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Cancer Therapy Vol 6, page 913
Cancer Therapy Vol 6, 913-922, 2008
Folk medicines for anticancer therapy-a current
status
Review Article
G.Venkateshwar Rao1, Sateesh Kumar1,2,*, Mujahidul Islam1, Saber E Mansour1
1
2
Department of Pharmacy, Faculty of Pharmacy, Omar-El-Mukhtar University, P.B. No. 919 Al-Beida, Libya
Department of Biotechnology, SCET, P.B.No. 17, Kodakara, Thrissur, Kerala, India
__________________________________________________________________________________
*Correspondence: Sateesh Kumar, Professor, Department of Biotechnology, SCET, P.B.No. 17, Kodakara, Thrissur, Kerala, India; email: [email protected]
Key words: Cancer therapy, folk-medicines, phytochemicals, pharmacology of anticancer activity
Abbreviations: cyclin dependent kinase, (Cdk); cyclooxygenase, (COX); cytotoxic to drug sensitive, (CEM); double-strand breaks,
(DSB); extract of dandelion leaf, (DLE); extract of Strychni Semen, (ESS); extracts of dandelion flower, (DFE); extracts of dandelion
root, (DRE); growth arrest and DNA damage, (GADD);, (GADD)-inducible transcription factor 153, (GADD153); hepatocellular
carcinoma, (HCC); homologous recombination, (HR); lipoxygenase, (LOX);, (-)-epigallocatechin-3-gallate, (EGCG);, (-)epigallocatechin, (EGC);, (-)-epicatechin-3-gallate, (ECG); mitochondrial membrane potential, (MMP); multidrug-resistant leukemia,
(CEM/VLB); N-acetylcysteine, (NAC); nasopharynx, (KB); nonhomologous end-joining, (NHEJ); reactive oxygen species, (ROS);
Rhus verniciflua Stokes, (RVS); Sarcoma Black, (SBL); sensitizer enhancement ratio, (SER); squamous cell carcinoma, (SCC);
Urokinase plasminogen activator, (uPA)
Received: 30 May 2008; Revised: 25 September 2008
Accepted: 22 October 2008; electronically published: November 2008
Summary
In recent years, medicinal plants have attracted a lot of attention globally. Since long time evidence has
accumulated to demonstrate promising potential of medicinal plants used in various traditional, complementary
and alternative systems especially for cancer treatment. Several folk medicinal plants have been studied for anti
cancer pharmacological activity in recent years. To understand the mechanism of action, the researchers have
worked at molecular level and several significant phytochemicals have been isolated based on the activity analysis of
the medicinal plant extracts with different solvents. The understanding of the mechanisms that alter growth and
metabolism in cancer cells will be discussed using established folk medicines, wherever it is possible. The present
review is aimed at compiling data on promising phytochemicals from folk medicinal plants for anticancer activity
that have been tested in various disease models using modern scientific methodologies. Although it is still unclear
whether nutraceuticals play a causal or supportive role in tumourigenisis, the special metabolic demands of cancer
cells provide a unique target for therapy and to achieve it folk medicines play an active role. Not in all of the studies,
the active components are identified nor their understanding rationalised.
drug-induced toxic side effects, have now turned to seek
help from the complementary and alternative medicine
hoping for a better cure.
I. Cancer therapy-a practical dilemma
Cancer is a dreadful disease and any practical
solution in combating this disease is of paramount
importance to public health. Therefore, besides the
rationalized allopathic drugs, it is worth evaluating the
folk medicine-a plant based therapy which is not a
systematized study. An alternative solution to allopathic
medicine embodied with severe side effects, is the use of
folk medicine plant preparations to arrest the insidious
nature of the disease. Many herbs have been evaluated in
clinical studies and are currently being investigated
phytochemically to understand their anti-tumour actions
against various cancers. Thus, cancer patients who already
got crippled with this disease, who are further burdened by
II. Necessity for understanding folkmedicine
Recently, a greater emphasis has been given towards
the researches on complementary and alternative medicine
that deals with cancer management. These days it became
more than the rule for scientists in search of a particular
medicinal properties to manipulate a synthetic compound
rather than to search the folk literature or to explore
known cures among indigenous peoples for clues that
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Rao et al: Folk medicines for anticancer therapy-a current status
might lead ultimately to a more efficacious product.
Unfortunately, this approach has often served only to
delay the application of many potential remedies. For
example, it was unfortunate that the first cosmopolitan
tranquiliser, derived from Rauvolfia, did not come into
general use until 1952 despite an ancient history of its
application in Ayurvedic (Hindu) medicine in India.
Nature is still humankind’s greatest chemist, and many
compounds that remain undiscovered in plants are beyond
the imagination of even our best researchers.
Existing remedies from folk medicine should be
rigorously examined for potential relevance in the
treatment of disease, especially in societies and third world
countries where modern medicine is scarce, or expensive
to buy or unavailable for various reasons. Promotion of
folk medicine is not to advocate a return to domestic
medicine but only where shown efficacious and valid
should it be retained and where proved invalid discarded.
Indeed, traditional medicine ought to compliment rather
than substitute for modern medicine. Developing nations
need to utilize the best available from both traditional and
modern medicine if in the foreseeable future adequate
health is to be enjoyed by their people. Biomedical
researchers should be able to augment traditional herbal
medicine by their unique discoveries.
tinctures. Isolated active constituents are used for applied
research for finding their bioactivity. For the last few
decades, phytochemical examination has been making
rapid progress and herbal products are becoming popular
as sources of plausible anticancer compounds. To facilitate
the readers to look at their areas of interest, we have tried
to discuss potential anti cancer phytochemcials as drugs in
this article. In this review anti-cancer pharmacological
investigations of important phytochemicals for current
status have been discussed although not conclusively.
In vitro anti cancer studies have demonstrated that
natural products of flavonoid type like luteolin and
quercetin have the power to inhibit the proliferation of
cells in human carcinoma of larynx and sarcoma-180 cell
lines (Elangovan et al, 1994). The nitrogenous
phytochemicals,
Phenanthroindolizidine
alkaloids
pergularinine and tylophorinidine isolated from Pergularia
pallida (Roxb.) Wight & Arn. (Asclepiadaceae) inhibited
the growth of Lactobacillus leichmanni cells by binding to
thymidylate synthetase (Rao et al, 1997). Anthraquinone
natural products like rubidianin, isolated from alcoholic
extract of Rubia cordifolia (Figure 2B) has demonstrated
significant antioxidant activity. It prevented lipid
peroxidation induced by ferrous sulphate and tbutylhydroperoxide. Rubidianin has shown activity in
dose-dependent manner. The anti-oxidant activity of
rubidianin was found to be better than mannitol, vitamin-e
and p-benzoquinone standards (Tripathi et al, 1997).
Withanolides, the active phytochemical constituents
of Withania somnifera Dunal(Solanaceae) are group of
pharmacologically active compounds present in the whole
plant. The chemistry of withanolides has been studied and
they are basically steroidal lactones with salient chemical
entities. Withanolides are similar to ginsenosides (the
active constituents of Panax ginseng) in structure and
activity. They are believed to be immunomodulatorhaving
anticancer activity. Withaferin-A is best studied
withanolide (Ali and Shuaib, 1997). Withaferin- A isolated
from the roots of Withania somnifera (Figure 3A) (ashwagandha), reduced survival of V79 cells in a dosedependent manner. LD50 for survival was 16 microM.
One-hour treatment with a non-toxic dose of 2.1 microM
before irradiation significantly enhanced cell killing,
giving a sensitizer enhancement ratio (SER) of 1.5 for
37% survival and 1.4 for 10% survival. SER increased
with drug dose, but at higher doses the increased lethality
appears to be due to two effects i.e. drug toxicity and radio
sensitization. The drug induced a G2/M block, with a
maximum accumulation of cells in G2-M phase at 4 h
after treatment with 10.5 microM withaferin A in 1 h
(Devi et al, 1996). Withaferin- A showed marked tumourinhibitory activity when tested in vitro against cells
derived from human carcinoma of nasopharynx (KB). It
also acted as a mitotic poison arresting the division of
cultured human larynx carcinoma cells at metaphase and
in HeLa cultures similar to star-metaphase. It also
produced significant retardation of the growth of Ehrlich
ascites carcinoma, Sarcoma 180, Sarcoma Black (SBL),
and E 0771 mammary adenocarcinoma in mice in doses of
10, 12, 15 mg/kg body-weight. Growth of Ehrlich ascites
carcinoma was completely inhibited in more than half the
III. Known and established folk
remedies
and
anti-cancer
therapy
formulation-a Global perspective
Natural products or related substances or extracts of
folk medicine accounted for 30% of the top 35 worldwide
natural product-based drugs sold (Butler, 2004) in recent
years. The plant-derived anticancer drugs, or the plantderived cancer chemotherapeutic agents were responsible
for approximately one third of the total anticancer drug
sales worldwide, or just under $4 billion dollars in 2007;
namely, the taxanes, paclitaxel and docetaxel, and the
camptothecin derivatives, irinotecan, topotecan, etc.
Historical experiences with plants as therapeutic tools
have helped to introduce single chemical entities in
modern medicine. Plants, especially those with
ethnopharmacological uses in tropical countries, have been
the primary sources of medicines for early drug discovery.
In fact, a recent analysis by Fabricant and Farnsworth
showed that the uses of 80% of 122 plant-derived drugs
were related to their original ethnopharmacological
purposes (Fabricant and Farnsworth, 2001). Current drug
discovery from folk-medicine plants has mainly relied on
bioactivity-guided isolation methods, also, for example,
bioactivity-guided isolation methods have led to
discoveries of the important anticancer agents, paclitaxel
from Taxus brevifolia (Figure 3b) and camptothecin from
Camptotheca acuminate (Figure 1a) (Fabricant and
Farnsworth, 2001).
IV. Principles in folk medicines:
Preventing cancer using folk remedies
Medicinal herbs of folk-origin are significant sources
of synthetic and herbal drugs. In the commercial market,
folk-medicinal herbs are used as raw drugs, extracts or
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Cancer Therapy Vol 6, page 915
mice, which survived for 100 days only without the
evidence of growth of the tumour. Withaferin-A arrested
mitosis in embryonic chicken fibroblast cells (Devi, 1996),
also it showed significant antitumor and radio sensitizing
effects in experimental tumors in vivo, without any
noticeable systemic toxicity. Withaferin A gave a
sensitizer enhancement ratio of 1.5 for in vitro cell killing
of V79 Chinese hamster cells at a non-toxic concentration
of approximately 2 microM (Uma and Akagi, 1996). A
free radical scavenging, anti-tumour and anti-carcinogenic
activity of gossypin has been reported (Babu et al, 2003).
Solanum pseudocapsicum (Figure 2A) L. (Solanaceae)
leaves has been reported to have Antitumor activity for the
total alkaloid fraction of this plant (Badami et al, 2003).
Several quinones of folk medicines have shown antitumour activity. In animal studies, plumbagin, a
napthoquinone from Plumbago rosea (Plumbaginaceae)
has shown anti tumour activity. The antitumour properties
of plumbagin were tested on mouse Ehrlich ascites
carcinoma.
Plumbagin
produced
inhibition
of
exponentially growing tumours. However mode of action
of anticancer activity of plumbagin remains unclear (Devi
et al, 1999).
Glychyrrhiza glabra L.(Fabaceae) called as
yashtimadhu in ancient text of folk-medicine of India,
called charaka samhitha. It yielded glycyrrhizin, a
triterpenoid saponin which inhibited the plaque formation
in DNA and RNA viruses. It has been proposed that
glycyrrhizin blocks the first steps on viral replication as
well as the viron exit from the capside (Badam, 1994).
Figure 1. Anticancer herbal flora; a. Camptotheca, b. B. monosperma, c. Euphorbia, d. Cephalotaxus, e. Combretum
Figure 2. Anticancer herbal flora; a. S. pseudocapsicum, b. R.cordifolia, c. P.caapensis, d. P. indica, e. Tripterygium wilfordii
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Rao et al: Folk medicines for anticancer therapy-a current status
Figure 3. Anticancer herbal flora; a. Withania somnifera, b. T. brevifolia, c. T. wilfordii, d. P. rosea, e. Vitis vitifera
In the authors laboratory, Butea monosperma L
(Figure 1B). (Fabaceae), which is a famous tree known as
- the flame of the forest, yielded a new flavone glycoside
which inhibited tumour cells in experimental models
(Tirupathi, 2007). Apocynin isolated from Picrorhiza
kurroa Royle. ex Benth.(Scrophulariaceae), a well known
folk medicine, is a potent NADPH oxidase inhibitor and
has anti-oxidant and anti-inflammatory activity (Basu,
1971). Embelin, a plant benzoquinone and the active
constituent of Embelia ribes Burm (Myrsinaceae) (vayu
vidangam in folk medicine) is isolated in authors
laboratory and demonstrated to have antioxidant activity.
It is also a valuable anthelmentic for the stomach besides
acting as antifertility agent of plant origin. Plumbagin
from Plumbago zeylanica L. (Plumbaginaceae) has anti
cancer activity in its roots and it is well described in the
ancient Indian folk-medicine book-charaka samhitha, and
its activity is found similar to embelin (Bhargava and
Dixit, 1985). A review of terpenoids as anti-inflammatory
and anticancer potential is also reported (Salminen et al,
2008).
(camptothecin, paclitaxel, epipodophyllotoxin, and
vinblastine (Butler, 2005). In addition, the phytochemical
combretastatin A4, was isolated from the South African
medicinal tree, Combretum caffrum (Figure 1e)
(Combretaceae), was derivatized to combretastatin A4
phosphate and AVE-8062 (Cirla and Mann, 2003; Pinney
et al, 2005). These analogs bind to tubulin leading to
morphological changes and then disrupt tumor
vasculature, and are in phase II trials (West and Price,
2004; Young and Chaplin; 2004).
Homoharringtonine, a cephalotaxus alkaloid from the
tree Cephalotaxus harringtonia (Figure 1d) (Powell et al,
1970), is an inhibitor of protein synthesis and is reported
to have activity against hematologic malignancies
(Kantarjian et al, 2001). Ingenol 3-O-angelate, which was
obtained from Euphorbia peplus (Figure 1c) (known as
“petty spurge” in England), is a potential topical
chemotherapeutic agent for skin cancer and exhibits its
action through activation of protein kinase (Kedei et al,
2004, Ogbourne et al, 2004). Phenoxodiol , a synthetic
analog of daidzein, a well known isoflavone from soybean
(Glycine max) and found in several other folk-medicines,
is being developed as a therapy for cervical, ovarian,
prostate, renal, and vaginal cancers, and induces apoptosis
through inhibition of anti-apoptotic proteins including
XIAP and FLIP (Kamsteeg et al, 2003). Phenoxodiol is
currently undergoing clinical studies in the United States
and Australia (Constantinou et al, 2003).
V. Natural products from folk
medicines which are under trial or for
approval as drugs
Some of the folk medicine described plant-derived
secondary metabolites and their semisynthetic derivatives,
are undergoing clinical trials as anticancer drugs
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Cancer Therapy Vol 6, page 917
Protopanaxadiol, a derivative of a triterpene aglycone
of several saponins from ginseng, Panax ginseng, exhibits
its apoptotic effects on cancer cells through various
signaling pathways, and is also reported to be cytotoxic
against multidrug resistant tumors (Shibata et al, 1963; Jia
et al, 2004). Triptolide, a diterpene triepoxide, was
isolated from Tripterygium wilfordii (Figure 3c), and
has been used for autoimmune and inflammatory diseases
in China for a long time as a folk medicine. PG490–88 , a
semisynthetic
analog
of
triptolide,
showed
antiproliferative and proapoptotic activities on primary
human prostatic epithelial cells as well as tumor regression
of colon and lung xenografts (Fidler and Chung, 2003).
mammalian fatty acid, arachidonic acid is metabolized by
one of two enzyme pathways, cyclooxygenase (COX) or
lipoxygenase (LOX) generating biologically active
metabolites that are involved in carcinogenesis. It has been
shown that the LOXs in particular are key regulators of
cell survival and apoptosis in cells. It has been shown also
that LOX is a regulator of human cancer development and
it is over expressed in a variety of tumors including breast,
colorectal, and prostate cancer, and cancer cell lines
(Pidge et al, 2002). It has been reported that inhibition of
oxidative enzymes such as 5-lipoxygenase and 12lipoxygenase trigger tumor cell apoptosis, reduce tumor
cell motility and invasiveness, or decrease tumor
angiogenesis and growth (Nie et al, 2001).
Phenols and polyphenols, the flavonoids and their
derivatives, are ubiquitous in plants and more than 8,000
different compounds are included in this group and many
of them are antioxidants. They have been associated with
the inhibition of atherosclerosis and cancer (MartinezValverde et al, 2000) and other biological activities.
Schewe and colleagues reported in 2001 on cocoas and
chocolates which are rich in (-)-epicatechin and its related
oligomers, the procyanidins. These compounds isolated
from the seeds of Theobroma cacao, trigger concentrationdependent inhibition of isolated rabbit 15-lipoxygenase-1.
(-)-Epicatechin and procyanidin nonamer also inhibited
the formation of 15-hydroxy-eicosatetraenoic acid
(Schewe et al, 2001). The polyphenols of green and black
tea also inhibit lipoxygenase dependent arachidonic acid
metabolism. At a concentration of 30 µg/mL, (-)epigallocatechin-3-gallate (EGCG), (-)- epigallocatechin
(EGC), and (-)-epicatechin-3-gallate (ECG) from green tea
and theaflavins from black tea inhibited LOX-dependent
activity by 30-75%. The formation of 5-, 12-, and 15-LOX
metabolites were inhibited to a similar extent (Hong et al,
2001). The polyphenols extracted form pomegranate
(Punica granatum) fermented juice and seed oil showed
strong antioxidant activity close to that of green tea (Thea
sinensis), and significantly greater than that of red wine
(Vitis vitifera) (Figure 3e). Flavonoids extracted from
seed oil showed 81% inhibition of soybean lipoxygenase.
Flavonoids extracted from fermented juice showed 2130% inhibition of soybean lipoxygenase though no
significant inhibition of sheep cyclooxygenase was found
(Schubert et al, 1999).
Curcumin is another natural phenol and ingredient of
food with antioxidant properties. It is a major component
of the Curcuma rhizomes, which is commonly used as a
yellow coloring and flavoring agent in foods in Asia. This
chemical is a naturally occurring polyphenolic
phytochemical isolated from the powdered rhizome of the
plant Curcuma longa and related species. Curcumin is
known as anti-inflammatory and is used for generations in
folk medicine. It is a potent inhibitor of oxidative
enzymes, such as lipoxygenase/cyclooxygenase, xanthine
dehydrogenase/oxidase and inducible nitric oxide synthase
(Li and Lin-Shia, 2001). By use of molecular modeling
methods, X-ray diffraction and mass spectrometry, it is
found that curcumin binds to active site of soybean
lipoxygenase and when illuminated by X-rays it degrades
VI.
Cellular
pathways
and
mechanisms that most likely to provide
leads and better answers –Mechanism of
some potential active ingredients
Pytochemicals isolated from folk medicines are
found to act as potent antioxidants and free radical
scavengers. These natural products are supposed to
minimize DNA damage by reacting with free radicals and
in this way they could prevent cancer. Some of the
Pytochemical antioxidants of folk medicines are inhibitors
of lipoxygenase and urokinase. Inhibition of these
enzymes by folk medicines could prevent or reduce cancer
growth and in this way their mechanism of action can be
established.
Folk medicine pytochemicals such as flavonols and
flavones were investigated to determine chemoprevention
activity against cancer. Urokinase plasminogen activator
(uPA) or other proteolytic enzymes, such as
metalloproteases, is commonly recognized as an important
factor in metastasis. The urokinase activates plasminogen
(nonactive form) turning it into its active form called
plasmin. Plasmin is a strong proteolytic enzyme and
hydrolyzes proteins of connective tissue and basement
membranes. It activates other latent proteolytic enzymes,
broadening the spectrum of proteins attacked. Procollagenase is activated to collagenase in this way.
Plasmin is a key enzyme in the mechanism responsible for
tissue remodeling, tumor invasion, angiogenesis and
development of distant metastasis. An increased amount or
activity of uPA, or urokinase plasminogen activator
receptor (uPAR) per cell, has been found in human cancer
cells lines with metastatic behavior (Conese and Blasi
1995). Natural products of folk-medicine, for example,
genistein and curcumin, are found to decrease uPA
(Santibanez, 2000), thus helping to fight against cancer.
Natural products of folk-medicine also affect
lipoxygenase activity which is also a cause for cancer.
Lipoxygenase enzymes are found in a wide variety of
plant and animal tissues. These enzymes have a non-heme
iron serving as a catalytic center for the stereo and
regiospecific dioxygenation of select carbon atoms in
polyunsaturated fatty acids for their metabolism. Eighteen
carbon chain fatty acids (e.g. linoleate) are the primary
substrates of the plant lipoxygenases while the mammalian
isozymes mainly catalyze the metabolism of fatty acids of
twenty chain carbon length (e.g. arachidonate). The
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Rao et al: Folk medicines for anticancer therapy-a current status
to
4-hydroxyperoxy-2-methoxyphenol
(SkrzypczakJankun et al, 2000).
Curcumin, the yellow component of turmeric of
curry powder,also inhibits cyclooxygenase-2, HER2,
tumor necrosis factor, EGFR, Bcr-abl, proteosome, and
vascular endothelial cell growth factor have been approved
for human use by the United States Food and Drug
Administration (FDA), curcumin as a single agent can
down-regulate all these targets. Curcumin can also activate
apoptosis, down-regulate cell survival gene products, and
up-regulate p53, p21, and p27. Although curcumin is
poorly absorbed after ingestion, multiple studies have
suggested that even low levels of physiologically
achievable concentrations of curcumin may be sufficient
for its chemopreventive and chemotherapeutic activity.
Thus, curcumin regulates multiple targets (multitargeted
therapy), which is needed for treatment of most diseases,
and it is inexpensive and has been found to be safe in
human clinical trials. This present article reviews the key
molecular mechanisms of curcumin action and compares
this to some of the single-targeted therapies currently
available for human cancer (Goel et al, 2008).
Onions and garlic are well used as food flavours and
are used commonly in folk medicines in Asia and Africa.
Belman and colleagues, investigated in 1989 the inhibition
of soybean lipoxygenase of onion and garlic constituents.
The di-(1-propenyl) sulfide was the only irreversible
inhibitor while Diallyl trisulfide, allyl methyl trisulfide,
and diallyl disulfide were competitive inhibitors, while 1propenylpropyl sulfide and (E, Z)-4,5,9-trithiadodeca1,6,11-triene 9-oxide (ajoene) were mixed inhibitors.
Sendl and colleagues 1992, also studied lipoxygenase
inhibitory activity of garlic.
Allium tuberosum L., is a known folk medicine that
has been extensively used in diet to treat diseases. In the
present study, the authors evaluated the effect of
thiosulfinates from Allium tumberosum L. on proliferation
of metastasis (DU145) and primary malignant tumor (RC58T/h/SA#4)-derived human prostate cancer cells.
Thiosulfinates decrease viable cell numbers in a dose- and
time-dependent manner and induce apoptosis. The
apoptosis induced by thiosulfinates is associated with the
activation of initiator caspase-8, and -9, and the effector
caspase-3. Thiosulfinates stimulated Bid cleavage,
indicating that the apoptotic action of caspase-8-mediated
Bid cleavage leads to the activation of caspase-9.
Thiosulfinates decreased the expression of the antiapoptotic protein Bcl-2, and increased the expression of
the pro-apoptotic protein Bax. Thiosulfinates also
increased the expression of AIF, a caspase-independent
mitochondrial apoptosis factor, in RC-58T/h/#4 cells and
induced DNA fragmentation and chromatin condensation.
These results indicate that thiosulfinates from Allium
tuberosum L. inhibit cell proliferation by inducing
apoptosis in RC-58T/h/#4 cells which may be mediated
via both caspase-dependent and caspase-independent
pathways (Kim et al, 2008).
Interest in the health-promoting effects of olive oil,
impelled de la Puerta et al. to investigate the antieicosanoid and antioxidant effects in leukocytes of the
principal phenolic compounds -oleuropein, tyrosol,
hydroxytyrosol, and caffeic acid of olive oil. All these
compounds inhibited leukotriene B4 generation at the 5lipoxygenase level with effectiveness noticed in the order:
hydroxytyrosol > oleuropein > caffeic acid > tyrosol (IC50
values: 15, 80, 200, and 500 µM) (de la Puert et al, 1999).
Artesunate is a semisynthetic derivative of
artemisinin, a natural product from the Chinese herb
Artemisia annua L. It exerts antimalarial activity, and,
additionally, artemisinin and its derivatives are active
against cancer cells. Artesunate induces apoptosis and
necrosis. It also induces DNA breakage in a dosedependent manner as shown by single-cell gel
electrophoresis. This genotoxic effect was confirmed by
measuring the level of gamma-H2AX, which is considered
to be an indication of DNA double-strand breaks (DSB).
Polymerase beta-deficient cells were more sensitive than
the wild-type to artesunate, indicating that the drug
induces DNA damage that is repaired by base excision
repair. irs1 and VC8 cells defective in homologous
recombination (HR) due to inactivation of XRCC2 and
BRCA2, respectively, were more sensitive to artesunate
than the corresponding wild-type. This was also true for
XR-V15B cells defective in nonhomologous end-joining
(NHEJ) due to inactivation of Ku80. The data indicate that
DSBs induced by artesunate are repaired by the HR and
NHEJ pathways. They suggest that DNA damage induced
by artesunate contributes to its therapeutic effect against
cancer cells (Li et al, 2008).
Annona glabra (pond apple), a tropical tree growing
wild in the Americas and Asia, is used in traditional
medicine against several human ailments, including
cancer. The extracts were highly cytotoxic to drug
sensitive (CEM) and multidrug-resistant leukemia
(CEM/VLB) cell lines. The seed extract was more potent
than leaf and pulp extracts, and the cytotoxicity values
were significantly lower than that for adriamycin.
Treatment of CEM and CEM/VLB cells with seed extract
induced apoptosis and necrosis in both sensitive and
resistant leukemia cells in a concentration-dependent
manner (Cochrane et al, 2008).
Melittin, a water-soluble toxic peptide derived from
bee venom of Apis mellifera was reported to have
inhibitory effects on hepatocellular carcinoma (HCC). By
utilizing both HCC cell lines and an animal model based
assay system, Rac1, which has been shown to be involved
in cancer cell metastasis, is highly expressed in aggressive
HCC cell lines and its activity correlated with cell motility
and cytoskeleton polymerization. In addition, Rac1dependent activity and metastatic potential of aggressive
HCC cells are remarkably high in both cellular and nude
mouse models. Evidence here suggest that melittin inhibits
the viability and motility of HCC cells in vitro, which
correlates with its suppression of Rac1-dependent activity,
cell motility, and microfilament depolymerization.
Furthermore, melittin suppresses both HCC metastasis and
Rac1-dependent activity in nude mouse models. The
specificity of the effect of melittin on Rac1 was confirmed
in HCC cells both in vitro and in vivo. Conclusion:
Melittin inhibits tumor cell metastasis by reducing cell
motility and migration via the suppression of Rac1-
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Cancer Therapy Vol 6, page 919
dependent pathway, suggesting that melittin is a potential
therapeutic agent for HCC (Lee et al, 2008).
The seed of Strychnos nux-vomica (Loganiaceae) has
been used in traditional Oriental medicine as a folk
remedy for the treatment of cancer. This study proved that
the water extract of Strychni Semen (ESS) treatment
would affect the growth of AGS human gastric carcinoma
cells. ESS was found to inhibit the growth of AGS cells in
a concentration-dependent manner. Cell cycle analysis
showed G2/M phase arrest and apoptosis in AGS cells
following ESS treatment. ESS-mediated G2/M arrest was
found to be associated with up-regulation of cyclin A,
Cdc2, tumor suppressor p53 and cyclin dependent kinase
(Cdk)
inhibitor
p21(WAF1/CIP1),
whereas
the
expressions of other G2/M regulatory proteins, including
cyclin B1 and Cdk2, were down-regulated compared with
the control. The induction of apoptotic cell death by ESS
was associated with down-regulation of anti-apoptotic
Bcl-2 and up-regulation of pro-apoptotic Bax expression.
Further results indicate that caspase-3, caspase-8 and
caspase-9 are all activated by ESS, together with cleavage
of downstream caspase-3 target proteins. Taken together,
the results of this study suggest the involvement of
multiple signaling pathways targeted by ESS in mediating
G2/M cell cycle arrest and apoptosis in AGS cells (Lee et
al, 2008).
Plants of the genus Taraxacum, commonly known as
dandelions, have a history of use in Chinese, Arabian and
Native American traditional medicine, to treat a variety of
diseases including cancer. In the present study, three
aqueous extracts were prepared from the mature leaves,
flowers and roots, and investigated on tumor progression
related processes such as proliferation and invasion. Their
results showed that the crude extract of dandelion leaf
(DLE) decreased the growth of MCF-7/AZ breast cancer
cells in an ERK-dependent manner, whereas the aqueous
extracts of dandelion flower (DFE) and root (DRE) had no
effect on the growth of either cell line. Furthermore, DRE
was found to block invasion of MCF-7/AZ breast cancer
cells while DLE blocked the invasion of LNCaP prostate
cancer cells, into collagen type I. Inhibition of invasion
was further evidenced by decreased phosphorylation levels
of FAK and src as well as reduced activities of matrix
metalloproteinases, MMP-2 and MMP-9. This study
provides new scientific data on TO and suggests that TO
extracts or individual components present in the extracts
may be of value as novel anti-cancer agents (Sigstedt et al,
2008).
Brucea javanica fruit is reported to have anticancer
properties in Chinese medicine and its extract has been
shown to possess antiproliferative and pro-apoptotic
activities on human carcinoma cells. In this study Fructus
Bruceae extract exhibited cytotoxic effects on the three
pancreatic adenocarcinoma cell lines, PANC-1, SW1990
and CAPAN-1; the effects were comparable to those
exhibited by camptothecin in the culture system. In
addition, Fructus Bruceae extract induced fragmentation of
genomic DNA, as evidenced by Hoechst staining and the
cell death detection ELISA (PLUS) assay. Western blot
analysis further showed down-regulation of pro-caspase 3
protein expression, indicating that the observed cytotoxic
effects of the extract were associated with induction of
apoptosis. These findings are not only significant in the
development of traditional Chinese medicine as an
alternative treatment for pancreatic cancer, but also in the
elucidation of the potential mechanism of Fructus Bruceae
extract in cancer therapy (Lau et al, 2008).
Ginger, the rhizome of Zingiber officinale, is a
traditional medicine with anti-inflammatory and
anticarcinogenic properties. This study examined the
growth inhibitory effects of the structurally related
compounds 6-gingerol and 6-shogaol on human cancer
cells. 6-Shogaol [1-(4-hydroxy-3-methoxyphenyl)-4decen-3-one] inhibits the growth of human cancer cells
and induces apoptosis in COLO 205 cells through
modulation of mitochondrial functions regulated by
reactive oxygen species (ROS). ROS generation occurs in
the early stages of 6-shogaol-induced apoptosis, preceding
cytochrome c release, caspase activation, and DNA
fragmentation. Up-regulation of Bax, Fas, and FasL, as
well as down-regulation of Bcl-2 and Bcl-X(L )were
observed in 6-shogaol-treated COLO 205 cells. Nacetylcysteine (NAC), but not by other antioxidants,
suppress 6-shogaol-induced apoptosis. The growth arrest
and DNA damage (GADD)-inducible transcription factor
153 (GADD153) mRNA and protein is markedly induced
in a time- and concentration-dependent manner in
response to 6-shogaol (Pan et al, 2008).
Rhus verniciflua Stokes (RVS) has been used in
traditional Eastern Asia medicine for the treatment of
gastritis and stomach cancer. The ethanol extract of RVSinduced G(1)-cell cycle arrest via accumulation of
p27(Kip1) controlled by Skp2 reduction and apoptosis in
AGS human gastric cancer cells. RVS-induced apoptosis
via caspase-9 activation (mitochondrial death pathway) is
mediated by the loss of mitochondrial membrane potential
(MMP, Deltapsi(m)) and the release of cytochrome C from
the mitochondrial intermembrane space. In addition, the
ethanol extract of RVS inactivated PI3K-Akt/PKB kinase
in a time-dependent manner. Moreover, combined
treatment of an ethanol extract of RVS and LY294002 (a
PI3K inhibitor) markedly increased apoptosis compared to
treatment with an ethanol extract of RVS alone. The role
of PI3K-Akt/PKB in this process was confirmed by
constitutive expression of inactive mutants of this kinase
in AGS cells. Finally, siRNA-mediated knockdown of
Akt/PKB expression resulted in a significant reduction in
AGS cell proliferation. Taken together, these results
suggest that an ethanol extract of RVS induces apoptosis
via a mitochondrial death pathway in human gastric cancer
cells, but not in normal cells, and inhibition of the PI3KAkt/PKB pathway enhanced the mitochondrial death
pathway (Kim et al, 2008).
The anticancer properties of extracts isolated from
Centaurea ainetensis, a plant species endemic to Lebanon
and which is often used in folk medicine is studied. The
authors performed bioassay-guided fractionation of
Centaurea ainetensis extracts using a panel of normal and
neoplastic murine cells to identify a component that is
associated with antitumor activities. Among several
compounds that were fractionated, the sesquiterpene
lactone, Salograviolide A, was identified and found to
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Rao et al: Folk medicines for anticancer therapy-a current status
Badami S, Shrishailappa SA, Manohara Reddy EP, Kumar P,
Vijayan P, Suresh B (2003) Antitumor activity of total
alkaloid fraction of Solanum pseudocapsicum leaves.
Phytother Res 9, 1001-1004.
Basu K, Dasgupta B, Bhattacharya SK, Debnath PK (1971)
Chemistry and pharmacology of apocynin, isolated from
Picrorhiza kurroa Royle ex Benth. Current Science 40, 603604.
Belman S, Solomon J, Segal A, Block E, Barany G (1989)
Inhibition of soybean lipoxygenase and mouse skin tumor
promotion by onion and garlic components. J Biochem
Toxicol 4, 151-160.
Bhargava SK, Dixit VP (1985) Anti-fertility effect of embelin in
female rats; anti-fertility effect of plumbagin in female rats.
Planta Medica 19, 29-34.
Butler MS (2005) Natural products to drugs: natural products
derived compounds in clinical trials. Nat Prod Rep 22, 162195.
Butler MS (2004) The role of natural product chemistry in drug
discovery. J Nat Prod 67, 2141-2153.
Cirla A, Mann J (2003) Combrestatins: from natural products to
drug discovery. Nat Prod Rep 20, 558-564.
Cochrane CB, Nair PK, Melnick SJ, Resek AP, Ramachandran C
(2008) Anticancer effects of Annona glabra plant extracts in
human leukemia cell lines. Anticancer Res 28, 965-71.
Conese M, Blasi F (1995) The urokinase/urokinase-receptor
system and cancer invasion. Baillieres Clin Haematol 8,
365-389.
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novel
isoflavone
derivative,
inhibits
dimethylbenz[!]anthracene (DMBA)-induced mammary
carcinogenesis in female Sprague-Dawley rats. Eur J
Cancer 39, 1012-1018.
de la Puerta R, Ruiz Gutierrez V, Hoult JR (1999) Inhibition of
leukocyte 5-lipoxygenase by phenolics from virgin olive oil.
Biochem Pharmacol 57, 445-449.
Devi PU (1996) Withania somnifera Dunal (Ashwagandha):
potential plant source of a promising drug for cancer
chemotherapy and radio sensitization. Indian J Exp Biol 34,
927-932.
Devi PU, Akagi K, Ostapenko V, Tanaka Y, Sugahara T (1996)
Withaferin- A: a new radio sensitizer from the Indian
medicinal plant Withania somnifera. Int J Radiat Biol 69,
193-7.
Devi PU, Akagi K, Ostapenko V, Tanaka Y, Sugahara T (1996)
Withaferin A: a new radiosensitizer from the Indian
medicinal plant Withania somnifera.. Int J Radiat Biol 69,
193-197.
Devi U, Solmon FE, Sharda AC (1999) Plumbagin- A Plant
Napthoquinone with Antitumour and Radimodifying
Properties. Pharmaceutical Biology 37, 231-236.
Elangovan V, Ramamoorthy N, Balasubramanian S (1994)
Studies on the antiproliferative effect of some naturally
occurring bioflavonoidal compounds against human
carcinoma of larynx and sarcoma-180 cell lines. Indian J
Pharmacol 26, 266-9.
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traditional medicine for drug discovery. Environ Health
Perspect 109, 69-75.
Fidler JM, Li K, Chung C (2003) PG490-88, a derivative of
triptolide, causes tumor regression and sensitizes tumors to
chemotherapy. Mol Cancer Ther 2, 855-862.
Ghantous A, Tayyoun AA, Lteif GA, Saliba NA, Gali-Muhtasib
H, El-Sabban M, Darwiche N (2008) Purified salograviolide
A isolated from centaurea ainetensis causes growth inhibition
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841-9.
exert the most significant growth inhibitory effects on
neoplastic cells. At concentrations that were non-cytotoxic
to primary keratinocytes, Centaurea ainetensis crude
extract and Salograviolide A preferentially inhibited the
proliferation of papilloma and squamous cell carcinoma
(SCC) cell lines without significantly affecting the growth
of normal cells. Flow cytometric analysis of DNA content
indicated that the inhibition of cell proliferation by
Centaurea ainetensis crude extract and Salograviolide A
was due to G0/G1 cell cycle arrest and increased preG0/G1, respectively. The increase in pre-G0/G1, and
presumably apoptosis induction, in Salograviolide Atreated keratinocytes was confirmed by DNA Hoechst
staining. Western blot analysis and electrophoretic
mobility shift assay showed that both the crude extract and
the isolated molecule differentially modulated key cell
cycle and apoptotic regulators as well as NF-kappaB
signaling. Salograviolide A-induced growth inhibition in
neoplastic cells was mediated by the accumulation of ROS
highlighting a potent oxidant role of this molecule. These
studies suggest the potential therapeutic effects of
Centaurea ainetensis, and its component, Salograviolide A,
against epidermal squamous cell carcinogenesis (Ghantous
et al, 2008).
VII. Future perspectives
medicine treatment of cancer
in
folk
Many new natural products of varied biological
activities are yet to come out from the folk medicines, but
they may be dead due to the fast disappearance of tropical
rainforests and with them the new and uninvestigated plant
species are becoming extinct. However, the traditional folk
medicines of India, called Ayurveda, a traditional Indian
medicine of plant drugs has been successful from very
early times in using these natural drugs and preventing or
suppressing various tumours using various lines of
treatment (Premalatha and Rajgopal, 2005). Ayurvedic
therapy was found to be able to cure these chronic diseases
better, which were previously not amenable to treatment
by western medical practices. This traditional Indian
medicine with its evolution through centuries has always
fascinated practitioners and researchers for its applications
in cancer treatment on a scientifically proven research
background. This may give good drug leads for cancer
treatment since it is a well proven therapy for centuries,
hence its systematic study and understanding is worth
considering by pharmaceutical industries in order to
develop their active ingredients as allopathic drugs for
cancer treatment.
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