Topical Review Article

Journal of Evidence-Based
Complementary & Alternative Medicine
Cancer Phytotherapy: 2017, Vol. 22(2) 299-309
ª The Author(s) 2016

Recent Views on the Role of Reprints and permission:

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DOI: 10.1177/2156587215625157
Antioxidant and Angiogenesis Activities journals.sagepub.com/home/cam

Mahmood Bahmani, PhD1, Hedayatollah Shirzad, PhD2,

Najmeh Shahinfard, MSc3, Laaleh Sheivandi, MSc2,
and Mahmoud Rafieian-Kopaei, PhD2

Abstract
Nowadays, increases in resistance of tumors to the current therapeutic agents have become a problematic issue. Therefore,
efforts to discover new anticancer compounds with high sensitivity of cancer cells are extending. Animal and laboratory
researches have shown that exogenous antioxidants are able to help prevent the free radical damage associated with the
development of cancer. However, researches in human beings have not demonstrated convincingly that taking antioxidants can
reduce the risk of developing cancer. Angiogenesis is also a natural condition that controls the formation of new blood vessels
from the available vessels. Today, it is believed that most of the cancers have angiogenesis potential and their growth, metastasis,
and invasion depend on angiogenesis. Several compounds with plant origin and with anti-angiogenic properties have been
identified. The aim of this study is to review recently published articles about anticancer drugs obtained from plants with anti-
oxidant and anti-angiogenesis properties.

Keywords
angiogenesis, antioxidants, cancer, medicinal plants, tumor

Received August 19, 2015. Received revised November 29, 2015. Accepted for publication December 8, 2015.

Plants are considered as important resources for researchers to in different countries have suggested that the prevalence of can-
prove and develop new drugs. Generally, using plants in the cer is less in people who eat higher amounts of fruits or vegeta-
treatment of cancer has a long history and thus plants have been bles that have antioxidant activity.9,10
primary resources for producing traditional drugs effective in There are more than 25 000 phytochemicals in different
the treatment of cancer.1 plants that often have biological effects.11 Diets rich in herbal
After identifying new proteins that had important regulatory resources provide necessary essential vitamins and minerals to
effects on the development of the tumors cell cycle, research in iso- the body. The ability of the molecules present in medicinal
lating molecules from plants and other natural organisms approved plants to bond therapeutic sites holds promise for achievement
that plants are important resources for synthesis inhibitors that have of natural products and compounds from plants that are effec-
potential to develop production of anticancer drugs.2 tive on cancer with low toxicity on healthy tissues.12
Moreover, researchers have reported a large number of plant Angiogenesis is also a natural condition that controls the for-
species that have been used in the treatment of cancer since mation of new blood vessels from the available vessels and has a
ancient times, and today, the tendency toward the use and eva-
luation of therapeutic effects of plants and their compounds as
potential anticancer drugs are increasing. So at the present time, 1
more than half of the used anticancer drugs are derived from nat- Razi Herbal Medicines Research Center, Lorestan University of Medical
Sciences, Khorramabad, Iran
ural resources like plants, microorganisms, and sea creatures.3 2
Medical Plants Research Center, Shahrekord University of Medical Sciences,
The mechanisms by which these drugs act on cancer cells are Shahrekord, Iran
3
mostly unclear. However, the role of oxidative stress in the Virtual School, Department of E-Learning in Medical Education, Tehran
induction of cancer and antioxidants in the prevention and treat- University of Medical Sciences, Tehran, Iran
ment of cancer is obvious, and most plants are good sources of
Corresponding Author:
antioxidants.4-8 Numerous studies have suggested that most can- Mahmoud Rafieian-Kopaei, PhD, Medical Plants Research Center, Shahrekord
cers are diet related. Furthermore, the risks of most kinds of can- University of Medical Sciences, Shahrekord 8166893669, Iran.
cers can be reduced by dietary changes. In this regard, the studies Email: [email protected]
300 Journal of Evidence-Based Complementary & Alternative Medicine 22(2)

crucial role in cancer development. This process, unlike cancer, supplementation for cancer prevention are inadequate to be
is the basis of several physiologic processes like embryonic concluded. The results of these trials are summarized below.
development, reproduction cycle, and wound healing.13 The first trial was a large-scale randomized trial investigat-
In fact, it is believed that most of the cancers have angiogen- ing the effect of antioxidants on cancer risk of healthy Chinese
esis potential and their growth, metastasis, and invasion depend people at increased risk of developing gastric and esophageal
on angiogenesis. Furthermore, the agents with anti-angiogenesis cancers. The participants were randomly assigned to take a
activities have the potential to control cancer development.14 combination of 50 mg selenium, 15 mg b-carotene, and
In this study, we aim to review present data on recently pub- 30 mg a-tocopherol per day for 5 years or no supplement. The
lished articles about the role of natural antioxidants and anti- results of the study demonstrated that the risk of developing
angiogenesis agents on cancer development. gastric cancer and/or esophageal cancer was not affected by
antioxidant supplementation. However, people who took anti-
oxidants had lower rates of death due to gastric cancer, but not
The Role of Plant Antioxidants on Cancer due to esophageal cancer.39 In this study, 10 years after antiox-
Free radicals, and in particular reactive oxygen species, are idant supplementation ended, reduced risk of gastric cancer
formed naturally in the body when an atom or a molecule either death was no longer found for those who took antioxidants,
loses or gains an electron. Free radicals play an important role in comparison to those who did not.40
in many normal cellular processes.15 However, at high concen- In a second trial, which was conducted in Finland, 5 to
trations, they can damage all major components of cells, 8 years of consumption of a-tocopherol and/or b-carotene
including proteins, DNA, and cell membranes. These damages could reduce the incidence of different cancers in middle-
to cells, especially damage to DNA, play a crucial role in the aged male smokers. The initial results of the study showed
development of cancer.16 Moreover, some environmental tox- an increase in the incidence of lung cancer in the participants
ins, such as cigarette smoke, may contain larger amounts of who took 20 mg per day b-carotene supplementation.41 There
free radicals or stimulate the body’s cells to produce more free were no effects of a-tocopherol or b-carotene supplementa-
radicals.16 Free radicals, other than cancer, are involved in a tion on the incidence of renal pelvis, bladder, ureter, pan-
wide variety of disorders, especially in degenerative diseases creas, colorectal, kidney, pharyngeal, laryngeal, or esophageal
such as neurological disorders,4,17 chronic inflammation, cancers.42
and the generation of damage, particularly during ischemia/ In a trial in the United States, daily supplementation with
reperfusion, diabetes,18,19 atherosclerosis,20,21 cardiovascular b-carotene and vitamin A on people who were at high risk of
diseases,22,23 and wound complications.24,25 These conditions lung cancer due to having a history of smoking or exposure
involve many changes, including alterations in the redox to asbestos showed that daily supplementation with both
state.26,27 Antioxidants, especially medicinal plants with 25 000 IU retinol and 15 mg b-carotene was associated with
antioxidant activity, have the ability to counteract these condi- increased lung cancer and increased death from all-cause mor-
tions.28,29 Various clinical and experimental studies have tality.43 A later report in 2004 showed that the adverse effects
demonstrated promising results for various conditions, espe- persisted up to 6 years after the consumption of these supple-
cially for the treatment and prevention of life-threatening dis- ments ended. However, the enhanced risks of all-cause mortal-
eases.30-33 These agents are also effective in inhibition of ity and lung cancer were no longer statistically significant.44
toxic agents induced complications.8,34 In another study in 1996, 50 mg b-carotene administration
The body makes some of the antioxidants that are called every other day for 12 years had no effect on cancer mortality,
endogenous antioxidants. However, the body relies on exogen- cancer incidence, and all-cause mortality among US male
ous sources of antioxidants for the rest of the antioxidants it subjects.45
needs.35 A lot of medicinal plants have antioxidant activ- Every other day administration of 50 mg b-carotene, 600 IU
ity24,32,33,36 and have shown promising results in cancer therapy. vitamin E, and 100 mg aspirin has also had no benefit or the
Here we try to present the role of plants having antioxidant activ- incidence of cancer and cardiovascular diseases in US women
ity in cancer therapy. of over 45 years.46 In 2005, similar results were published for
In laboratory and preclinical studies in cancer prevention37 vitamin E consumption.47
or immune system stimulation,38 promising results have been In a trial published in 2004, daily supplementation with 100
achieved. However, whether or not taking dietary antioxidants mg selenium, 20 mg zinc, 6 mg b-carotene, 30 mg vitamin E,
can prevent or reduce the risk of developing cancer in humans and 120 mg vitamin C, for a median of 7.5 years, had no effect
is not clear. The cohort and case-control studies that have on the incidence of cardiovascular or cancer diseases or all-
investigated the use of dietary antioxidants in the risk of cancer cause mortality.48
in humans have achieved mixed results. Due to inadequate In an international trial reported in 2005, no effect of daily
control for biases that might influence the results, observa- supplementation with 400 IU a-tocopherol, which was admi-
tional studies must be viewed with caution. Randomized con- nistered for 7 years was seen in the incidence of major cardio-
trolled clinical trials are considered to provide more reliable vascular events—such as stroke, heart attack or death from
evidence of the harm or benefit of a health-related interven- heart disease, cancer incidence or death from cancer in people
tion. However, the randomized controlled trials of antioxidant diagnosed with cardiovascular disease or diabetes.49
Bahmani et al 301

The next trial was conducted in the United States, began in matrix and basal lamina and as a result strong connections
2001 and was stopped in 2008. The trial investigated whether between endothelial cells are disjointed. When this process is
daily supplementation with 200 mg selenium, 400 IU vitamin continued, endothelial cells can be created and as a result immi-
E, or both would reduce the incidence of prostate cancer in gration and reproduction are organized for forming new capil-
men over 50 years. The results showed that the use of these sup- lary tubes. In many crucial states of diseases, the control of
plements for a period of about 5.5 years did not affect the inci- angiogenesis is disturbed. When the cells of patients unnatu-
dence of prostate or other cancers.4 Updated findings, reported rally produce large amounts of angiogenesis factors like
in 2011, demonstrated that, following 1.5 years of supplements, endothelial cell growth factor (VEGF), fibroblastic growth
the cases of prostate cancer among men taking vitamin E alone factor (FGF-2), and hepatocyte growth factor, these factors
were 17% more compared to the placebo group.50 No increase overpass effects of the natural inhibitors like angiostatin, endo-
in prostate risk was observed for men assigned to take vitamin statin, and thrombospondin and thus excessive angiogenesis
E plus selenium or selenium alone compared with men occurs.
assigned to take a placebo.49 Generally, there are more than 70 other diseases like obe-
In a trial that was conducted in 2009, the use of 500 mg vita- sity, rheumatoid arthritis, and asthma that are related to the
min C, 400 IU vitamin E, or a combination of the two, every unnatural angiogenesis.55 Today, it is believed that most of the
other day for a median of 7.6 years, did not reduce the inci- cancers have angiogenesis potential and their growth, metasta-
dence of prostate cancer or other cancers, including leukemia, sis, and invasion depend on angiogenesis.14
melanoma, lymphoma, and cancers of the bladder, pancreas, One of the first identified and isolated anti-angiogenic
lung, colon, and rectum.52 agents was a natural compound, namely, Fumagillin, which
The aforementioned randomized controlled clinical trials is an antibiotic secreted from the Aspergillus fumigatus fungi.33
did not show that dietary antioxidant supplements are bene- Gradually, other different compounds with plant origin and
ficial in primary cancer prevention. However, it is possible with anti-angiogenic properties were identified and even effec-
that the lack of benefit in clinical studies can be related to tive compounds of some of them were isolated. Now, different
the effects of the tested antioxidants. They all were con- research models are used to screen plants that have anti-
sumed as purified chemicals and they might be opposed angiogenic activities.56 Results of studies show that foods,
when they are consumed in foods, which contain complex especially those with plant origin, have the potential to prevent
mixtures of minerals, vitamins, and various antioxidants. one third of cancers.14 So consumption of a plant diet might
This acquire a more complete understanding of the antioxi- prevent development and improvement of chronic diseases
dant content of individual foods, how the various antioxi- like malignant tumors whose development is associated with
dants interact with each other, and the factors that influence angiogenesis.57 However, it has been suggested that single
the uptake and distribution of food-derived antioxidants in the anti-angiogenic factors have limited efficacy. Useful natural
body. These are all active areas of ongoing cancer prevention products contain a range of complex organic chemicals that
research. may have synergic activity. Possibly, other than interacting
Another question that might be raised is that whether with multiple angiogenesis pathways, they also act on other
or not people already diagnosed with cancer should take pathways like cell signaling and the apoptosis pathways or
antioxidant supplements? A randomized controlled trial influence collision between cancer cells and immunity system
reported that antioxidant supplements during cancer treat- and so inhibit angiogenesis.58
ment might alter the effectiveness or reduce the toxicity Some of the anti-angiogenic factors also have anticoagulant
of specific therapies.53 Other trials have reported mixed activity that may decrease metastasis of tumor cells.59 In addi-
results; some of them found that people who took antioxi- tion, other anti-angiogenic compounds have been identified
dants during cancer therapy had worse outcomes, especially and isolated during the past years by conducting extensive
if they were smokers. researches. Examples are isolation of the inhibitory compound,
Additional large randomized controlled studies are neces- camptothecin from Camptotheca acuminate in 1966, identifi-
sary to provide clear evidence about the benefits or harms of cation and isolation of the angiogenesis-inhibiting compound
taking antioxidant supplements during cancer treatment. The taxol from Taxus baccata plant in 1971, isolation of combretas-
role of natural compounds with angiogenesis inhibitory activity tin from Combretum caffrum in 1987, and other studies in the
in cancer therapy. field of identification of anti-angiogenic properties of different
Angiogenesis is a natural condition that controls the plants and their effective compounds.
formation of new blood vessels from the available vessels. It should be noted that different plants contain very active
This process is the basis of several physiologic processes compounds that some of them have properties effective on
like embryonic development, reproduction cycle, and wound angiogenesis. In fact, plants are complex chemical cocktails
healing.13,54 with different properties. It means that not just one mechanism
In the natural formation of the new blood vessels, which is a of a plant acts on cancer in angiogenesis but may include sev-
completely controlled process, endothelial cells receive stimu- eral mechanisms.
lator massage and secret special enzymes like matrix metallo- Some of reliable anticancer drugs obtained from plants with
proteinase and heparin that cause digestion of the extracellular anti-angiogenic properties are introduced below.
302 Journal of Evidence-Based Complementary & Alternative Medicine 22(2)

Taxol pathway of E-cadherin/b-catenin/Akt that leads to the rapid

collapse of vessels and necrosis. This compound has a synergis-
Researchers identified an extract made from the bark of the
tic effect with monoclonal anti–VE-cadherin antibody (when
Pacific yew tree with the scientific name Taxus brevifolia in
this antibody is administered in low doses), which stops aggre-
1962 that has anticancer properties. The active compound in
gation of new vessels and so inhibits tumor growth. These find-
this extract was then identified in 1971and named taxol, which
ings show that CA4P selectively induces regression of unstable
is a complex diterpene (Figure 1).46 Thereafter, taxol was pro-
tumor neovessels and through disruption in the mentioned sig-
duced synthetically and used.
naling pathway.44,61
Taxol combats cancer cells that are multiplying by disrupt-
Some other natural compounds derived from plants with
ing their microtubule skeleton. Results of studies done by
anti-angiogenic activity are presented in Table 1.11
researchers have shown that taxol at low picomolar concentra-
Some other plants and their derivatives that specifically
tions inhibits angiogenesis by inhibiting VEGF production and
inhibit the vessels’ endothelia growth factor (VEGF) and have
controlling the protein expression of the hypoxia-inducible fac-
antiangiogenic activity include the following: Artemisia
tors. With regard to anti-angiogenic properties represented by
annua or Chinese wormwood (containing 95% artemisinin),
taxol, its antitumor properties are further confirmed. It has been
Vsicum album or European mistletoe (containing mistletoe
many years since the clinical application of taxol in the treat-
lectin III (ML3A), Curcuma longa or turmeric (containing
ment of cancer has been approved and it is yet used.59
95% curcumin), Camellia sinensis or green tea (containing
95% phenols; 50% epigallocatechin), Vitis vinifera or grape
Camptothecin seed extract (containing 95% proanthocyanidins), Angelica
sinensis or Dong quai (containing 4-hydroxyderricin), Scutel-
Camptothecin was first isolated from the Camptotheca acumi- laria baicalensis or Chinese skullcap (containing 95% baica-
nate tree, a tree native to China, using the bioactivity-directed lin and flavonoids), Polygonum cuspidatum or Japanese
fractionation technique (Figure 1). Camptothecin, as an antic- knotweed (containing 20% resveratrol), Silybum marianum
ancer agent, was studied for 15 years and finally its exclusive or milk thistle (containing 80% silymarin), and magnolia seed
procedure to kill tumor cells was identified. This compound cones (containing 90% honokiol).
traps topoisomerase I-DNA complexes, inhibits DNA replica- Some plant-derived compounds such as curcumin, gingiber,
tion, and leads to killing of cancer cells. The discovery of this bromelain, epigallocatechin-3 gallate, resveratrol, proantho-
issue encouraged researchers to produce compounds similar to cyanidin, and antioxidants present in plants (vitamins A, C,
camptothecin that have solubility in water and maintain their E, selenium, zinc, carotenoids, flavonoids) have inhibitory
anticancer activity. Finally, 2 compounds similar to camptothe- activity on the cyclooxygenase enzyme in the angiogenesis
cin, namely topotecan and trinotecan, were approved by the US pathway.11
Food and Drug Administration in 1990 to be used to treat
colon, lung, and ovarian cancers.60 In 1999, it was shown that
camptothecin and topotecan inhibit the growth of the human Soybean Grains and Its Effective Compounds
endothelial cells in vitro in a nontoxic manner and this inhibi- The prevalence rate of breast and prostate cancer is very low in
tion continues up to 96 hours after the drug is stopped. They Asian countries like Japan and China compared to European
also suggested that these 2 compounds are effective in angio- countries and the United States of America. Studies show that
genesis unlike the unspecific toxic drug, cisplatin or TNP- this important difference in the prevalence rate of cancer in dif-
470, in inhibition of angiogenesis. For this reason, in addition ferent ethnic groups depends to some extent on eating habits. In
to activities like killing tumors, camptothecin possibly pos- fact, one of the main differences in nutrition of these 3 types of
sesses an indirect in vivo antitumor effect mediated through the population is that Japanese and Chinese use food in their diet
inhibition of angiogenesis.45 that usually contain plant products including soybean. More-
over, Fotsis et al51 by studying the urine of persons who have
used large amounts of plant foods observed that urine of these
Combretastatin people contain isoflavones of soya and its metabolites, spe-
Combretastatin is a microtubule-targeting agent found in the cially genistein, which inhibits proliferation of endothelial cells
bark of the African bush willow tree (Combretum caffrum), of brain capillaries. Other studies also have suggested that pure
identified in 1987 as an anticancer agent. More studies led to genistein has a strong dose-dependent inhibiting effect on the
the production of phosphate derivatives in aqueous solution proliferation of the endothelial cells. Genistein also inhibits
with more bioavailability. Vincent et al61 also suggested that proliferation of other vessels’ endothelial cells like cells
combretastatin A4 phosphate (CA4P; Figure 1) selectively tar- derived from the bovine adrenal cortex and the aorta.52
gets endothelial cells and destroys new tumor vessels in mice Isoflavonoids are present mainly in vegetables. Soybean
by disrupting the function of the junctional molecule of cad- grains and its products contain large amounts of isoflavonoids.
herin in endothelial cells. CA4P also increases permeability These observations and epidemiological and laboratory evi-
of endothelial cells and inhibits immigration and formation dence have shown that consumption of diets rich of soybean
of capillary tube mainly through disrupting the signaling products is associated with lower risk of getting cancer.
Bahmani et al 303

Figure 1. The chemical structure of factors affecting angiogenesis that have been obtained from medicinal drugs.

Flavonoids like 3,4-dihydroxyflavone, 1,3-dihydroxyflavone, have approved that genistein inhibits proliferation of VEGF-
fisetin, apigenin, and lutlin can inhibit in vitro angiogenesis induced endothelial cells and signaling molecules of tyrosine
in the micromolar concentration range.62 Studies of researchers phosphorylation in the micromolar range. Moreover, genistein
304 Journal of Evidence-Based Complementary & Alternative Medicine 22(2)

Table 1. Natural Compounds That Have Direct or Indirect Anti-Angiogenic Potential.

No. Plant Name Compound Possible Mechanism

1 Camellia sinensis (green tea) EGCG Abrogates VEGF signaling by interfering with formation of VEGF receptor-2
complex
2 Camptotheca acuminate Camptothecin Blocks topoisomerase I, inhibits EC proliferation and tube formation, decreases
HIF1a and VEGF expression
3 Combretum caffrum Combretastatin Inhibits tubulin assembly
4 Cordyceps militaris Unknown Inhibits FGF-2 expression in EC and MMP-expression in tumor cells
5 Ganoderma lucidum Polysaccharide, peptide Causes EC apoptosis by reducing Bcl-2 expression and increasing Bax
expression, decreases VEGF secretion from tumor cells
6 Glycine max (soybean) Genistein Suppresses VEGF and FGF-2 expression, inhibits receptor tyrosine kinase,
inhibits activation of NF-kB and Akt signaling pathways
7 Glycyrrhiza uralensis (liquorice) Isoliquiritin Inhibits tube formation
8 Panax ginseng Ginsenosides Rb1 Inhibits VEGF production by tumor cells
9 Sinomenium acutum Sinomenine G1-G0 arrest of ECs
10 Salvia miltiorrhiza (danshen) Cryptotanshinone G1-G0 arrest of ECs, apoptosis of ECs
11 Taxus brevifolia Taxol Disrupts microtubule cytoskeleton inhibits VEGF production, inhibits HIF-1a
protein
12 Tripterygium wilfordii Hook.f Triptolide Inhibits VEGF expression and secretion from ECs, inhibits COX-1, COX2, and
5-lipoxygenase, decreases transcription of the gene encoding inducible nitric
oxides synthase
13 Vinca rosea Vincristine Disrupts microtubule cytoskeleton, inhibits VEGF production
14 Vitis spp (grape) Resveratrol Disrupts Src-dependent VE cadherin tyrosine phosphorylation

inhibits effectively the mast cell chemotaxis as facilitator of angiogenesis when it is administered orally without important
new vessels’ formation in response to some incentive factors side effects. This compound, as one of the most promising
of angiogenesis. This compound can inhibit angiogenesis chemical factors that inhibits cancer, has attracted excessive
through different methods like adjusting the activity of proteo- attention in recent years. For this reason, there is possibility
lytic enzymes.62 Moreover, genistein suppress expression of to discover and identify more polyphenols in natural products
VEGF and FGF-2 and inhibits phosphorylation of the receptor as compounds that lead to discovery of more strong synthetic
tyrosine kinase and activation of Akt. The mentioned com- inhibitors of angiogenesis. Resveratrol may treat heart muscle
pound prevents activation of NF-kB that leads to apoptosis damage through inducing angiogenesis by VEGF and the
even in cancer cells resistant to apoptosis. receptor tyrosine kinase FLK-1 (angiogenesis induction). How-
Genistein as a phytostrogen also targets estrogen and andro- ever, recent inconsistent findings should be evaluated.65
gen signaling pathways in carcinogenesis and has antioxidant
properties. Generally, in vivo and in vitro studies have shown Allium hirtifolium
that this isoflavone is a promising factor to treat or inhibit can-
cer. This peptide is called Kunitz trypsin inhibitor and its anti- This plant is one of the important species in Allium genus that
angiogenic property has been approved.63 has been used in many countries including Iran as condiment
since the ancient times and has been used also in the traditional
treatment of cancer. This plant has known properties like effect
Green Tea on hematologic indices, antioxidant potential, and antifungal
Green tea, especially one of its compounds named epigalloca- and antibacterial properties. Moreover, the study of its chemi-
techin gallate (EGCG; Figure 1), inhibits angiogenesis signifi- cal components shows that it has many compounds like organo-
cantly. EGCG inhibits production of cytokine-induced IL-8, soulfurs and polyphenols that are very similar to compounds
inhibits AKt activation (induced by VEGF), and also prevents available in other species in the same family. Aqueous extract
phosphorylation of V-E cadherin in physiologic concentra- of Allium hirtifolium has a dose-dependent inhibitory effect on
tions. Findings also show that drinking green tea can be effec- the angiogenesis.66
tive in inhibiting and treatment of angiogenesis-dependent
diseases like cancer and diabetic retinopathy.64 Artemisia annua (Chinese Wormwood)
One of the compounds extracted from the Artemisia annua
Red Grape plant is the active compound of artemisin that has anti-
Red grape is a delicious fruit that contains a compound named angiogenic effects. This compound has been used in traditional
resveratrol (Figure 1). This compound can be found in peanut, medicine as an antimalarial medication. Recently, researchers
morus, and some other medicinal plants like Polygonum cuspi- have shown that this compound applies the toxic effect on
datum. Studies have suggested that this compound inhibits cancer cells via induction of apoptosis. Artesunate also is a
Bahmani et al 305

semisynthetic derivative of artemisinin that has anti-angiogenic shown that honokiol inhibits proliferation of blood vessels’
activity in a dose-dependent manner. Moreover, the in vivo endothelial cells and so decreases tumor growth.71
anti-angiogenic effect of artemisinin using transplantation of
cancer cells of human ovary in nude mice has been evaluated Silybum marianum (Milk Thistle)
and approved.67
Silymarin and silibinin are polyphenolic flavonoids isolated
from fruits and seeds of Silybum marianum. Results obtained
Viscum album (European Mistletoe) from studies of researchers indicate that silymarin has strong
Viscum album, also known as iscador, often is used as an antic- antitumor activity against types of tumors like ovary cancer via
ancer agent. Laboratory studies show that compounds of this decreasing expression of VEGF and EGFR.72,73
plant via VEGF expression inhibit the angiogenesis and also
induce apoptosis in cancer cells. Using extract of this plant in Ginkgo Biloba
a mouse model leads to decreased lung metastasis and increase
An extract of this plant has anticancer effect having some prop-
in survival. Also, a clinical study performed on individuals with
erties like gene regulation and anti-angiogenic activities. An
different cancers indicates increase in their survival and long-
extract of this plant contains about 25% flavonoids (ginkgo,
evity. Of course, more studies are required to specify different
flavone glycosides) and about 5% terpenoids (ginkgolides and
aspects of therapeutic effects of this plant.67
bilobalides). Its most strong flavonoid is ginkgolide B. An
extract of this plant inhibits angiogenesis via decreasing the
Curcuma longa (Curcumin) VEGF expression.74
It is a compound that interacts with cancer cells in different lev-
els. Its antimetastatic effects are applied to some extent via a Plants Rich of Quercetin
decrease in expression of the matrix metalloproteinase enzyme Quercetin is a flavonoid compound that is found in apple,
(MMP-2) and increase in expression of the tissue inhibitor of onion, red grapes, black-berry, citrus, cherry, broccoli, and also
metalloproteinase 1 (TIMP1). It should be recalled that the some of the species in the Allium family. This flavone inhibits
mentioned enzymes have an important role in regulating angio- angiogenesis through different mechanisms like interacting
genesis and tumor cell invasion. Studies have also suggested with cyclooxygenase-2 and 5-lipooxigenase, VEGFR enzymes,
that this compound inhibits transcription of angiogenesis fac- HER-2 intracellular signaling pathways, and also nuclear tran-
tors VEGF and bFGF and also decreases production of nitric scription protein NF-kB. Quercetin may enhance anticancer
oxide in endothelial cells that have an important role in the effects of tamoxifen drug via its anti- angiogenic activity.75
development of angiogenesis and tumor growth. Other activi-
ties of this compound include binding to CD13 antibody
expressed by blood vessel components and inhibiting its activ-
Poria cocos
ity, decreasing expression of VEGF and MMP-9, and inhibiting Studies have suggested that this extract inhibits placket accu-
EGF and VEGF receptors and also resisting intracellular sig- mulation and apparently it has anti-angiogenic effect via
naling pathway of tyrosine kinases.68,69 decreasing expression of the NF-kB.76

Scutellaria baicalensis (Chinese Skullcap) Panax ginseng

Baicalin and baicalein are main derivations of the Chinese Lipophilic compounds of ginseng namely saponins and ginse-
skullcap plant. These 2 compounds are strong compounds that nosids have anticancer activities including inhibiting angiogen-
decrease activity of VEGF, bFGF, 12-lipooxigenase, and also esis and inducing apoptosis in tumor cells.77
matrix metalloproteinase. This plant is one of the known
Chinese plants that have shown activity against the develop- Rabdosia rubescens Hara (Rabdosia)
ment of prostate cancer.70
Rabdosia has been used to treat cancer since ancient time. This
plant is one of the Chinese plants known as pc-spes and has
Magnolia officinalis (Chinese Magnolia Tree) activity against the prostate cancer. This plant includes 2 diter-
penoids named ponicidin and oridonin that have significant
Grains present in the fruit of Chinese magnolia contain sub-
anti-angiogenic activity.78
stances that inhibit new blood vessels formation. The active
component of this compound is honokiol. This component can
decrease angiogenesis to some extent through regulating
expression of the endothelial cell growth factor derived from
Conclusions
placket and also transforming growth factor-b. Moreover, this Nowadays, increases in resistance of tumors to the current ther-
compound inhibits nitric oxide synthesis and tumor necrosis apeutic agents have become a problematic issue. Therefore, the
factor expression. Studies using laboratory animals also have efforts of researchers to discover new anticancer compounds
306 Journal of Evidence-Based Complementary & Alternative Medicine 22(2)

with high sensitivity of cancer cells are extending. Some of learning impairment induced by bilateral electric lesions of the
cytotoxic drugs inhibit angiogenesis and have minimum toxi- nucleus Basalis of Meynert in rat. Neurochem Res. 2014;39:
city. Studies on new plants will lead to discovery of new antic- 353-360.
ancer drugs from plant sources and this success will be very 6. Hosseini-asl K, Rafieian-kopaei M. Can patients with active
important. duodenal ulcer fast Ramadan? Am J Gastroenterol. 2002;97:
Animal and laboratory researches have shown that exogen- 2471-2472.
ous antioxidants are able to help prevent the free radical dam- 7. Sedighi M, Rafieian-Kopaei M, Noori-Ahmadabadi M. Kelussia
age associated with the development of cancer. However, odoratissima Mozaffarian inhibits ileum contractions through
researches in humans have not demonstrated convincingly that voltage dependent and beta adrenergic receptors. Life Sci J.
taking antioxidants can reduce the risk of developing cancer. 2012;9:1033-1038.
Furthermore, a wide variety of medicinal plants, including 8. Heidarian E, Rafieian-Kopaei M. Protective effect of artichoke
Allium sativum, Stachys lavandulifolia, Artemisia abrotanum, (Cynara scolymus) leaf extract against lead toxicity in rat. Pharm
and Salvia officinalis have been shown to have antioxidant Biol. 2013;51:1104-1109.
activity.29,33,35,79-98 More important, it has been shown that 9. Nasri H, Rafieian-Kopaei M. Medicinal plants and antioxidants:
there is a correlation between antioxidant activity and antican- why they are not always beneficial? Iran J Public Health. 2014;
cer effects of some medicinal plants such as garlic.38 If antiox- 43:255-257.
idants are one of the main components of anticancer therapy, 10. Rafieian-Kopaei M. Medicinal plants and the human needs.
then those plants that have antioxidant activity should all have J HerbMed Plarmacol. 2012;1:1-2.
anticancer property. These may be worth examining. 11. Gordaliza M. Natural products as leads to anticancer drugs. Clin
Transl Oncol. 2007;9:767-776.
Acknowledgments 12. Nasri H, Shirzad H. Toxicity and safety of medicinal plants.
The authors would like to acknowledge the Razi Herbal Medicines J HerbMed Plarmacol. 2013;2:21-22.
Research Center, Lorestan University of Medical Sciences, Khorra- 13. Folkman J. Fundamental concepts of the angiogenic process. Curr
mabad, Iran, for supporting this study. Mol Med. 2003;3:643-651.
14. Griggs J, Metcalfe JC, Hesketh R. Targeting tumor vasculature:
Author Contributions the development of combretastatin A4. Lancet Oncol. 2001;2:
All the authors contributed equally to the writing of the first draft of 82-87.
the article. 15. Rafieian-Kopaei M, Baradaran A, Rafieian M. Oxidative stress
and the paradoxical effects of antioxidants. J Res Med Sci.
Declaration of Conflicting Interests
2013;18:629.
The authors declared no potential conflicts of interest with respect to
16. Bouayed J, Bohn T. Exogenous antioxidants—double-edged
the research, authorship, and/or publication of this article.
swords in cellular redox state: health beneficial effects at physio-
Funding logic doses versus deleterious effects at high doses. Oxid Med Cell
Longev. 2010;3:228-237.
The authors disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: This article was 17. Rafieian-Kopaei M, Heidarian E, Saghaei E, Mokhtari S. Effects
prepared with support from the Razi Herbal Medicines Research of Zizyphus jujube extract on memory and learning impairment
Center, Lorestan University of Medical Sciences, Khorramabad, Iran. induced by bilateral electric lesions of the nucleus Basalis of
Meynert in rat. Neurochem Res. 2014;39:353-360.
Ethical Approval 18. Kiani MA, Khodadad A, Mohammadi S, Mobarhan MG, Saeidi
As no human or animal subjects were involved in this study, ethical M, Jafari SA. Effect of peppermint on pediatrics’ pain under
approval is not required. endoscopic examination of the large bowel. J HerbMed Pharma-
col. 2013;2:41-44.
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