tea, are
observed to involve anticancer activity including antioxidant, antiinflammatory,
photoprotective and antiphotocarcinogenic effects in in
vivo, in vitro and in chemical assays.
|MMPs (type IV collagenases, zinc dependent proteinases involved in matrix turnover) and VEGF expressions are decreased whereas an
increase in expression of TIMP1 (tissue inhibitor of MMP) have been
observed upon green tea catechin treatments [14,20]. EGCG degrades
the basement membrane via MMP inhibition and facilitates cell
invasion in tumor cells. It also deregulate the expression of membranetype
1 matrix metalloproteinase (MT1-MMP) which generates an
active form of MMP-2 from proMMP-2 .
|MAP kinase family members Erk-1 and Erk-2 influence VEGF
expression. Thus, inhibition of them leads to lower expression of
VEGF. EGCG might exert its effect by chelation of divalent cations
essential for the activity of some receptor kinases that are involved
in Erk-1 and -2 activation. Moreoever, EGCG downregulates VEGF
expression via inhibition of activator protein 1 (AP-1) which binds to
the promoter region of VEGF. Inhibition of VEGFR-1 and -2 tyrosine
phosphorylation has also been reported . EGCG is able to influence
COX-2 expression since COX-2 promoter involve binding sites for
NFκB and AP-1. Reduced COX-2 level leads to a reduced activation of
MMP and angiogenic PGE2 expression .
|EGCG has an inhibitory activity against platelet-induced growth
factor-BB (PIGFBB) induced intracellular signalling transduction
pathway in vascular smooth muscle cells (VSMCs), several MAPkinase
isoforms in VSMCs after PDGF-BB activation and the tyrosine
phosphorylation of various kinases. EGCG exerts its interference
with angiogenesis by targeting multiple other pathways. It reduces
the level of inducible NOS (iNOS) by increased IκB kinase activity
[12,21]. Expression of vascular endothelial cell antigens, e.g.CD31
are downregulated  protein kinase C (PKC) [11,22] together with
angiogenic factors MMP-2 and -9, VEGF, CD31  activities are
reduced and EGFR signalling is suppressed .
|Soy beans isoflavones: Genistein: Soy beans, whose 55%
production occurs in America and the rest in Asia, are one of the
most important global crops. Differences among Caucasian and Asian
populations were observed in terms of cancer prevalence as a result of
|Genistein, an isoflavone phytoestrogen isolated from soy beans,
has been well studied in terms of its pharmacological features. Like
other phenolics, it inhibits bFGF-induced neovascularization as well
as migration and proliferation of endothelial cells  in addition to
downregulation of VEGF expression . MMP/TIMP proteolytic
balance is shifted towards proteolysis inhibition upon genistein
exposure. Moreover, it suppresses the VEGF/bFGF-stimulated increase
of TIMP-1 expression and decrease in TIMP-2 expression . It was
shown to inhibit angiogenesis in renal cell carcinoma .
|Further anti-angiogenic effects include; inhibition of NFκB,
inhibition of TGF-β signaling being an important feature in upregulating
angiogenesis, inhibition of protein tyrosine kinase (PTK)
and PTK-mediated signaling pathways, modulation of the Akt signaling
pathway, down-regulation of several genes relevant for angiogenesis
pathways (Type IV collagenases, protease M, VEGF, uPAR, neuropilin,
bone-derived growth factor-1 (BPGF-1), lysophosphatidic acid
receptor, aminopeptidase, thrombospondin-1, proteinase-activated
receptor), suppression of AP-1/CREB-binding to the COX-2 promoter
leading to lower COX-2 levels (COX-2 increases cell proliferation and
VEGF production), dose-dependent inhibition of expression/excretion
of VEGF, PDGF, tissue factor, urokinase plasminogen activator, MMP-2
and -9 as well as up-regulation of angiogenesis inhibitors: plasminogen
activator inhibitor-1, endostatin, angiostatin, thrombospondin-2 [25-
|Curcumin fromc curcuma longa: Turmeric, which is a popular
Indian spice, takes the yellow color from curcumin. Curcumin
involves several functional groups such that two polyphenolic rings are
connected by two α,β-unsaturated carbonyl groups.
|APN (CD13/aminopeptidase N) is irreversibly inhibited by
curcumin. It has been reported that curcumin down-regulates MMP-
2 and MMP-9 in addition to TIMP-1 (tissue inhibitor of MMP) upregulation,
and it also down-regulates VEGF and bFGF. VEGFR and
EGFR are also inhibited  and aminopeptidase inhibition leads to
anti-angiogenic effects . iNOS expression is found to decrease which
results in less NO production in endothelial cells [11,12]. It has also
been reported that COX-1 and COX-2, which play role in angiogenesis
in endothelium, as well as inhibition of TNF-α induced activation
of NFκB, has been reported to be downregulated . Curcumin
in nude mice xenografted with hepatocarcinoma cells inhibited
tumor neocapillary density significantly by oral administration .
Curcumin inhibits HIF-1 activity leading to down-regulation of HIF-
1 target genes. Moreover, curcumin suppressed HIF-1 and VEGF in
tumors as shown in mice bearing Hep3B hepatoma .
|Red wine polyphenols: Resveratrol: RWPCs involve various antiangiogenic
properties such as inhibition of growth factor induced VEGF
expression in vascular smooth muscle cells due to their antioxidant
properties, by preventing the formation of intracellular reactive oxygen
species and phosphorylation of p38 MAP kinase. RWPC treatment
also leads to down-regulation of cyclin A gene expression, inhibition
of MMP-2, and inhibition of p38 MAPK and PI3-kinase/Akt pathways
|Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a phytochemical
belonging to phytoalexin class produced by plants in case of pathogen
attack. Modulation of NFκB, expression  and activity of COX
enzymes  were observed effects of resveratrol. With antioxidant
and anti-angiogenic properties, it affects all stages of carcinogenesis and
causes reduction in microvessel density [34,35]. Treatment of HUVECs
with 1 to 2.5 μmol/l resveratrol significantly reduced VEGF-mediated
migration and tube formation but not cell proliferation [36,37]. Same
concentration of resveratrol was shown to disrupt VEGF-mediated
tyrosine phosphorylation of vascular endothelial (VE)-cadherin and
its complex partner, beta-catenin. It also inhibited VEGF-induced
endogenous Src kinase activation . iNOS down-regulation and
consequently up-regulated VEGF expression were also reported . It
can suppress the growth of new blood vessels and capillary endothelial
cell growth by targeting both VEGF-and FGF-receptor mediated
angiogenic responses through inhibition of MAPK phosphorylation in
endothelial cells. Resveratrol can increase mitochondrial function and
improve energy balance in mice via stimulating metabolic regulator
PGC-1a (peroxisome proliferator- activated receptor coactivator-1a)
deacetylation by the sirtuin Sirt1 (Silent Information Regulator 1)
. Sirt1 activation by resveratrol inhibits breast carcinogenesis in
BRCA1 mutant mice . It has been reported that chemical similarity
to phytoestrogens might lead to growth stimulatory effects in human
breast cancer cells . Some studies point out that it retards the
development of blood vessels leading to suppression of tumor growth.
|Other polyphenols: Various other anti-angiogenic phenolic
compounds can be found in different sources e.g. pomegranate,
parsley, celery and Silybum marianum. Pomegranate involves diverse
key components in different categories: i.e. catechins and epicatechins,
anthocyanidins and flavonoids. Decline in COX activity, NO
production and VEGF expression together with upregulation of the
anti-angiogenic migration inhibitory factor (MIF) are leading factors for anti-angiogenic activity. Combretastatin, a stilbenoid derivative
isolated from Combretum caffrum, targets tubulin, inhibits angiogenesis
and reduces metastasis. Parsley, celery and onion are other sources
involving anti-angiogenic flavonols They exert the corresponding
effects by interaction with multiple key structures in the pathway of
angiogenesis, e.g. COX-2, EGF-receptor or NFκB transcription protein.
Silybinin, a flavolignan isolated from Silybum marianum,decreases
VEGF secretion, iNOS, COX and HIF-1α expression [12,41-43].
|OptiBerryIH141 is a cyanidin belonging to antho-cyanines
class isolated from berries. It inhibits H2O2-and TNF-α-induced
VEGF expression, basal MCP-1 transcription and angiogenesis .
3-Hydroxy-flavone is a flavonol which prevents VEGF/bFGF-induced
MMP-1 and uPA expression. It activates pro-MMP-2 and modulates
their inhibitors TIMP-1 and -2 and PAI-1 . Apigenin, isolated from
Petroselinum crispum, inhibits expression of hypoxia-inducible factor
1 (HIF-1), VEGF and TIMP-1  in various types of cancer cells
under normoxic and hypoxic conditions leading to antiangiogenesis
effects and autophagy in tumors [43,45]. Combretastatin belongs to
the stilbenoid phenol class. Its binding to tubulin reduces metastasis by
inhibiting angiogenesis .
|Quercetin, which is a flavone found in red grapes, citrus, apples,
onions, raspberries, cherries, broccoli, and leafy greens, inhibits
angiogenesis through multiple mechanisms such as interaction with
the COX-2 and lipoxygenase (LOX)–5 enzymes, the EGF receptor,
the HER-2 intracellular signaling pathway, and the NF-κB nuclear
transcription protein. [46,47]. It was shown to inhibit hypoxia-induced
VEGF expression in NCI-H157 cells together with suppression in
STAT-3 tyrosine phosphorylation [11,48]. Inhibition of STAT-3
function is correlated with decrease in VEGF expression implying that
STAT-3 inhibition might be involved in angiogenesis inhibition .
It was shown to possibly enhance the anticancer effect of tamoxifen
through antiangiogenesis in a prostate cancer xenograft model .
|Rosmarinic Acid (RA), a water-soluble polyphenolic compound
found in many Lamiaceae herbs, involves an antiangiogenic effect
with its ability to reduce the intracellular ROS level, H2O2-dependent
VEGF expression, and IL-8 release of endothelial cells . Figure 1
represents the inhibitory effects of antiangiogenic phytochemicals and
nutraceuticals on cancer progression.
|Other classes of phytochemicals and nutraceuticals
|α-Tocopherol has been studied to reduce VEGF levels . Iscador, a widely used extract of Viscum albumL. (Viscaceae), has been shown
to have antiangiogenic effect through downregulation of VEGF, and it
induces apoptosis of cancer cells [52,53]. It was reported to reduce lung
metastases and increase survival rate in a mouse model .
|γ-Tocotrienol from palm (Nigella sativa) inhibited cobalt(II)
chloride-induced accumulation of HIF-1α and paracrine secretion of
VEGF, which leads to decreased activation of ERK-1/ERK-2 in a study
conducted with SGC-7901 (human gastric adenocarcinoma) cell line
|Alliin, found in garlic, involves inhibitory effect against FGF-2-
induced human endothelial cell tube formation and VEGF-induced
angiogenesis in a chick chorioallantoic membrane (CAM) model .
|Allyl isothiocyanate (AITC) has antiangiogenic properties with
its inhibitory effect against NO synthesis and TNF-α production as
shown in a C57BL/6 mouse model bearing B16-F10 melanoma cells
.It reduced vessel sprouting in Swiss albino mice into which Ehrlich
ascites tumor cells were transplanted with antiangiogenic activity
associated with reduction of VEGF expression . Intraperitoneal
administration of AITC decreased in vivo capillary formation in
mouse B16F-10 melanoma model . AITC suppressed HUVEC
proliferation, migration, invasion and tube formation .
|Artemisinin, a sesquiterpene extracted from Artemisia annuaL.
(Asteraceae), has been used clinically as an antimalarial drug .
It decreased the VEGF expression in tumor cells and the KDR/flk-1
expression in endothelial cells [11,61]. It involved an inhibitory effect
on NF-κB activation  and its anti-angiogenic effect is superior to its
|Artesunate, a semisynthetic derivative of artemisinin, inhibited
angiogenesis in a dose-dependent manner significantly. It inhibited cell
proliferation of human umbilical vein endothelial cell (HUVEC) more
than that of cancer cells, fibroblast cells, and human endometrial cells
indicating that antiangiogenic activity of artesunate is greater than its
cytotoxicity. An in vivo study, where human ovarian cancer cells (HO-
891) were transplanted in nude mice to evaluate the antiangiogenic
effect of artemisinin, has shown that tumor growth was decreased
and microvessel density was reduced without any toxicity to the host
animals. Its antiangiogenic potential was also found in K562 cells in
vitro and in vivo .
|Caffeic acid, isolated from Coffea arabica, suppressed STAT-3-
mediated HIF-1 and VEGF expression, consequently vascularization
and angiogenesis are inhibited in mice bearing Caki-I human renal
carcinoma cells .
|Capsaicin, an alkaloid isolated from chili pepper, which belongs to
the Capsicum genus, showed inhibitory activity against VEGF-induced
proliferation, DNA synthesis, capillary-like tube formation of primary
cultured human endothelial cells, VEGF-induced vessel sprouting in
a rat aortic ring assay. It also inhibits VEGF-induced vessel formation
together with VEGF-induced p38 MAPK, p125 (FAK), and AKT
activation as shown in a mouse Matrigel plug assay . It also inhibits
chemotactic motility, and induced G1 phase arrest in endothelial cells
. It was reported that capsaicin inhibited carcinogenesis of the skin,
colon, lung, tongue and prostate depending on signal transducers and
activators of transcription (STAT)3 inhibition in multiple myeloma
cells . In these studies, capsaicin blocked both the inducible and
the constitutive activation of STAT3 and this effect is associated with
downregulation of the expression of the genes involved in cell survival,
proliferation and angiogenesis .
|Dovitinib, which is a quinolone with a strong affinity for FGFR in
addition to multiple RTKs, has been shown to involve efficacy against
metastatic renal cell carcinoma in clinical trials .
|Eicosapentaenoic acid (EPA), an omega-3 fatty acid, was observed
to lower VEGF-stimulated tube formation and migration in HUVECs
. In addition, certain matrix metalloproteinases (MMPs) associated
with endothelial cell migration were diminished upon conjugated EPA
treatment . Docosahexenoic acid (DHA) is another omega-3 fatty
acid having similar antiangiogenic effects with EPA. Treatment with
EPA and DHA reduced COX-2 and VEGF expression levels, resulting
in diminution of microvessel formation in tumor mice  probably
via deregulation of extracellular signal-regulated kinases (ERK-1/2)
and HIF-1 in colon cancer cells. Besides, they showed to inhibit tumor
invasion of brain-metastatic melanoma cells by downregulating COX-
2 mRNA expression . Particularly, DHA decreased the expression
of β-catenin target genes such as MMPs and VEGF, leading to
antiangiogenic and antimetastatic effects .
|Emodin, which is an anthraquinone derivative isolated from the
rhizomes of Rheum palmatum, suppressed various angiogenic processes
both in vitro and in vivo . It inhibited bFGF-induced proliferation,
migration and tube formation of HUVECs stimulated with VEGF in a
dose-dependent manner . Furthermore, emodin induced cell cycle
arrest of HUVECs in the G0/G1 phase. It also decreased VEGF-induced
tube formation of human dermal microvascular endothelial cells. Basal
secretion of MMP-2 is inhibited by emodin. In vivo, it suppressed
angiogenesis in the chicken CAM and VEGF-induced angiogenesis of
the Matrigel plug in mice .
|Flavopiridol, isolated from Dysoxylum binectariferum, decreaseed
hypoxia-mediated HIF-1α expression, tumor cell migration and VEGF
secretion in human U87MG and T98G glioma cell lines, reduced
vascularity of intracranial syngeneic GL261 gliomas upon flavopiridol
treatment in animal models supported the in vitro data .
|Gambogic acid, isolated from gamboge tree, Garciniahanburyi, was
reported to inhibit VEGFR-2 and downstream kinases such as c-Src,
FAK, and AKT. In HUVEC and human prostate cancer cells (PC3), it
inhibited angiogenesis .
|Gingerol, contained in ginger, inhibited capillary-like tube
formation, endothelial cell sprouting in rat aorta and formation of new
blood vessels in mouse cornea .
|Hypericin, an isolate from Hypericumperforatum, has been shown to
block the invasion and migration of endothelial cells and inhibit matrix
metalloproteinases as well as in vitro capillary-like tube formation. Its
antiangiogenic effect was also observed in animal experiments [77,78].
Hyperforin, another bio-active compound of Hypericumperforatum,
inhibited angiogenesis in vitro as well as in vivo .
|Isoliquiritigenin, which is a flavonoid found in licorice, reduced
cell migration and invasion of the human prostate cancer cells DU145
and LNCaP . It was studied that a disruption in c-Jun N-terminal
kinase (JNK)/activator protein-1 (AP-1) pathway could be responsible
for decreased production of proangogenic factors .
|Lariciresinol, a lignan isolated from flaxseed (Linum usitatissimum),
has been found to attenuate tumor growth and angiogenesis, and
reduce microvessel density (MVD) in hormone responsive preclinical
breast cancer models (DMBA-induced mammary carcinoma in rats
and MCF-7 breast cancer xenografts in athymic mice) .
|Liver and lung metastases of lymphoma and melanoma cells in experimental and spontaneous metastasis models were inhibited upon
subcutaneous administration of bLfcin (0.5 mg/mouse) . Ability of
bLf to inhibit tumor angiogenesis was found at the same study by the
reduced number of tumor-induced blood vessels and tumor growth
suppression in the early stage of carcinogenesis .
|Luteolin, a commonly observed flavone, could cause a decrease in
VEGF-induced survival and proliferation of HUVECs through PI3K/
AKT-dependent pathways .
|ML-1, which is a lectin, potentiates anticancer efficacy of TNF-α
[41,84,85]. Gallotannin, which is referred as penta-1,2,3,4,6-O-galloylbeta-
d-glucose (PGG) isolated from Gallnut of Rhus chinensis MILL,
has been reported to inhibit proliferation, migration and tube formation
of endothelial cells [86,87] and also induce apoptosis in prostate cancer
|Oleanolic acid is a triterpene isolated from Clove (Syzygium
aromaticum). Its main antiangiogenic effects are; inhibition of BAEC
(bovine aortic endothelial cells) proliferation  and induction of
iNOS and COX-2.
|Perillyl alcohol, which can be found in lavender and citrus, caused
a decrease in VEGF release from cancer cells and an induction in Ang2
expression by endothelial cells. This implies that perillyl alcohol might
suppress neovascularization and induce vessel regression .
|Phenethyl isothiocyanate (PEITC) has been observed to suppress
HUVEC survival, migration and tube formation . It effectively
interfered with hypoxia-induced HIF transcriptional activity and the
induction of the endogenous HIF target genes VEGF-A, BNIP3, CAIX
and GLUT1 in human MCF7 breast cancer cells .
|Sanguinarine, a quaternary ammonium salt from the group of
benzylisoquinoline alkaloids isolated from bloodroot (Sanguinaria
Canadensis), exerted its antiangiogenic effect by directly suppressing
the proliferative effect of VEGF on endothelial cells through
downregulation of VEGF-induced AKT activation .
|Shark cartilage (SC) is another source of anti-angiogenic natural
compounds with its observed ability to inhibit bFGF induced
angiogenesis in the Matrigel mouse model .
|Sulforaphane (SFN), an isothiocyanate isolated from broccoli
(Brassica oleraceaitalica), was shown to inhibit NF-κB-regulated VEGF
expression in human prostate cancer cells . Its antiangiogenic
activity also worked through activation of forkhead homeobox type O
transcription factors, inhibition of MEK/ERK and PI3K/AKT pathways
as observed in HUVECs . It also reduced both the proliferation
and the matrigel-dependent tube forming ability of HUVEC cells .
SFN caused reduction of microcapillary density in a placental vessel
fragment outgrowth assay in a dose dependent manner in ex vivo
tissue culture models . SFN was observed to reduce blood vessel
density in MIA-PaCa2 xenografts in vivo . SFN was able to inhibit
tubulin polymerization in vitro and in intact cells had been recognized
[100,101]. Tubulin plays important role in angiogenesis in addition to
proliferation of endothelial cells, and it is essential for morphogenesis
and migration [100,101].
|Taxol, a diterpene obtained from the bark of Taxus brevifolia,
involves antiangiogenic activity via inhibition of VEGF production and
HIF-α expression shown in human leukemia cell lines . It binds
to tubulin dimers causing interruption of mitosis and chromosome
breakage [10,103]. Ginkgolide B is another diterpene causing
downregulation of VEGF . EGb 761 is a diterpene isolated from ginkgo leaf extract. T-Lymphocytes are the main spleen cell population
involved in inducing angiogenesis and this effect is reduced by EGb
761. It also downregulates VEGF, platelet derived from growth factor,
transforming growth factor-β2 and iNOS (without influencing iNOSmediated
NO production) .
|Ursolic acid, a triterpene isolated from rosemary (Rosmarinus
officinalis), reduceed VEGF, NO and proinflammatory cytokine levels.
It also inhibited capillary formation in C57BL/6 mice bearing B16-F10
melanoma cells . In addition, it caused inhibition of BAEC (bovine
aortic endothelial cells) proliferation  and induction of iNOS
and COX-2. Growth of prostate cancer xenografts was dramatically
suppressed by ursolic acid in vivo . It was reported to inhibit tumor
promotion, metastasis, angiogenesis and proliferation of a variety of
tumor cells, including human multiple myeloma cells  melanoma
cells  and breast cancer cells . It inhibited cell proliferation
and induced apoptosis in human androgen-independent DU145 and
androgen-dependent LNCaP prostate cancer cell lines . These
results were correlated with the inhibition of the canonical NF-κB
signaling pathway as well as STAT3 phosphorylation through the
upstream inhibition of JAK2 and Src activation .
|Perspectives for phytochemicals in anti-angiogenic cancer
|Despite promising experimental results for most of the compounds
in the literature, clinical trials for them yielded irregular results. Clinical
trials should be performed in a well organized and randomized manner
with placebo controls. Same criterias of evidence based medicine
should be referred for phytochemicals to develop anti-cancer drugs.
|Pharmacological effects are limited due to metabolism of
secondary plant metabolites in the vertebrate organism . This
may be overcome by using modified derivatives of phytochemicals
with improved pharmacological features . Animal experiments
are required to understand the potential of phytochemicals for antiangiogenic
treatment of cancer. This step is a prerequisite for clinical
|Cancer therapy with phytochemicals might be promising for
collecting further experimental knowledge to enable pharmacological
refinement of future therapeutic options.
|Cancer progression involves many steps including angiogenesis,
which is essential for development of new blood vessels and thus
nutrition of tumor cells.Various signalling pathways play role in
angiogenesis. Targeting the VEGF (vascular endothelial growth factor)
signalling pathway with synthetic small molecules might be a promising
option. Many synthetic small molecules and phytochemicals have been
identified to be anti-angiogenic and observed to bind to VEGFRTyrosine
Kinase domain with high affinity as validated by molecular
docking. Further studies are required to understand the angiogenesis
mechanism to identify new therapy options with small molecules and
- Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6: 273-286.
- Folkman J (2006) Angiogenesis. Annu Rev Med 57: 1-18.
- Shang B, Cao Z, Zhou Q (2012) Progress in tumor vascular normalization for anticancer therapy: challenges and perspectives. Front Med 6: 67–78.
- Wahl O, Oswald M, Tretzel L, Herres E, Arend J, et al. (2011) Inhibition of Tumor Angiogenesis by Antibodies, Synthetic Small Molecules and Natural Products, Current Medicinal Chemistry 18: 3136-3155.
- Fintelmann VWRF (2006) In Lehrbuch der Phytotherapie; Hippokrates, USA.
- Mills SBK (1999) Principles and Practice of Phytotherapy: Modern Herbal Medicine. Elsevier Ltd, Oxford.
- Nagle DG, Zhou YD, Mora FD, Mohammed KA, Kim YP (2004) Mechanism targeted discovery of antitumor marine natural products. Curr Med Chem 11: 1725-1756.
- D'Incalci M, Simone M, Tavecchio M, Damia G, Garbi A, Erba E (2004) New drugs from the sea. J Chemother16: 86-89.
- Paper DH (1998) Natural products as angiogenesis inhibitors. Planta Med64: 686-695.
- El Sayed KA (2005) Natural products as angiogenesis modulators. Mini Rev Med Chem 5: 971-993.
- Yance DR Jr, Sagar SM (2006) Targeting angiogenesis with integrative cancer therapies. Integr Cancer Ther 5: 9-29.
- Singh RP, Agarwal R (2007) Inducible nitric oxide synthase-vascular endothelial growth factor axis: a potential target to inhibit tumor angiogenesis by dietary agents. Curr Cancer Drug Targets 7: 475-483.
- Furness MS, Robinson TP, Ehlers T, Hubbard RB 4th, Arbiser JL, et al. (2005) Antiangiogenic agents: studies on fumagillin and curcumin analogs. Curr Pharm Des11: 357-373.
- Demeule M, Michaud-Levesque J, Annabi B, Gingras D, Boivin D, et al. (2002) Green tea catechins as novel antitumor and antiangiogenic compounds. Curr Med Chem Anticancer Agents 2: 441-463
- Liby KT, Yore MM, Sporn MB (2007) Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 7: 357–369.
- Hyun DH, Emerson SS, Jo DG, Mattson MP, de Cabo R (2006) Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging. ProcNatlAcadSci USA 103: 19908–19912.
- Pearson KJ, Lewis KN, Price NL, Chang JW, Perez E, et al. (2008) Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. ProcNatlAcadSci USA 105: 2325–2330.
- Ungvari Z, Parrado-Fernandez C, Csiszar A, de Cabo R (2008) Mechanisms underlying caloric restriction and lifespan regulation: implications for vascular aging. Circ Res 102: 519–528.
- Le Marchand L (2002) Cancer preventive effects of flavonoids--a review. Biomed Pharmacother 56: 296-301.
- Katiyar S, Elmets CA, Katiyar SK (2007) Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair. J Nutr Biochem18: 287-296.
- Beltz LA, Bayer DK, Moss AL, Simet IM (2006) Mechanisms of cancer prevention by green and black tea polyphenols. Anticancer Agents Med Chem 6: 389-406.
- Yang CS, Wang X, Lu G, Picinich SC (2009) Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. Nat Rev Cancer 9: 429-439.
- Camouse MM, Hanneman KK, Conrad EP, Baron ED (2005) Protective effects of tea polyphenols and caffeine. Expert Rev Anticancer Ther 5: 1061-1068.
- Jung YD, Ellis LM (2001) Inhibition of tumour invasion and angiogenesis by epigallocatechin gallate (EGCG), a major component of green tea. Int J Exp Pathol 82: 309-316.
- Sarkar FH, Li Y (2003) Soy isoflavones and cancer prevention. Cancer Invest 21: 744–757.
- Banerjee S, Li Y, Wang Z, Sarkar FH (2008) Multi-targeted therapy of cancer by genistein. Cancer Lett 269: 226-242.
- Fotsis T, Pepper MS, Montesano R, Aktas E, Breit S, et al. (1988) Phytoestrogens and inhibition of angiogenesis. Baillieres Clin Endocrinol Metab 12: 649-666.
- Anand P, Thomas SG, Kunnumakkara AB, Sundaram C, Harikumar KB, et al. (2008) Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem Pharmacol 76: 1590-1611.
- Granci V, Dupertuis YM, Pichard C (2010) Angiogenesis as a potential target of pharmaconutrients in cancer therapy. Curr Opin Clin Nutr Metab Care 13: 417–422.
- Choi H, Chun YS, Kim SW, Kim MS, Park JW (2006) Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: a mechanism of tumor growth inhibition. Mol Pharmacol 70: 1664–1671.
- Oak MH, El Bedoui J, Schini-Kerth VB (2005) Antiangiogenic properties of natural polyphenols from red wine and green tea. J Nutr Biochem 16: 1-8.
- Leiro J, Arranz JA, Fraiz N, Sanmartín ML, Quezada E, et al. (2005) Effect of cis-resveratrol on genes involved in nuclear factor kappa B signaling. Int Immunopharmacol5: 393-406
- Benitez DA, Pozo-Guisado E, Alvarez-Barrientos A, Fernandez-Salguero PM, Castellón EA (2006) Mechanisms involved in resveratrol-induced apoptosis and cell cycle arrest in prostate cancer-derived cell lines. Journal of Andrology 28: 282-293.
- Cao Y, Fu ZD, Wang F, Liu HY, Han R (2005) Anti-angiogenic activity of resveratrol, a natural compound from medicinal plants. J Asian Nat Prod Res 7: 205 - 213.
- Garvin S, Ollinger K, Dabrosin C (2006) Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenograftsin vivo.Cancer Lett 231: 113–122.
- Varinska L, Mirossay L, Mojzisova G, Mojzis J (2010) Antiangogenic effect of selected phytochemicals. Pharmazie 65: 57–63.
- Lin MT, Yen ML, Lin CY, Kuo ML (2003) Inhibition of vascular endothelial growth factor-induced angiogenesis by resveratrol through interruption of Src-dependent vascular endothelial cadherin tyrosine phosphorylation. Mol Pharmacol 64: 1029–1036.
- Tosetti F, Noonan DM, Albini A (2009) Metabolic regulation and redox activity as mechanisms for angioprevention by dietary phytochemicals, Int J Cancer 125: 1997–2003.
- Wang RH, Zheng Y, Kim HS, Xu X, Cao L, et al. (2008) Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell 32: 11–20.
- Gehm BD, McAndrews JM, Chien PY, Jameson JL (1997) Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci USA 94: 14138–14143.
- Pryme IF, Bardocz S, Pusztai A, Ewen SW (2006) Suppression of growth of tumour cell linesin vitroand tumoursin vivoby mistletoe lectins. Histol Histopathol 21: 285-299.
- Aggarwal BB, Ichikawa H (2005) Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle 4: 1201-1215.
- Ruela-de-Sousa RR, Fuhler GM, Blom N, Ferreira CV, Aoyama H, et al. (2010) Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy. Cell Death and Disease 1: 1-11.
- Bagchi D, Sen CK, Bagchi M, Atalay M (2004) Anti-angiogenic, antioxidant, and anti-carcinogenic properties of a novel anthocyanin-rich berry extract formula. Biochemistry (Mosc) 69: 75-80.
- Fang J, Zhou Q, Liu LZ, Xia C, Hu X (2007) Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression. Carcinogenesis 28: 858–864.
- Banerjee T, Van der Vliet A, Ziboh VA (2002) Downregulation of COX-2 and iNOS by amentoflavone and quercetin in A549 human lung adenocarcinoma cell line. Prostaglandins LeukotEssent Fatty Acids 66: 485-492.
- Igura K, Ohta T, Kuroda Y, Kaji K (2001) Resveratrol and quercetin inhibit angiogenesis in vitro. Cancer Lett171: 11-16.
- Noori-Daloii MR, Momeny M, Yousefi M, Shirazi FG, Yaseri M, (2011) Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell line (PC-3): implications for nutritional transcriptomics and multi-targettherapy. Med Oncol. 28: 1395-404.
- Ansó E, Zuazo A, Irigoyen M, Urdaci MC, Rouzaut A, et al. (2010) Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism. BiochemPharmacol 79: 1600–1609.
- Ma ZS, Huynh TH, Ng CP, Do PT, Nguyen TH, et al. (2004) Reduction of CWR22 prostate tumor xenograft growth by combined tamoxifen-quercetin treatment is associated with inhibition of angiogenesis and cellular proliferation. Int J Oncol24: 1297-1304.
- Huang SS, Zheng RL (2006) Rosmarinic acid inhibits angiogenesis and its mechanism of action in vitro. Cancer Letters 239: 271–280
- Harmsma M, Grommé M, Ummelen M, Dignef W, Tusenius KJ, et al. (2004) Differential effects of Viscum album extract, IscadorQu on cell cycle progression and apoptosis in cancer cells. Int J Oncol 25: 1521-1529.
- Park WB, Lyu SY, Kim JH, Choi SH, Chung HK, et al. (2001) Inhibition of tumor growth and metastasis by Korean mistletoe lectin is associated with apoptosis and antiangiogenesis. Cancer BiotherRadiopharm 16: 439-447.
- Zarkovic N, Vukovic T, Loncaric I, Miletic M, Zarkovic K, et al. (2001) An overview on anticancer activities of the Viscum album extract Isorel. Cancer BiotherRadiopharm 16: 55-62.
- Bi S, Liu JR, Li Y, Wang Q, Liu HK, et al. (2010) Gamma-tocotrienol modulates the paracrine secretion of VEGF induced by cobalt(II) chloride via ERK signaling pathway in gastric adenocarcinoma SGC-7901 cell line. Toxicology 274: 27–33.
- Mousa AS, Mousa SA (2005) Anti-angiogenesis efficacy of the garlic ingredient alliin and antioxidants: Role of nitric oxide and p53. Nutr Cancer 53: 104–110.
- Thejass P, Kuttan G (2007a) Allyl isothiocyanate (AITC) and phenyl isothiocyanate (PITC) inhibit tumour-specific angiogenesis by downregulating nitric oxide(NO) and tumour necrosis factoralpha (TNF-alpha) production. Nitric Oxide 16: 247–257.
- Kumar A, D'Souza SS, Tickoo S, Salimath BP, Singh HB (2009) Antiangiogenic and proapoptotic activities of allyl isothiocyanate inhibit ascites tumor growthin vivo. Integr Cancer Ther 8: 75–87.
- Thejass P, Kuttan G (2007b) Inhibition of endothelial cell differentiation and proinflammatory cytokine production during angiogenesis by allyl isothiocyanate and phenyl isothiocyanate. Integr Cancer Ther 6: 389–399.
- Mueller MS, Runyambo N, Wagner I, Borrmann S, Dietz K, et al. (2004) Randomized controlled trial of a traditional preparation of Artemisia annuaL. (Annual Wormwood) in the treatment of malaria. Trans R Soc Trop Med Hyg 98: 318-321.
- Chen HH, Zhou HJ, Wu GD, Lou XE (2004) Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGFreceptor KDR/flk-1. Pharmacology 7: 1-9.
- Aldieri E, Atragene D, Bergandi L, Riganti C, Costamagna C, et al. (2003)Artemisinin inhibits inducible nitric oxide synthase and nuclear factor NF-kB activation. FEBS Lett 552: 141-144.
- Zhou HJ, Wang WQ, Wu GD, Lee J, Li A (2007) Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells. Vascul Pharmacol 47: 131–138.
- Jung JE, Kim HS, Lee CS, Park DH, Kim YN, et al. (2007) Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells. Carcinogenesis 28: 1780–1787
- Min JK, Han KY, Kim EC, Kim YM, Lee SW, et al. (2004) Capsaicin inhibitsin vitroandin vivoangiogenesis. Cancer Research 64: 644–651.
- Trécul A, Morceau F, Dicato M, Diederich M (2012) Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network. Genes Nutr 7: 111–125.
- Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, et al. (2007) Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin Cancer Res 13: 3024–3032.
- Hutson TE (2011) Targeted therapies for the treatment of metastatic renal cell carcinoma: clinical evidence. Oncologist 16: 14–22
- Spencer L, Mann C, Metcalfe M, Webb M, Pollard C, et al. (2009) The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential, Eur J Cancer 45: 2077–2086.
- Tsuzuki T, Shibata A, Kawakami Y, Nakagawa K, Miyazawa T (2007) Conjugated eicosapentaenoic acid inhibits vascular endothelial growth factor-induced angiogenesis by suppressing the migration of human umbilical vein endothelial cells. J Nutr 137: 641–646
- Denkins Y, Kempf D, Ferniz M, Nileshwar S, Marchetti D (2005) Role of omega-3 polyunsaturated fatty acids on cyclooxygenase-2 metabolism in brain-metastatic melanoma. J Lipid Res 46: 1278–1284
- Calviello G, Resci F, Serini S, Piccioni E, Toesca A, et al. (2007) Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, downregulation of surviving and apoptosis in human colorectal cancer cells not expressing COX-2. Carcinogenesis 28: 1202–1209.
- Kwak HJ, Park MJ, Park CM, Moon SI, Yoo DH, et al. (2006) Emodin inhibits vascular endothelial growth factor-A-induced angiogenesis by blocking receptor-2 (KDR/Flk-1) phosphorylation. Int J Cancer 118: 2711–2720.
- Newcomb EW, Ali MA, Schnee T, Lan L, Lukyanov Y, et al. (2005) Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1alpha expression in human glioma cells by a proteasome-independent pathway: Implications forin vivotherapy. Neuro Oncol 7: 225–235.
- Yi T, Yi Z, Cho SG, Luo J, Pandey MK, et al. (2008) Gambogic acid inhibits angiogenesis and prostate tumor growth by suppressing vascular endothelial growth factor receptor 2 signaling. Cancer Research 68: 1843–1850.
- Kim EC, Min JK, Kim TY, Lee SJ, Yang HO, Han S, et al. (2005)-Gingerol, a pungent ingredient of ginger, inhibits angiogenesisin vitroandin vivo. Biochemical and Biophysical Research Communications 335: 300–308.
- Lavie G, Mandel M, Hazan S, Barliya T, Blank M, et al. (2005) Anti-angiogenic activities of hypericinin vivo:potential for ophthalmologic applications. Angiogenesis 8: 35–42.
- Yee KK, Soo KC, Olivo M (2005) Anti-angiogenic effects of Hypericinphotodynamic therapy in combination with Celebrex in the treatment of human nasopharyngeal carcinoma. Int J Mol Med 16: 993–1002.
- Martínez-Poveda B, Quesada AR, Medina MA (2005) Hyperforin, a bioactive compound of St. John’s Wort, is a new inhibitor of angiogenesis targeting several key steps of the process. Int J Cancer 117: 775–780.
- Kwon GT, Cho HJ, Chung WY, Park KK, Moon A, et al. (2009) Isoliquiritigenin inhibits migration and invasion of prostate cancer cells: possible mediation by decreased JNK/AP-1 signaling. J Nutr Biochem 20: 663–676.
- Saarinen NM, Wärri A, Dings RP, Airio M, Smeds AI, et al. (2008) Dietary lariciresinol attenuates mammary tumor growth and reduces blood vessel density in human MCF-7 breast cancer xenografts and carcinogen-induced mammary tumors in rats. Int J Cancer123: 1196–1204.
- Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki K, et al. (1997) Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice. Jpn J Cancer Res 88: 184–190.
- BBagli E, Stefaniotou M, Morbidelli L, Ziche M, Psillas K, et al. (2004) Luteolin inhibits vascular endothelial growth factor-induced angiogenesis; Inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3'-kinase activity. Cancer Res 64: 7936–7946.
- Pryme IF, Dal TM, Tilrem P (2007) Oral mistletoe lectins: A case for their use in cancer therapy. Cancer Therapy 5: 287-300.
- Pryme IF, Bardocz S, Pusztai A, Ewen SW (2002) Dietary mistletoe lectin supplementation and reduced growth of a murine non-Hodgkin lymphoma. Histol Histopathol 17: 261-271.
- Huh JE, Lee EO, Kim MS, Kang KS, Kim CH, et al. (2005) H.Penta-O-galloyl-beta-Dglucose suppresses tumor growth via inhibition of angiogenesis and stimulation of apoptosis: roles of cyclooxygenase-2 and mitogen-activated protein kinase pathways. Carcinogenesis 26: 1436–1445.
- Zhang J, Li L, Kim SH, Hagerman AE, Lü J (2009) Anti-cancer, anti-diabetic and other pharmacologic and biological activities of penta-galloyl-glucose. Pharm Res 26: 2066–2080.
- Hu H, Lee HJ, Jiang C, Zhang J, Wang L, et al. (2008) Penta-1,2,3,4,6-O-galloyl-beta-D-glucose induces p53 and inhibits STAT3 in prostate cancer cells in vitroand suppresses prostate xenograft tumor growthin vivo. Mol Cancer Ther 7: 2681–2691.
- Hu H, Zhang J, Lee HJ, Kim SH, Lü J (2009) Penta-O-galloyl-beta-D-glucose induces S- and G(1)-cellcycle arrests in prostate cancer cells targeting DNA replication and cyclin D1. Carcinogenesis 30: 818–823.
- Loutrari H, Hatziapostolou M, Skouridou V, Papadimitriou E, Roussos C, et al. (2004) Papapetropoulos A. Perillyl alcohol is an angiogenesis inhibitor. J PharmacolExp Ther 311: 568–575.
- Xiao D, Singh SV (2007) Phenethyl isothiocyanate inhibits angiogenesisin vitro and ex vivo. Cancer Res 67: 2239–2246.
- Wang XH, Cavell BE, Syed Alwi SS, Packham G (2009) Inhibition of hypoxia inducible factor by phenethyl isothiocyanate. Biochem Pharmacol 78: 261–272
- Basini G, Bussolati S, Santini SE, Grasselli F (2007) Sanguinarine inhibits VEGF-induced angiogenesis in a fibrin gel matrix. BioFactors 29: 11-18.
- Dupont E, Falardeau P, Mousa SA, Dimitriadou V, Pepin MC, et al. (2002) Alaoui-Jamali M.A. Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue. Clin Exp Metastasis 19: 145–153.
- Xu C, Shen G, Chen C, Gélinas C, Kong AN (2005) Suppression of NF-kappaB and NF-kappaBre gulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells. Oncogene 24: 4486–4495.
- Davis R, Singh KP, Kurzrock R, Shankar S (2009) Sulforaphane inhibits angiogenesis through activation of FOXO transcription factors. Oncol Rep 22: 1473–1478.
- Asakage M, Tsuno NH, Kitayama J, Tsuchiya T, Yoneyama S, et al. (2006) Sulforaphane induces inhibition of human umbilical vein endothelial cells proliferation by apoptosis. Angiogenesis 9: 83–91.
- Bertl E, Bartsch H, Gerhäuser C (2006) Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention. Mol Cancer Ther 5: 575–585.
- Kallifatidis G, Rausch V, Baumann B, Apel A, Beckermann BM, Groth A, et al. (2009) Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Gut 58: 949–63.
- Jackson SJ, Singletary KW (2004) Sulforaphane inhibits human MCF-7 mammary cancer cell mitotic progression and tubulin polymerization. J Nutr 134: 2229–2236.
- Smith TK, Lund EK, Parker ML, Clarke RG, Johnson IT (2004) Allyl-isothiocyanate causes mitotic block, loss of cell adhesion and disrupted cytoskeletal structure in HT29 cells. Carcinogenesis 25: 1409–1415.
- Avramis IA, Kwock R, Avramis VI (2001) Taxotere and vincristine inhibit the secretion of the angiogenesis inducing vascular endothelial growth factor (VEGF) by wild-type and drugresistant human leukemia T-cell lines. Anticancer Res 21: 2281–2286.
- Slichenmyer WJ, Von Hoff DD (1990) New natural products in cancer chemotherapy. J Clin Pharmacol 30: 770-788.
- DeFeudis FV, Papadopoulos V, Drieu K (2003) Ginkgo biloba extracts and cancer: a research area in its infancy. Fundam Clin Pharmacol 17: 405-417.
- Kanjoormana M, Kuttan G (2010) Antiangiogenic activity of ursolic acid. Integrative Cancer Therapies 9: 224–235.
- Pathak AK, Bhutani M, Nair AS, Ahn KS, Chakraborty A, et al. (2007) Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol Cancer Res 5: 943–955.
- Manu KA, Kuttan G (2008) Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-kappaB mediated activation of bcl-2 in B16F–10 melanoma cells. Int Immunopharmacol 8: 974–981.
- Kassi E, Sourlingas TG, Spiliotaki M, Papoutsi Z, Pratsinis H, et al. (2009) Ursolic acid triggers apoptosis and Bcl-2 downregulation in MCF-7 breast cancer cells. Cancer Invest 27: 723–733.
- Shanmugam MK, Manu KA, Ong TH, Ramachandran L, Surana R, et al. (2011a) Inhibition of CXCR4/CXCL12 signaling axis by ursolic acid leads to suppression of metastasis in transgenic adenocarcinoma of mouse prostate model. Int J Cancer 129: 1552–1563.
- Shanmugam MK, Rajendran P, Li F, Nema T, Vali S, et al. (2011b) Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice. J Mol Med 89: 713–727.
- Yang CS, Maliakal P, Meng X (2002) Inhibition of carcinogenesis by tea. Annu Rev Pharmacol Toxicol 42: 25-54.