Herbal Medicines Affecting Angiogenesis

6 Herbal Medicines Affecting Angiogenesis V.L. KUMARa, B. GURUPRASADa AND V. KUMAR,b,*

Abstract Plants have been used in the traditional medicinal system for the treatment of various diseases including those related to angiogenesis, i.e., formation of new blood vessels. A wide range of plants and phytochemicals are known to possess angiogenesis-modulating properties and have been used to treat conditions like cancers, rheumatoid arthritis, psoriasis and diabetic retinopathy where excessive angiogenesis takes place. In various experimental and clinical studies, plants have been shown to impart their beneficial effect by causing angio-supression. Phytochemicals such as flavonoids, polyphenols and terpenes have been demonstrated to inhibit the expression of various growth factors and matrix metalloproteinases. Plant derived drugs like genistein, taxol, resveratrol and camptothecin are well known to exert their anti-cancer effect by inhibiting angiogenic stimulators like vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor and epidermal growth factor. Some of the plants like Aloe vera, Calendula have also been reported to induce neo-vascularization that is beneficial in wound healing, myocardial infarction, non–union fractures and conditions associated with vascular insufficiency. Thus, plants offer new insights into the treatment of angiogenesis-related health problems after giving due consideration to their safety and toxicity. Key words: Anti-angiogenic, Herbal medicine, Medicinal plant, Phytochemicals, Pro-angiogenic Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029, India b Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi - 110 067, India * Corresponding author: E-mail: XXXXXXXXXXXX, a

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Introduction Plants have always been used in various traditional medicinal systems like Ayurveda, Unani, Chinese, Egyptian and Greek to treat or prevent various diseases. The first documented use of medicinal plants was by Sumerians and Akkaidians as early as 2600 BC (Samuelsson, 1999). Hundreds of herbal remedies were identified and listed by the Egyptians around 1500 BC. The usage of medicinal plants was recorded by the Chinese in their Materia Medica in 1100 BC (Joy et al., 2001). During 1000 BC Ayurveda, the Indian traditional system of medicine documents the use of plants to the times of Charaka and Sushruta (Cragg et al., 1997). Since ancient times, plants as whole or their parts have been used to treat or prevent various diseases. It is interesting to note that most drugs which are now being produced synthetically were initially discovered from plants. It is estimated by the World Health Organization (W.H.O) that approximate2.2ly 80% of the world’s population uses traditional medicine for their primary health care needs (Kappor, 1990). The usage of drugs based on plants is as high as 25% even in developed countries. Plants continue to serve as a source of new drugs with the discovery, advent and understanding of various diseases (Farnsworth et al., 1985). Angiogenesis is a crucial multi step process characterized by the formation of new blood vessels from the pre-existing vasculature. The induction and rate of angiogenesis depends on the balance between the pro-angiogenic and anti-angiogenic factors (Ferrara and Kerbel, 2005; Folkman, 1971). The important pro-angiogenic factors include Activator protein-1, angiogenin, angiotropin, angiopoietin, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), vascular permeability factor (VPF), marix metalloproteinase (MMP). While the important anti-angiogenic factors include angioarrestin, angiostatic steroids, angiostatin, anti-thrombin III, thrombospondin-1v, transforming growth factor-beta (TGF-â), tumstatin, vasculostatin and vasostatin (Fig. 1). The formation of new vasculature is executed broadly in a five step process namely a) angiogenesis initiation, b) angiogenesis amplification, c) vascular proliferation, d) vascular stabilization and e) angiogenesis suppression (Fan et al., 2006; Griffioen and Molema, 2000). Numerous medicinal plants are finding their use in angiotherapy by stimulating or inhibiting angiogenesis. The commonly used models and assays to screen agents affecting angiogenesis are given in Fig. 2. This review discusses the important plants or plant-derived active constituents that have demonstrated to have ‘pro’- or ‘anti’- angiogenic properties.


Herbal Medicines Affecting Angiogenesis

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Fig. 1: Angiogenesis and its modulation. ECM, extracellular matrix; bFGF, basic fibroblast growth factor; MMP, matrix metalloprotease; TGF-b, transforming growth factor beta; VEGF, vascular endothelial growth factor

Fig. 2: (Contd...)


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Fig. 2: Commonly used assays/models for the evaluation of angiogenic activity.

Plants Exhibiting Anti-angiogenic Property (Fig. 3) Ginseng Ginseng is a root of Panax ginseng (Family: Araliaceae). The genus Panax was named by a botanist Carl Meyer deriving it from the greek words ‘Pan’ and ‘akos’ meaning ‘all’ and ‘healing’ respectively (Gillis, 1997). Ginseng has been used in traditional Chinese medicine for the treatment of cancers (Chang et al., 2003). Ginsenosides, a group of triterpinoid saponins exhibit the pharmacological properties reported for this plant. There are more than 30 types of ginsenosides that have been classified as protopanaxadiol type (e.g., Rg3, Rh2, and Rb1) and protopanaxatriol type (e.g., Rg1, Re and Rf) (Liu and Xiao, 1992). The ginsenoside Rg3 has been shown to inhibit angiogenesis in a bFGF-induced in vivo neovascularisation model (Yue at al., 2006). Rb1, another ginsenoside, has been demonstrated to exhibit antiangiogenic property in matrigel, an in vitro model through activation of estrogen receptor â that results in an increase in pigment epithelium derived factor, an inhibitor of endothelial migration (Duh et al., 2002; Leung et al., 2007). Recently, Compound K, an active ginseng metabolite has been shown to exert its anti-angiogenic effect through inhibition of p38 mitogen-activated protein kinases (MAPK) and Akt/PKB kinase in bFGF stimulated human umbilical vein endothelial cells (HUVEC). In preclinical studies carried out in mouse model of ovarian and lung cancer, the combination of



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Fig. 3: (Contd...)


138

Fig. 3:


Plants exhibiting Anti-angiogenic property. bFGF, basic fibroblast growth factor; ECM, extracellular matrix; HIF, hypoxia inducible factor; MMP, matrix metalloprotease; TGF-b, transforming growth factor beta; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor



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ginsenoside Rg3 with standard anti-neoplastic agents has been shown to exhibit superior anti-tumour effect that resulted in improved quality of life and survival (Liu et al., 2009; Xu et al., 2007). Ginseng has also been shown to improve the quality of life and to decrease fatigue in cancer patients, however, its anti-tumour or anti-angiogenic effect remains to be evaluated (Kim et al., 2006). Taxol Taxol is an active constituent extracted from the pacific yew tree Taxus brevifolia (Family: Taxaceae). Taxol was first extracted from the bark of the tree by two scientists - Monroe E. Wall and Mansukh C. Wani. Following its commercial development by Bristol-Myers Squibb (BMS) its generic name was changed to paclitaxel and was sold under the trade name of TAXOL (Goodman and Walsh, 2001). Paclitaxel is a well known and clinically used drug in the treatment of ovarian, breast and lung cancers and Kaposi’s sarcoma (Saville, 1995). It is well known to exhibit its anti-cancer effect by virtue of its cytotoxic property that is attributed to its ability to inhibit microtubule breakdown during cell division. Apart from its cytotoxic property it is known to exhibit anti-angiogenic effect that is evident from its ability to inhibit endothelial cell chemotaxis and invasiveness at concentrations lower than those exhibiting cytotoxic effect. Paclitaxel has been shown to inhibit endothelial cell proliferation, motility and cord formation in an in vitro matrigel assay. It has also been demonstrated to inhibit angiogenesis in vivo and to decrease the levels of MMP-2 (Belotti et al., 1996). Docetaxel, another taxane prepared semisythetically, can also inhibit angiogenesis in squamous and adenocarcinoma models in mice (22). The anti-angiogenic effect of paclitaxel is mediated through inhibition of VEGF and hypoxiainducible factor-á production (Avramis et al., 2001; Escuim et al., 2005). Combretastatin Combretastatins are natural stilbenoid phenols that are isolated from the South African bushwillow tree Combretum caffrum (Family: Combretaceae) (Petit et al., 1989). The anti-cancer effects of combretastatins are attributed to the inhibition of microtubule polymerization (Lin et al., 1989). Of different molecules that belong to the combretastatin group, Combretastatin A-4 phosphate (CA4P) exhibits potent anti-angiogenic property. In vitro and in vivo studies have demonstrated that CA4P inhibits angiogenesis by inhibiting the interaction between endothelium and cadherin (Vincent et al., 2005). It has also been demonstrated to decrease the level of hypoxia inducible factor 1, a stimulator of angiogenesis (Dachs et al., 2006). Another molecule of the combretastatin group, AVE8062 has also been reported to exhibit anti-angiogenic effect both in in vitro and in vivo studies (Delmonte


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and Sessa, 2009). Combretastatins CA4P and AVE8062 are being studied for their efficacy as anti-cancer agents in phase II and phase III studies. When used as monotherapy, CA4P has been shown to decrease the vascularity of tumors in patients with refractory solid tumors (Dowlati et al., 2002; Rustin et al., 2003; Stevenson et al., 2003). The interim report of a study where the drug was administered in patients of anaplastic thyroid carcinoma shows clinical benefit with progression free interval of e” 3 months in 28% patients (Cooney et al., 2004). Its administration as combination therapy has also shown efficacy in solid tumours and ovarian cancer (Bilenker et al., 2005; Ng et al., 2007; Rustin et al., 2010; Zweifel et al., 2011). AVE8062 is being evaluated for its efficacy in cancer, both as monotherapy and as combination therapy, in clinical studies (Delmonte and Sessa, 2009). Genistein Genistein is an isoflavonoid derived from soy products (Soy, Soya, Soybean etc.). It is an inhibitor of protein- tyrosine kinase and topoisomerase-II and well known to possess anti-cancer properties in breast and prostate cancer in in vitro and in vivo studies. It also exhibited anti-angiogenic effect in these studies (Banerjee et al., 2008). Genistein is also shown to inhibit the invasion of tumour cells, metastasis of breast cancer cells (MDA-MB-435) and expression of angiogenic MMP-2 and-9 (Li et al., 1999). Genistein also shows anti-angiogenic property in prostate cancer cells (PC-3) and inhibits the expression of MMP-2 and -9, VEGF, TGF-â and other angiogenic factors (Li and Sarkar, 2002). Genistein after having demonstrated its antiangiogenic and anti-cancer properties in preclinical studies and following its safety and toxicity evaluation in phase I human studies has also shown efficacy in phase II studies in prostate carcinoma patients. In these patients administration of genistein was associated with a decrease in the rate of rise of ‘prostate specific antigen’ levels without any symptoms of toxicity (Miltyk et al., 2003). Resveratrol Resveratrol is a stilbene found in grapes, fruits and other plants, and exists in both cis- and trans-stereoisomeric forms. The anti-cancer activity of resveratrol was first demonstrated in a dimethylbenz (a) anthracene (DMBA)-induced tumour model. Later, numerous in vitro and in vivo studies have demonstrated its anti-angiogenic potential. Resveratrol administration is associated with a decrease in the formation of tubes in a matrigel model and fibronectin induced endothelial cell adhesion and migration (Cao et al., 2005).The action of resveratrol is mediated through inhibition of MMP2 activity in HUVEC model, while in DMBA-induced tumour it suppressed



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NF-êB binding to DNA and the activation of activator protein 1 (Banerjee et al., 2002; Li et al., 2003; Uchiyama et al., 2010). Resveratrol has also been shown to inhibit VEGF and bFGF induced angiogenesis by inhibiting production of nitric oxide and induction of cyclooxygenase (COX) respectively (Banerjee et al., 2002). However, in spite of its efficacy in in vitro and in vivo experiments, the studies demonstrating its efficacy in inhibiting angiogenesis or tumour formation in humans are not available as yet. Thunder God Vine Tripteygium wilfordii (Family: Celastraceae) also called Thunder God Vine is a commonly used plant in traditional Chinese medicine for the treatment of rheumatoid arthritis (Tao and Lipsky, 2000). Celastrol, an active purified constituent of the plant has been demonstrated to exhibit anti-angiogenic activity by inhibiting endothelial proliferation, migration and tube formation in in vitro matrigel model. This effect was also substantiated through its ability to inhibit formation of new vessels in an in vivo Chorio-allantoic membrane (CAM) model (Huang et al., 2008). It also inhibits development of prostate cancer in nude mice (Yang et al., 2006). With the effect being demonstrated in in vitro and in vivo models the research into the possible mechanism of action of celastrol has revealed that it acts by inhibiting the expression of VEGF receptor having no effect on VEGF expression in human glioma cell cultures (Huang et al., 2008). Triptolide, a diterpinoid extracted from the plant also inhibits TA-K cells (Anaplastic thyroid carcinoma cell line) induced neo-vascularisation of matrigel plug and decreases the invasion of the TA-K cells. It has been established that triptolide decreases the NFêB transcriptional activity and down regulates the expression of NF-êB downstream genes in TA-K cells (Zhu et al., 2009). Its anti-angiogenic effect has also been demonstrated in zebra fish model where it has been shown to decrease the expression of angiopoeitin-2 and its corresponding receptor tie2 offering one of the possible mechanism of actions for the drug (He et al., 2009). Cinnamon Cinnamon, commonly used as an oil and spice, is the dried outer bark of the tree Cinnamomum cassia (Family: Lauraceae) that commonly grows in the evergreen forests. The anti-tumour effect of cinnamon extracts has been reported in the traditional Chinese system of medicine and in some in vitro studies (Kamei et al., 2000; Kwon et al., 2009; Schoene et al., 2005). In melanoma cell line the extract decreased the level of pro-angiogenic factors like EGF, FGF, VEGF-a and TGF-b along with the inhibition of expression of their mRNA (Lu et al., 2010). The extract of cinnamon inhibits VEGF induced in vitro endothelial cell proliferation, migration and tube formation by inhibiting VEGFR2 kinase activity and in vivo tumour induced


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neo-vascularisation (Lu et al., 2010). It has been observed that cinnamon extract has an inhibitory effect on tristetraprolin induced VEGF expression (Cao et al., 2007; Essafi-Benkhadir et al., 2007). Camptothecin Camptothecin is an alkaloid extracted from the plant Camptotheca acuminata (Family: Nyssaceae). The efficacy of camptothecin has been demonstrated in various cancers like that of lung, colon, ovary, breast and pancreas (Knight et al., 1999; Lee et al., 2008; Sun et al., 2003; Van Hattum et al., 2002; Wang et al., 2008). Though the anti-tumour activity is attributed to its effect on the cell cycle, some studies have demonstrated anti-angiogenic property of camptothecin. It was observed that different camptothecin analogues namely 9-amino-20(S)-camptothecin, topotecan and camptosar exhibit inhibitory effect on bFGF induced angiogenesis in mice cornea (O’Leary et al., 1999). Camptothecin has been shown to inhibit endothelial cell growth in in vitro HUVEC and in vivo angiogenesis models such as disc angiogenesis system, mouse melanoma model and nude mouse model of human colon cancer (Clements et al., 1999; Ji et al., 2007; Liu et al., 2010). Green Tea Camellia sinensis (Family: Theaceae), commonly known as green tea, is rich in poylphenols and catechins. Green tea is well known for its antioxidant and anti-tumour effects that are attributed to the catechins namely epicatechin, epicatechin-3-gallate and epigallocatechin-3-gallate (EGCG) (Anderson et al., 2001; Chung et al., 2003; Lim et al., 2006; Nakazato et al., 2005; Sun et al., 2006). Apart from the anti-tumour effects, green tea has demonstrated anti-angiogenic potential in various in vitro and in vivo models. EGCG inhibits endothelial proliferation in in vitro HUVEC and decreases the density of the vessels in a model of rodent breast cancer (Cao and Cao, 1999). The possible mechanism of action by which EGCG inhibits angiogenesis is by inhibiting bFGF expression as demonstrated in human colorectal cancer cells (Sukhthankar et al., 2008). The other mechanisms of action for EGCG include inhibition of expression of VEGF, angiopoietin-1 and -2, and MMP (Siddiqui et al., 2008). Curcumin Curcumin is a phenolic compound derived from the plant Curcuma longa (Family: Zingiberaceae). It has been reported to possess anti-inflammatory, anti-oxidant and anti-cancer properties (Huang et al., 1991, 1997; Jovanovic et al., 2001; Singh et al., 1998). Curcumin exhibits anti-angiogenic property in various hepatoma, glioblastoma, prostate and ovarian carcinoma



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xenograft models (Lin et al., 2007; Perry et al., 2010; Shankar et al., 2008; Yoysungnoen et al., 2008). Using intra vital microscopy, both curcumin and its reduced analog tetrahydrocurcumin have been shown to decrease angiogenesis in HepG2-implanted nude mouse model of hepatocellular carcinoma (Yoysungnoen et al., 2009). Numerous mechanisms that have been put forth for the anti-angiogenic property of curcumin include inhibition of pro-angiogenic factors like bFGF, VEGF, angiopoetin-1 and 2, matrix metalloproteinase and transcription factors like NF-êB and AP-1 (Gururaj et al., 2002; Mohan et al., 2000; Yoysungnoen et al., 2006). Curcumin has been shown to decrease the expression of cell adhesion molecules like Ecadherin and ICAM -1 in melanoma and breast cancer cell lines that are considered to be important in angiogenesis and metastasis (Ray et al., 2003; Yodkeeree et al., 2010). Besides above mentioned plants (Fig. 3), a number of other plants are also known to exhibit anti-angiogenic property. Table 1 gives active constituents and mechanism of action of some of these plants.

Plants Exhibiting Pro-angiogenic Property (Fig. 4) Aloe vera Aloe barbadensis, commonly known as Aloe vera, belongs to the family Liliacae. Aloe vera has long been used by Greeks, Romans and Indians in their traditional medicinal systems for the treatment of various diseases. It is used to promote wound healing in many countries (Amar et al., 2008; Marshall, 1990; Reynolds and Dweck, 1999). Using CAM assay the angiogenic property has been demonstrated in different compounds isolated from this plant of which beta-sitosterol is most potent. Beta-sitosterol has been shown to stimulate angiogenesis in in vitro HUVEC and matrigel assays (Moon et al., 1999). It has been shown to enhance new vessel formation in ischaemia-induced brain damage in Mongolian gerbil. The pro-angiogenic property of beta-sitosterol is mediated through enhanced expression of proteins like von Willebrand factor, VEGF, VEGFR and blood vessel matrix laminin (Choi et al., 2002). Oral administration of Aloe vera in diabetic rats has been shown to promote wound healing, extracellular matrix deposition and epithelialization of experimentally induced wound. It has been shown to increase the expression of angiogenic factors VEGF and transforming growth factor TGF-â1 as revealed by immunohistochemical analysis (Atiba et al., 2010). Recently a systematic review of different studies where Aloe vera gel was used to promote wound healing in burns has revealed its efficacy in promoting wound healing in first and second degree burn patients as compared to conventional treatments (Maenthaisong et al., 2007). (Figure 4 Summaries the List of Plants Exhibiting Pro Pro-Angiogenic Property).


PDF created with pdfFactory Pro trial version www.pdffactory.com Chloroform-methanol extract Pterogynidine

Licochalcone

Deguelin

Methanol extract

Juliborside J8

Baicalein Baicalin Andrographalide

-HUVEC -CAM -HUVEC -Aortic ring HUVEC-MMP -Matrigel -HUVEC -Matrigel

Kim et al., 2010 Lee et al., 2005 Lopes et al., 2009

¯ VEGFR-2 ¯ bFGF. –

Table. 1: (Contd...)

Kim et al., 2008

Jung et al., 2007

Hua et al., 2009

–

–

–

Sheeja et al., 2007

¯ VEGF

-Aortic ring -B16F10 (melanoma cells) -HME cells -CAM -CAM

Albizia julibrissin (Family: Fabaceae) Ulmus davidiana var. japonica (Family:Ulmaceae) Mundulea sericea (Family: Fabaceae) Glycyrrhiza inflate (Family: Leguminosae) Beninkasa hispida (Family: Cucurbitaceae) Alchornea glandulosa (Family: Euphorbiaceae)

Xiao and Singh, 2008 Liu et al., 2003

CAM

Lu et al., 2010

¯ MMP-2 activity ¯ VEGF &VEGFR –

Bovine Aortic endothelial cells HUVEC

Z-guggulsterone

You et al., 2002

–

HUVEC

Acetylbupleurotoxin (P1) Bupleurotoxin (P2) a- Chaconine

Ref.

Bupleurum longiradiatum (Family:Apiaceae) Solanum tuberosum (Family: Solanaceae) Commiphora mukul (Family: Burseracae) Scutellaria baicalensis (Family: Lamiaceae) Andrographis paniculata (Family: Acanthaceae)

Mechanism

Model/Assay

Active constituent/ extract

Plant

Table 1: Plants exhibiting anti-angiogenic property

144 RPMP Vol. 32 — Ethnomedicine and Therapeutic Validation

-HUVEC -HUVEC -Matrigel -CAM -HUVEC -CAM

Cucurbitacin Deoxypodophyllotoxin Decursin Decursinol angelate Total glucosides

-CAM

Ethanol extract

Salvia plebeian (Family: Lamiaceae) Cucubita pepo (Family: Cucurbitaceae) Pulsatilla koreana (Family: Ranunculaceae) Angelica gigas (Family: Apiaceae)

Paeonia lactiflora Pall (Family: Paeoniaceae)

-Matrigel -Migration of LoVo cells CAM

Silibinin

Silymarin (Family: Asteraceae)

Model/Assay


Plant

Table. 1: (Contd...)

Kim et al., 2002 Jung et al., 2009b Deng et al., 2010

¯ VEGFR-2 ¯ VEGF

Dong et al., 2010

¯ VEGFR –

Jung et al., 2009a

Yang et al., 2003

¯ VEGF –

Ref.

Mechanism

Herbal Medicines Affecting Angiogenesis 145


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Fig. 4: Plants exhibiting Pro-angiogenic property. Egr-1, early growth response factor-1; PDGF, platelet-derived growth factor; TGF-?, transforming growth factor beta; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; vWF, von Willebrand factor

Yellow leader Astragalus membranaceus (Family: Fabaceae) is also known yellow leader or ‘huang qi’ and has been used in traditional Chinese medicine for speedy healing and treatment of diabetes. Formononetin is an active constituent extracted from the root of this plant which is commonly used to improve micro circulation and promote wound healing in alternative system of medicine (Huh et al., 2009). Formononetin has pro- angiogenic activity in in vitro HUVEC and ex-vivo angiogenesis assay. It was observed that formononetin increases the expression of the angiogenic factors VEGF, bFGF, TGF-b1, PDGF and early growth response factor-1 (Egr-1) in the HUVECs. The formononetin induced expression of Egr-1 could be suppressed by specific inhibitors of extracellular signal-regulated kinase (Erk-1) and p38 MAPK thereby indicating the involvement of ERK1/2 and p38 MAPK pathways in its angiogenic effect (Huh et al., 2011). In experimentally induced fracture in rats, formononetin has been shown to induce early fracture healing by promoting angiogenesis. Its pro-angiogenic effect was associated with an increase in the level of VEGF mRNA and VEGF as revealed by immuno-histochemical analysis of the tissue at the fracture site (Huh et al., 2009). Some of other plants exhibiting pro-angiogenic property are listed in Table 2.


Cornus officianalis (Family: Cornaceae) Uncaria rhynchophylla (Family: Rubiaceae) Centella asiatica (Family: Apiaceae) Picrorhiza kurrooa (Family: Scrofulariaceae) Calendula officinalis (Family: Asteraceae) Equisetum arvense (Family: Equisetaceae) Synadenium umbellatum (Family: Euphorbiaceae) Alternanthera brasiliana (Family: Amaranthaceae)

Plant

–

-CAM

Methanol extract

-CAM -Excised wound

–

-Excised wound

–

–

Vaseline-lanolin base ointment Aqueous extract

Singh et al., 2007

- VEGF

-CAM

Shukla et al., 1999

Ethanol extract

Picroliv

Asiaticoside

MeloReis et al., 2010 Barua et al., 2009

Parente et al., 2011 Ozay et al., 2010

Choi et al., 2005

Yao et al., 2009

Ref.

- VEGF & VEGFR - VEGF & bFGF –

Mechanism

-Focal cerebral ischaemia -HUVECs -Matrigel -CAM -Punch wounds -Rat aorta ring

Model/Assay

Cornel iridoid glycoside) Ethanol extract


Table 2: Plants exhibiting Pro-angiogenic property

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Under normal physiological conditions, angiogenesis is well regulated through a balance between the pro- and anti-angiogenic factors. Unregulated angiogenesis is observed in conditions like tumor growth and metastasis, proliferative retinopathy, rheumatoid arthritis and psoriasis where it is desirable to suppress it. On the other hand stimulation of angiogenesis would prove beneficial in chronic wounds, vascular insufficiency, delayed fracture healing and ischemic heart disease. Some of the agents that have demonstrated anti-angiogenic property in pre-clinical studies have shown efficacy as anti-cancer agents and as adjuvants to chemo- and radio-therapy (Kumar and Kumar, 2010). Fufang, - a composite formula has been used in traditional Chinese medicine (TCM) to treat angiogenesis related diseases for more than 1,000 years. It was demonstrated that the fufang of Sinomenium acutum, Sophora flavescens, Phellodendron amurense and Dioscorea hypoglauca exhibits anti-angiogenic property in collagen induced arthritis model (Li et al., 2003). Another fufang from Astragalus membranaceus and Angelica sinensis, commonly used to enhance circulation and healing has been demonstrated exhibit pro-angiogenic property in the CAM model (Song et al., 2004). Genistein and combretastatins have shown efficacy in some clinical studies and will be available for the use of general patients following large clinical trials. These agents will have to pass the stages where safety, efficacy and toxicity are evaluated in both pre-clinical and clinical studies in order to obtain regulatory acceptance before their use in humans.

References Amar, S., Resham, V. and Saple, D.G. 2008. Aloe vera a short review. Ind. J. Dermatol. 3(4): 163–166. Anderson, R.F., Fisher, L.J., Hara, Y., Harris, T., Mak, W.B., Melton, L.D. and Packer, J.E. 2001. Green tea catechins partially protect DNA from (.)OH radical-induced strand breaks and base damage through fast chemical repair of DNA radicals. Carcinogenesis 22(8): 1189–1193. Aoki, S., Watanabe, Y., Sanagawa, M., Setiawan, A., Kotoku, N. and Kobayashi, M. 2006. Cortistatins A, B, C, and D, anti-angiogenic steroidal alkaloids, from the marine sponge Corticium simplex. J. Am. Chem. Soc. 128(10): 3148–3149. Atiba, A., Ueno, H. and Uzuka, Y. 2010. The effect of aloe vera oral administration on cutaneous wound healing in type 2 diabetic rats. J. Vet. Med. Sci. (Ahead of print) Avramis, I.A., Kwock, R. and Avramis, V.I. 2001. Taxotere and vincristine inhibit thesecretion of the angiogenesis inducing vascular endothelial growth factor (VEGF) by wild-type and drug-resistant human leukemia T-cell lines. Anticancer Res. 21: 2281–2286. Banerjee, S., Bueso-Ramos, C. and Aggarwal, B.B. 2002. Suppression of 7, 12dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 62: 4945–4954.



149

Banerjee, S., Li, Y., Wang, Z. and Sarkar, F.H. 2008. Multi-targeted therapy of cancer by genistein. Cancer Lett. 269(2): 226–242. Barua, C.C., Talukdar, A., Begum, S.A., Sarma, D.K., Fathak, D.C., Barua, A.G. and Bora, R.S. 2009. Wound healing activity of methanolic extract of leaves of Alternanthera brasiliana Kuntz using in vivo and in vitro model. Indian J. Exp. Biol. 47(12): 1001–1005. Belotti, D., Vergani, V., Drudis, T., Borsotti, P., Pitelli, M.R., Viale, G., Giavazzi, R. and Taraboletti, G. 1996. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res. 2(11): 1843–1849. Bilenker, J.H., Flaherty, K.T., Rosen, M., Davis, L., Gallagher, M., Stevenson, J.P., Sun, W., Vaughn, D., Giantonio, B., Zimmer, R., Schnall, M. and O’Dwyer, P.J. 2005. Phase I trial of combretastatin a-4 phosphate with carboplatin. Clin Cancer Res. 11: 1527–1533. Cao, Y. and Cao, R. 1999. Angiogenesis inhibited by drinking tea. Nature 398: 381. Cao, Y., Fu, Z.D., Wang, F., Liu, H.Y. and Han, R. 2005. Anti-angiogenic activity of resveratrol, a natural compound from medicinal plants. J Asian Nat Prod Res. 7(3): 205–213. Cao, H., Polansky, M.M. and Anderson, R.A. 2007. Cinnamon extract and polyphenols affect the expression of tristetraprolin, insulin receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes. Arch Biochem Biophys. 459(2): 214–222. Chang, Y.S., Seo, E.K., Gyllenhaal, C. and Block, K.I. 2003. Panax ginseng: a role in cancer therapy? Integr. Cancer Ther. 2: 13–33. Choi, S., Kim, K.W., Choi, J.S., Han, S.T., Park, Y.I., Lee, S.K., Kim, J.S. and Chung, M.H. 2002. Angiogenic activity of beta-sitosterol in the ischaemia/reperfusiondamaged brain of Mongolian gerbil. Planta Med. 68(4): 330–335. Choi, D.Y., Huh, J.E., Lee, J.D., Cho, E.M., Baek, Y.H., Yang, H.R., Cho, Y.J., Kim, K.I., Kim, D.Y. and Park, D.S. 2005. Uncaria rhynchophylla induces angiogenesis in vitro and in vivo. Biol. Pharm. Bull. 28(12): 2248–2252. Chung, F.L., Schwartz, J., Herzog, C.R. and Yang, Y.M. 2003. Tea and cancer prevention: studies in animals and humans. J. Nutr. 133(10): 3268S–3274S. Clements, M.K., Jones, C.B., Cumming, M. and Daoud, S.S. 1999. Antiangiogenic potential of camptothecin and topotecan. Cancer Chemother. Pharmacol. 44(5): 411–416. Cooney, M.M., Radivoyevitch, T., Dowlati, A., Overmoyer, B., Levitan, N., Robertson, K., Levine, S.L., DeCaro, K., Buchter, C., Taylor, A., Stambler, B.S. and Remick, S.C. 2004. Cardiovascular safety profile of combretastatin a4 phosphate in a single-dose phase I study in patients with advanced cancer. Clin Cancer Res. 10(1 Pt 1): 96–100. Cragg, G.M., Newman, D.J. and Snader, K.M. 1997. Natural products in drug discovery and development. J. Nat. Prod. 60: 52–60. Dachs, G.U., Steele, A.J., Coralli, C., Kanthou, C., Brooks, A.C., Gunningham, S.P., Currie, M.J., Watson, A.I., Robinson, B.A. and Tozer, G.M. 2006. Anti-vascular agent Combretastatin A-4-P modulates hypoxia inducible factor-1 and gene expression. BMC Cancer. 6: 280. Delmonte, A. and Sessa, C. 2009. AVE8062: a new combretastatin derivative vascular disrupting agent. Expert Opin. Investig. Drugs 18(10): 1541–1548.


150


Deng, H., Yan, C., Xiao, T., Yuan, D. and Xu, J. 2010. Total glucosides of Paeonia lactiflora Pall inhibit vascular endothelial growth factor-induced angiogenesis. J. Ethnopharmacol. 127(3): 781–785. Dong, Y., Lu, B., Zhang, X., Zhang, J., Lai, L., Li, D., Wu, Y., Song, Y., Luo, J., Pang, X., Yi, Z. and Liu, M. 2010. Cucurbitacin E, a tetracyclic triterpenes compound from Chinese medicine, inhibits tumor angiogenesis through VEGFR2-mediated Jak2-STAT3 signaling pathway. Carcinogenesis. 31(12): 2097–2104. Dowlati, A., Robertson, K., Cooney, M., Petros, W.P., Stratford, M., Jesberger, J., Rafie, N., Overmoyer, B., Makkar, V., Stambler, B., Taylor, A., Waas, J., Lewin, J.S., McCrae, K.R. and Remick, S.C. 2002. A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenousschedule in patients with advanced cancer. Cancer Res. 62: 3408–3416. Duh, E.J., Yang, H.S., Suzuma, I., Miyagi, M., Youngman, E., Mori, K., Katai, M., Yan, L., Suzuma, K., West, K., Davarya, S., Tong, P., Gehlbach, P., Pearlman, J., Crabb, J.W., Aiello, L.P., Campochiaro, P.A. and Zack, D.J. 2002. Pigment epithelium-derived factor suppresses ischemia induced retinal neovascularization and VEGF-induced migration and growth. Invest. Ophthalmol. Vis. Sci. 43: 821–829. Escuin, D., Kline, E.R. and Giannakakou, P. 2005. Both microtubule-stabilizing and microtubule destabilizing drugs inhibit hypoxia-inducible factor-1a accumulation and activity by disrupting microtubule function. Cancer Res. 65: 9021–9028. Essafi-Benkhadir, K., Onesto, C., Stebe, E., Moroni, C. and Pagès, G. 2007. Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation. Mol. Biol. Cell. 18(11): 4648–4658. Fan, T., Yeh, J., Leung, K.W., Yue, P.Y.K. and Wong, R.N.S. 2006. Angiogenesis: from plants to blood vessels. Trends Pharmacol Sci. 27(6): 297–309. Farnsworth, N.R., Akerele, O., Bingel, A.S., Soejarto, D.D. and Guo, Z. 1985. Medicinal plants in therapy. Bull World Health Organ. 63: 965–981. Folkman, J. 1971. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285: 1182–1186. Ferrara, N. and Kerbel, R.S. 2005. Angiogenesis as a therapeutic target. Nature 438: 967–974. Gillis, C.N. 1997. Panax ginseng pharmacology: a nitric oxide link? Biochem Pharmacol. 54: 1–8. Goodman, J. and Walsh, V. 2001. The Story of Taxol: Nature and Politics in the Pursuit of an Anti-Cancer Drug. Cambridge University Press, Cambridge, UK p. 17. Griffioen, A.W. and Molema, G. 2000. Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev. 52(2): 237–268. Gururaj, A.E., Belakavadi, M., Venkatesh, D.A., Marmé, D. and Salimath, B.P. 2002. Molecular mechanisms of anti-angiogenic effect of curcumin. Biochem Biophys Res Commun. 297: 934–942.



151

He, M.F., Liu, L., Ge, W., Shaw, P.C., Jiang, R., Wu, L. and Wand But, P.P. 2009. Antiangiogenic activity of tripterygium wilfordii and its terpenoids. J. Ethnopharmacol. 121(1): 61–68. Hua, H., Feng, L., Zhang, X.P., Zhang, L.F. and Jin, J. 2009. Anti-angiogenic activity of julibroside J8, a natural product isolated from Albizia julibrissin. Phytomedicine 16(8): 703–711. Huang, M.T., Lysz, T., Ferraro, T., Abidi, T.F., Laskin, J.D. and Conney, A.H. 1991. Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis. Cancer Res. 51: 813–819. Huang, M.T., Ma, W., Yen, P., Xie, J.G., Han, J., Frenkel, K., Grunberger, D. and Conney, A.H. 1997. Inhibitory effects of topical application of low doses of curcumin on 12-O-tetradecanoylphorbol-13-acetateinduced tumor promotion and oxidized DNA bases in mouse epidermis. Carcinogenesis 18: 83–88. Huang, Y.L., Zhou, Y.X., Zhou, D., Xu, Q.N., Ye, M., Sun, C.F. and Du, Z.W. 2003. Celastrol in the inhibition of neovascularization. Zhonghua Zhong Liu Za Zhi. 25(5): 429–432. Huang, Y., Zhou, Y., Fan, Y. and Zhou, D. 2008. Celastrol inhibits the growth of human glioma xenografts in nude mice through suppressing VEGFR expression. Cancer Lett. 264(1): 101–106. Huh, J.E., Nam, D.W., Baek, Y.H., Kang, J.W., Park, D.S., Choi, D.Y. and Lee, J.D. 2011. Formononetin accelerates wound repair by the regulation of early growth response factor-1 transcription factor through the phosphorylation of the ERK and p38 MAPK pathways. Int Immunopharmacol. 11(1): 46–54. Huh, J.E., Kwon, N.H., Baek, Y.H., Lee, J.D., Choi, D.Y., Jingushi, S., Kim, K.I. and Park, D.S. 2009. Formononetin promotes early fracture healing through stimulating angiogenesis by up-regulating VEGFR-2/Flk-1 in a rat fracture model. Int. Immunopharmacol. 9(12): 1357–1365. Ji, Y., Hayashi, K., Amoh, Y., Tsuji, K., Yamauchi, K., Yamamoto, N., Tsuchiya, H., Tomita, H., Bouvet, M. and Hoffman, R.M. 2007. The camptothecin derivative CPT-11 inhibits angiogenesis in a dual-color imageable orthotopic metastatic nude mouse model of human colon cancer. Anticancer Res. 27(2): 713–8. Jovanovic, S.V., Boone, C.W., Steenken, S., Trinoga, M. and Kaskey, R.B. 2001. How curcumin works preferentially with water solubleantioxidants. J. Am. Chem. Soc. 123: 3064–3068. Joy, P.P., Thomas, J., Mathew, S., and Skaria, B.P. 2001. Medicinal Plants. In: Bose, T.K., Kabir, J., Das, P. and Joy, P.P. Eds., Tropical Horticulture Vol. 2, Naya Prakash, Calcutta, pp. 449–632. Jung, H.J., Jeon, H.J., Lim, E.J., Ahn, E.K., Song, Y.S., Lee, S., Shin, K.H., Lim, C.J. and Park, E.H. 2007. Anti-angiogenic activity of the methanol extract and its fractions of Ulmus davidiana var. japonica. J. Ethnopharmacol. 112(2): 406–409. Jung, H.J., Song, Y.S., Lim, C.J. and Park, E.H. 2009a. Anti-inflammatory, antiangiogenic and anti-nociceptive activities of an ethanol extract of Salvia plebeia R. Brown. J. Ethnopharmacol. 126(2): 355–360. Jung, M.H., Lee, S.H., Ahn, E.M. and Lee, Y.M. 2009b. Decursin and decursinol angelate inhibit VEGF-induced angiogenesis via suppression of the VEGFR-2signaling pathway. Carcinogenesis. 30(4): 655–661.


152


Kamei, T., Kumano, H., Iwata, K., Nariai, Y. and Matsumoto, T. 2000. The effect of a traditional Chinese prescription for a case of lung carcinoma. J. Altern. Complement. Med. 6(6): 557–559. Kappor, L.D. 1990. CRC Handbook of ayurvedic medicinal plants. CRC Press, Boca Raton, Florida, U.S.A pp. 416-417. Kim, J.H., Park, C.Y. and Lee, S.J. 2006. Effects of sun ginseng on subjective quality of life in cancer patients: a double-blind, placebo-controlled pilot trial. J. Clin. Pharm. Ther. 31(4): 331–334. Kim, J.H., Kim, J.H., Yu, Y.S., Park, K.H., Kang, H.J., Lee, H.Y. and Kim, K.W. 2008. Antiangiogenic effect of deguelin on choroidal neovascularization. J. Pharmacol. Exp. Ther. 324(2): 643–647. Kim, Y., Kim, S.B., You, Y.J. and Ahn, B.Z. 2002. Deoxypodophyllotoxin; the cytotoxic and antiangiogenic component from Pulsatilla koreana. Planta Med. 68 (3): 271-274 Kim, Y.H., Shin, E.K., Kim, D.H., Lee, H.H., Park, J.H. and Kim, J.K. 2010. Antiangiogenic effect of licochalcone A. Biochem Pharmacol. 80(8): 1152–1159. Knight, V., Koshkina, M.V., Waldrep, J.C., Giovanella, B.C. and Gilbert, B.E. 1999. Anticancer effect of 9-nitrocamptothecin liposome aerosol on human cancer xenografts in nude mice. Cancer Chemoth Pharm. 44: 177–186. Kumar, V.L. and Kumar, V. 2010. Anti cancer properties of plant derived food, phytochemicals and plant expressed recombinant pharmaceuticals. In: V.K. Gupta ed., Comprehensive bioactive natural products: Vol. 1 potential and challenges, eds, Gupta VK. Studium press LLC, U.S.A, pp. 307–321. Kwon, H.K., Jeon, W.K., Hwang, J.S., Lee, C.G., So, J.S., Park, J.A., Ko, B.S. and Im, S.H. 2009. Cinnamon extract suppresses tumor progression by modulating angiogenesis and the effector function of CD8+ T cells. Cancer Lett. 278(2): 174– 182. Lee, D.H., Kim, S-W., Suh, C., Lee, J-S., Lee, J.H., Lee, S-J., Ryoo, B.Y., Park, K., Kim, J.S., Heo, D.S. and Kim, N.K. 2008. Belotecan, new camptothecin analogue, is active in patients with small-cell lung cancer: results of a multicenter early phase II study. Ann Oncol. 19: 123–127. Lee, K.H., Choi, H.R. and Kim, C.H. 2005. Anti-angiogenic effect of the seed extract of Benincasa hispida Cogniaux. J. Ethnopharmacol. 97(3): 509–513. Leung, K.W., Cheung, L.W.T., Pon, Y.L., Wong, R.N.S., Mak, N.K., Fan, T.P., Au, S.C., Tombran-Tink, J. and Wong, A.S. 2007. Ginsenoside-Rb1 inhibits tubelike structure formation of endothelial cells by regulating pigment epithelium derived factor through estrogen receptor beta. Br. J. Pharmacol. 152: 207–215. Li, S., Lu, A.P., Wang, Y.Y. and Li, Y.D. 2003. Suppressive effects of a Chinese herbal medicine qing-luo-yin extract on the angiogenesis of collagen-induced arthritis in rats. Am. J. Chin. Med. 31: 713–720. Li, Y., Bhuiyan, M. and Sarkar, F.H. 1999. Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435cells by genistein. Int. J. Oncol. 15: 525–533. Li, Y. and Sarkar, F.H. 2002. Down-regulation of invasion and angiogenesis-related genes identified by cDNA microarray analysis of PC3 prostate cancer cells treated with genistein. Cancer Lett. 186: 157–164.



153

Li, Y.T., Shen, F., Liu, B.H. and Cheng, G.F. 2003. Resveratrol inhibits matrix metalloproteinase-9 transcription in U937 cells. Acta pharmacologica Sinica 24: 1167–1171. Lin, C.M., Singh, S.B., Chu, P.S., Dempcy, R.O., Schmidt, J.M., Pettit, G.R. and Hamel, E. 1988. Interactions of tubulin with potent and synthetic analogs of the antimitotic agent combretastatin: a structure-activity study. Mol Pharmacol. 34: 200–208. Lim, Y.C., Lee, S.H., Song, M.H., Yamaguchi, K., Yoon, J.H., Choi, E.C. and Baek, S.J. 2006. Growth inhibition and apoptosis by (-)-epicatechin gallate are mediated by cyclin D1 suppression in head and neck squamous carcinoma cells. Eur. J. Cancer 42: 3260–3266. Lin, Y.G., Kunnumakkara, A.B., Nair, A., Merritt, W.M., Han, L.Y., Armaiz-Pena,, G.N., Kamat, A.A., Spannuth, W.A., Gershenson, D.M., Lutgendorf, S.K., Aggarwal, B.B. and Sood, A.K. 2007. Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway. Clin Cancer Res. 13: 3423-3430. Liu, T.G., Huang, Y., Cui, D.D., Huang, X.B., Mao, S.H., Ji, L.L., Song, H.B. and Yi, C. 2009. Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice. BMC Cancer 9: 250. Liu, C.X. and Xiao P.G. 1992. Recent advances on ginseng research in China. J. Ethnopharmacol. 36: 27–38. Liu, J.J., Huang, T.S., Cheng, W.F. and Lu, F.J. 2003. Baicalein and baicalin are potent inhibitors of angiogenesis: Inhibition of endothelial cell proliferation, migration and differentiation. Int. J. Cancer 106(4): 559–565. Liu, X.P., Zhou, S.T., Li, X.Y., Chen, X.C., Zhao, X., Qian, Z.Y., Zhou, L.N., Li, Z.Y., Wang, Y.M., Zhong, Q., Yi, T., Li, Z.Y., He, X. and Wei, Y.Q. 2010. Anti-tumor activity of N-trimethyl chitosan-encapsulated camptothecin in a mouse melanoma model. J. Exp. Clin. Cancer Res. 29: 76. Lopes, F.C., Rocha, A., Pirraco, A., Regasini, L.O., Silva, D.H., Bolzani, V.S., Azevedo, I., Carlos, I.Z. and Soares, R. 2009. Anti-angiogenic effects of pterogynidine alkaloid isolated from Alchornea glandulosa. BMC Complement Altern Med. 9: 15. Lu, J., Zhang, K., Nam, S., Anderson, R.A., Jove, R., and Wen, W. 2010. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling. Carcinogenesis. 31(3): 481–488. Lu, M.K., Chen, P.H., Shih, Y.W., Chang, Y.T., Huang, E.T., Liu, C.R. and Chen, P.S. 2010. Alpha-Chaconine inhibits angiogenesis in vitro by reducing matrix metalloproteinase-2. Biol. Pharm. Bull. 33(4): 622–630. Marshall, J.M. 1990. Aloe vera gel: what is the evidence? Pharm. J. 24: 360–362. Maenthaisong, R., Chaiyakunaprukm, N., Niruntraporn, S. and Kongkaew, C. 2007. The efficacy of aloe vera used for burn wound healing: a systematic review. Burns. 33(6): 713–718. Melo-Reis, P.R., Andrade, L.S., Silva, C.B., Araújo, L.M., Pereira, M.S., Mrue, F.and Chen-Chen, L. 2010. Angiogenic activity of Synadenium umbellatum Pax latex. Braz. J. Biol. 70(1): 189–194.


154


Miltyk, W., Craciunescu, C.N., Fischer, L., Jeffcoat, R.A., Koch, M.A., Lopaczynski, W., Mahoney, C., Jeffcoat, R.A., Crowell, J., Paglieri, J.and Zeisel, S.H. 2003. Lack of significant genotoxicity of purified soy isoflavones (genistein, daidzein, and glycitein) in 20 patients with prostate cancer. Am. J. Clin. Nutr. 77(4): 875–882. Mohan, R., Sivak, J., Ashton, P., Russo, L.A., Pham, B.Q., Kasaharam, N., Raizmanm, M.B., and Fini, M.E. 2000. Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B. J Biol Chem. 275: 10405–10412. Moon, E.J., Lee, Y.M., Lee, O.H., Lee, M.J., Lee, S.K., Chung, M.H., Park, Y.I., Sung, C.K., Choi, J.S. and Kim, K.W. 1999. A novel angiogenic factor derived from Aloe vera gel: beta-sitosterol, a plant sterol. Angiogenesis 3(2): 117–123. Nakazato, T., Ito, K., Ikeda, Y. and Kizaki, M. 2005. Green tea component, catechin, induces apoptosis of human malignant B cells via production of reactive oxygen species. Clin. Cancer Res. 11: 6040–6049. Ng, Q.S., Goh, V., Carnell, D., Meer, K., Padhani, A.R., Saunders, M.I. and Hoskin, P.J. 2007. Tumor antivascular effects of radiotherapy combined with combretastatin a4 phosphate in human non-small-cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 67(5): 1375–1380. O’Leary, J.J., Shapiro, R.L., Ren, C.J., Chuang, N., Cohen, H.W. and Potmesil, M. 1999. Antiangiogenic effects of camptothecin analogues 9-amino-20(S)camptothecin, topotecan, and CPT-11 studied in the mouse cornea model. Clin. Cancer Res. 5(1): 181–187. Ozay, Y., Ozyurt, S., Guzel, S., Cimbiz, A., Olgun, E.G. and Cayci, M.K. 2010. Effects of Equisetum arvense ointment on dermal wound healing in rats. Wounds. 22(10): 261–267. Parente, L.M., Andrade, M.A., Brito, L.A., Moura, V.M., Miguel, M.P., Lino-Júnior Rde, S., Tresvenzol, L.F., Paula, J.R. and Paulo, N.M. 2011. Angiogenic activity of Calendula officinalis flowers L. in rats. Acta Cir. Bras. 26(1): 19–24. Perry, M.C., Demeule, M., Régina, A., Moumdjian, R. and Béliveau, R. 2010. Curcumin inhibits tumor growth and angiogenesis in glioblastoma xenografts. Mol. Nutr. Food Res. 54(8): 1192–1201. Pettit, G.R., Singh, S.B., Hamel, E., Lin, C.M., Alberts, D.S. and Garcia-Kendall, D. 1989. Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. Experientia 45: 209–211. Ray, S., Chattopadhyay, N., Mitra, A., Siddiqi, M. and Chatterjee, A. 2003. Curcumin exhibits antimetastatic properties by modulating integrin receptors, collagenase activity and expression of Nm23 and E-cadherin. J Environ Pathol Toxicol Oncol. 22: 49–58. Reynolds, T. and Dweck, A.C. 1999. Aloe vera leaf gel: a review update. J Ethnopharmacol. 68: 3–37. Rustin, G.J., Galbraith, S.M., Anderson, H., Stratford, M., Folkes, L.K., Sena, L., Gumbrell, L. and Price, P.M. 2003. Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results. J. Clin. Oncol. 21: 2815– 2822.



155

Rustin, G.J., Shreeves, G., Natha.n, P.D., Gaya, A., Ganesan, T.S., Wang, D., Boxall, J., Poupard, L., Chaplin, D.J., Stratford, M.R., Balkissoon, J. and Zweifel, M. 2010. A Phase Ib trial of combretastatin A-4 phosphate (CA4P) in combination with carboplatin or paclitaxel chemotherapy in patients with advanced cancer. Br. J. Cancer 102(9): 1355–1360. Sandur, S.K., Ichikawa, H., Pandey, M.K., Kunnumakkara, A.B., Sung, B., Sethi, G. and Aggarwal, B.B. 2007. Role of pro-oxidants and antioxidants in the antiinflammatory and apoptotic effects of curcumin (diferuloylmethane). Free Radic. Biol. Med. 43: 568–580. Sartippour, M.R., Shao, Z.M., Heber, D., Ma, J., Lu, Q, Go, V.L. and Nguyen, M. 2002. Green tea inhibits vascular endothelial growth factor (VEGF) induction in human breast cancer cells. J. Nutr. 132: 2307–2311. Sato, Y., Kamiyama, H., Usui, T., Saito, T., Osada, H., Kuwahara, S. and Kiyota, H. 2008 . Synthesis and anti-angiogenic activity of cortistatin analogs. Biosci Biotechnol Biochem. 72(11): 2992–2997. Saville, M., Lietzau, J., Pluda, J., Feuerstein, I., Odom, J., Wilson, W., Humphrey, R., Feigal, E., Steinberg, S., and Broder, S. 1995. Treatment of HIV-associated Kaposi’s sarcoma with paclitaxel. Lancet. 346: 26–28. Schimming, R., Hunter, N.R., Mason, K.A. and Milas, L. 1999. Inhibition of tumor neo-angiogenesis and induction of apoptosis as properties of docetaxel (taxotere). Mund Kiefer Gesichtschir. 3(4): 210–212. Schoene, N.W., Kelly, M.A., Polansky, M.M. and Anderson, R.A. 2005. Water-soluble polymeric polyphenols from cinnamon inhibit proliferation and alter cell cycle distribution patterns of hematologic tumor cell lines. Cancer Lett. 230(1): 134– 140. Shankar, S., Ganapathy, S., Chen, Q. and Srivastava, R.K. 2008. Curcumin sensitizes TRAIL resistant xenografts: molecular mechanisms of apoptosis, metastasis and angiogenesis. Mol. Cancer 7: 16. Sheeja, K., Guruvayoorappan, C. and Kuttan, G. 2007. Antiangiogenic activity of Andrographis paniculata extract and andrographolide. Int. Immunopharmacol. 7(2): 211–221. Shukla, A., Rasik, A.M., Jain, G.K., Shankar, R., Kulshrestha, D.K., and Dhawan, B.N. 1999. In vitro and in vivo wound healing activity of asiaticoside isolated from Centella asiatica. J. Ethnopharmacol. 65(1): 1–11. Siddiqui, I.A., Malik, A., Adhami, V.M., Asim, M., Hafeez, B.B., Sarfaraz, S. and Mukhtar, H. 2008. Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis. Oncogene 27(14): 2055–2063. Singh, A.K., Sharma, A., Warren, J., Madhavan, S., Steele, K., RajeshKumar, N.V., Thangapazham, R.L., Sharma, S.C., Kulshreshtha, D.K., Gaddipati, J. and Maheshwari, R.K. 2007. Picroliv accelerates epithelialization and angiogenesis in rat wounds. Planta Med. 73(3): 251–256. Singh, S.V., Hu, X., Srivastava, S.K., Singh, M., Xia, H., Orchard, J.L. and Zaren, H.A. 1998. Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin. Carcinogenesis. 19: 1357–1360.


156


Song, Z.H., Ji, Z.N., Lo, C.K., Dong, T.T., Zhao, K.J., Li, O.T., Haines, C.J., Kung, S.D. and Tsim, KW. 2004. Chemical and biological assessment of a traditional Chinese herbal decoction prepared from Radix astragali and Radix Angelicae sinensis: orthogonal array design to optimize the extraction of chemical constituents. Planta Med. 70: 1222–1227. Stevenson, J.P., Rosen, M., Sun, W., Gallagher, M., Haller, D.G., Vaughn, D., Giantonio, B., Zimmer, R., Petros, W.P., Stratford, M., Chaplin, D., Young, S.L., Schnall, M. and O’Dwyer, P.J. 2003. Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow. J. Clin. Oncol. 21: 4428–4438. Sukhthankar, M., Yamaguchi, K., Lee, S.H., McEntee, M.F., Eling, T.E., Hara, Y. and Baek, S.J. 2008. A green tea component suppresses posttranslational expression of basic fibroblast growth factor in colorectal cancer. Gastroenterology 134(7): 1972–1980. Sun, C.L., Yuan, J.M., Koh, W.P. and Yu, M.C. 2006. Green tea, black tea and colorectal cancer risk: a meta-analysis of epidemiologic studies. Carcinogenesis. 27(7): 1301–1309. Sun, F.X., Tohgo, A., Bouvet, M., Yagi, S., Nassirpour, R., Moossa, A.R. and Hoffman, R.M. 2003. Efficacy of Camptothecin Analog DX-8951f (Exatecan Mesylate) on Human Pancreatic Cancer in an Orthotopic Metastatic Model. Cancer Res. 63: 80–85. Tao, X. and Lipsky, P.E. 2000. The Chinese anti-inûammatory and immunosuppressive herbal remedy Tripterygium. Rheum Dis. Clin. North Am. 26: 29–50. Uchiyama, T., Toda, K. and Takahashi, S. 2010. Resveratrol inhibits angiogenic response of cultured endothelial F-2 cells to vascular endothelial growth factor, but not to basic fibroblast growth factor. Biol. Pharm. Bull. 33(7): 1095–1100. Van Hattum, A.H., Pinedo, H.M., Schluper, H.M., Erkelens, C.A., Tohgo, A. and Boven, E. 2002. The activity profile of the hexacyclic camptothecin derivative DX-8951f in experimental human colon cancer and ovarian cancer. Biochem Pharmacol. 64: 1267–1277. Vincent, L., Kermani, P., Young, L.M., Cheng, J., Zhang, F., Shido, K., Lam, G., Bompais-Vincent, H., Zhu, Z., Hicklin, D.J., Bohlen, P., Chaplin, D.J., May, C. and Rafii, S. 2005. Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelialcadherin signaling. J. Clin. Invest. 115: 2992–3006. Wang, L.M., Li, Q.Y., Zu, Y.G., Fu, Y.J., Chen, L.Y., Lv, H.Y., Yao, L.P. and Jiang, S.G. 2008. Antiproliferative and pro-apoptotic effect of CPT13, a novel camptothecin analog, on human colon cancer HCT8 cell line. Chem-Biol Interact. 176: 165–172. Xiao, D. and Singh, S.V. 2008. z-Guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, inhibits angiogenesis in vitro and in vivo. Mol. Cancer Ther. 7(1): 171–180. Xu, T.M., Xin, Y., Cui, M.H., Jiang, X. and Gu, L.P. 2007. Inhibitory effect of ginsenoside Rg3 combined with cyclophosphamide on growth and angiogenesis of ovarian cancer. Chin Med J. 120(7): 584–588.



157

Yang, S.H., Lin, J.K., Chen, W.S. and Chiu, J.H. 2003. Anti-angiogenic effect of silymarin on colon cancer LoVo cell line. J. Surg. Res. 113(1): 133–138. Yang, H., Chen, D., Cui, Q.C., Yuan, X. and Dou, Q.P. 2006. Celastrol, a triterpene extracted from the Chinese “Thunder of God Vine,” is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res. 66(9): 4758–4765. Yao, R.Q., Zhang, L., Wang, W. and Li, L. 2009. Cornel iridoid glycoside promotes neurogenesis and angiogenesis and improves neurological function after focal cerebral ischemia in rats. Brain Res. Bull. 79(1): 69–76. Yodkeeree, S., Ampasavate, C., Sung, B., Aggarwal, B.B. and Limtrakul, P. 2010. Demethoxycurcumin suppresses migration and invasion of MDA-MB-231 human breast cancer cell line. Eur. J. Pharmacol. 627: 8–15. You, Y.J., Lee, I.S., Kim, Y., Bae, K.H. and Ahn, B.Z. 2002. Antiangiogenic activity of Bupleurum longiradiatum on human umbilical venous endothelial cells. Arch. Pharm. Res. 25(5): 640–642. Yoysungnoen, P., Wirachwong, P., Bhattarakosol, P., Niimi, H. and Patumraj, S. 2006. Effects of curcumin on tumor angiogenesis and biomarkers, COX-2 and VEGF, in hepatocellular carcinoma cell-implanted nude mice. Clin Hemorheol Microcirc. 34: 109–115. Yoysungnoen, P., Wirachwong, P., Changtam, C., Suksamrarn, A. and Patumraj, S. 2008. Anti-cancer and anti-angiogenic effects of curcumin and tetrahydrocurcumin on implanted hepatocellular carcinoma in nude mice. World J Gastroenterol. 14(13): 2003-2009. Yue, P.Y., Wong, D.Y., Wu, P.K., Leung, P.Y., Mak, N.K., Yeung H.W., Liu, L., Cai, Z., JIang, Z.H., Fan, T.P. and Wong, R.N. 2006. The angiosuppressive effects of 20(R)- ginsenoside Rg3. Biochem Pharmacol. 72: 437–445. Zhu, W., Ou, Y., Li, Y., Xiao, R., Shu, M., Zhou, Y., Xie, J., He, S., Qiu, P. and Yan, G. 2009 .A small-molecule triptolide suppresses angiogenesis and invasion of human anaplastic thyroid carcinoma cells via down-regulation of the nuclear factor-kappa B pathway. Mol. Pharmacol. 75(4): 812–819. Zweifel, M., Jayson, G.C., Reed, N.S., Osborne, R., Hassan, B., Ledermann, J., Shreeves, G., Poupard, L., Lu, S.P., Balkissoon, J., Chaplin, D.J. and Rustin, G.J. 2011. Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer. Ann Oncol. [Epub ahead of print.
