Download Evidence-based review on anticancer effects of commonly

Journal of Advanced Clinical & Research Insights (2014), 2, 73–77
REVIEW ARTICLE
Evidence-based review on anticancer effects of commonly
used herbs
V. Saranya, N. Malathi
Department of Oral Pathology, Faculty of Dental Sciences, Sri Ramachandra University, Chennai, Tamil Nadu, India
Keywords
Biochemoprevention, cancer, medicinal
properties of plants, phytochemicals
Correspondence
Dr. Malathi. N, Professor and Head,
Department of Oral Pathology, Faculty of
Dental Sciences, Sri Ramachandra University,
Porur, Chennai - 600 116, Tamil Nadu, India.
Tel.: 044-24765512, Extension 8271,
E-mail: [email protected]
Abstract
Cancer, a disease with high morbidity and mortality rates, is a challenge to human life.
The current therapeutic strategies are associated with adverse effects which necessitate
alternate treatment with less adverse effects. In addition to this, cancer prevention is
desirable which has led to a new concept called biochemoprevention. In this regard,
medicinal properties of plants can be exploited for cancer prevention and management as
they can be procured cost effectively and are less likely to produce adverse effects as they
are diet derived. This article reviews the phytochemicals and evidence-based preventive
and therapeutic effects of some commonly used plants with medicinal properties against
cancer.
Received 05 August 2014;
Accepted 02 October 2014
doi: 10.15713/ins.jcri.19
Introduction
Cancer continues to be a challenge to human life as the disease
has high morbidity and mortality rates. Though surgery,
chemotherapy, and radiotherapy remain the “Gold Standard”
measures of cancer therapy, they are associated with adverse
effects. Despite the recent advances in therapeutic strategies,
the 5 years survival rate of one of the most commonly occurring
cancer like oral cancer is as low as 62% with no improvement in
the quality of life of the affected individuals.[1] Hence, treatment
modality with less adverse effects will be of great benefit to
the affected patients. Furthermore, research in the field of
oncology has led to better understanding of the molecular
mechanisms of carcinogenesis that has revealed that cancer
is a largely preventable disease. Hence, a new concept called
biochemoprevention has evolved not only to prevent but also
combat the shortcomings of cancer therapy. Chemoprevention
or biochemoprevention refers to pharmacological intervention
with synthetic or natural compounds that may prevent, inhibit,
or reverse carcinogenesis.
The use of medicinal plants for the management of various
diseases including cancer has been carried out several 100 years
ago during the period of Charaka, the Father of Medicine and
Susrutha, the Father of Surgery. With the advent of Modern
medicine, traditional medicine has lost its importance. Hence,
the medicinal properties of plants which are our natural resources
must be re-explored to prevent and treat cancer. The advantages
of utilizing medicinal properties of plants for cancer prevention
and management include easy availability, cost effective, and
less likely to produce side effects as most of these plants or plant
parts are diet derived. This article highlights evidence-based
preventive and therapeutic effects of some commonly used
plants with medicinal properties against cancer.
Review
Neem
Azadirachta indica commonly known as neem in English
and Vembu in Tamil is native to our country and is known
for several medicinal properties including antimicrobial,
antioxidant, antidiabetic. It also finds its use in preparation
of cosmetics, toothbrush fertilizer, and toothbrush. This
could be attributed to more than 140 compounds present
in various parts of the plant. Recently, research has been
carried out to demonstrate the antineoplastic effects of
this plant. Ethanolic extract of neem leaves caused both
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Anticancer effects of commonly used herbs
reduction in tumor size and decrease in tumor progression
even after cessation of treatment with neem extract in N
methyl N nitrosurea induced mammary tumors in Sprague
Drawley rats. Molecular analysis revealed up-regulation
of proapoptotic genes and proteins such as p53, B-cell
lymphoma 2 (Bcl2), bax, caspases, phosphatase and tensin
homolog, c-Jun N-terminal kinases and down-regulation
of oncogenes such as vascular endothelial growth factor
(VEGF), cyclin dependent kinase 1, nuclear factor kappa B
(NF kappa B), mitogen-activated protein kinase 1 (MAP1).[2]
Glycoproteins present in neem leaves also exert anti-cancer
effects by restricting tumor growth in murine, These proteins
alter tumor microenvironment by increasing CD 8 (Cluster
of differentiation 8) T-cells, protect T-cells from Anergy,
decrease activation-induced T-cell death by decreasing
expression of FAS receptor. Cytotoxicity of sarcoma cells was
caused due to increased expression of performin, granzyme
B in lymphocytes.[3] These results shed light on the fact that
neem extracts possess immunomodulatory effects hence aid
in targeted therapy against malignant cells, sparing normal
cells. Hence, these extracts are less likely to produce side
effects.
Tulasi
Oscimum sanctum commonly known as Tulasi in Tamil and
Holy basil in English is a sacred plant of Hinduism. The
aromatic plant has several medicinal properties and has been
used several 1000 years ago for the management of various
diseases and ailments like common cold, fever, acne, headache,
stress, aphthous ulcers, asthma, bronchitis, tuberculosis, ecema.
It also has been used as an expectorant for management of
cough, antimicrobial agent in preventing diarrhea, analgesic
for pain management. Other medicinal properties include
immunomoduation, hypolipidemic, and hepatoprotective.
Phytochemical constituents that confer these properties are
oleanic acid, urosolic acid, rosmatinic acid, eugenol, carvacol,
linalool, beta carophyllene, beta elemene, germaserene.
O. sanctum possesses cancer preventive and therapeutic
properties. Important phytochemicals such as eugenol,
rosmarinic acid, apigenin, silosterol, carnosic acid, lutrolen,
myrtenal present in tulasi prevent chemical-induced cancers
of the skin, lung, oral cavity, liver by induction of apoptosis,
prevention of angiogenesis and metastasis, antioxidant activity,
and alteration of genes.[4] Flavonoids such as ornitine, vicenin,
protect normal tissue from therapeutic radiation and prevent
radiation-induced mortality in mice. Eugenol, rosmarinic acid,
and apigenin present in Holy basil prevent radiation-induced
deoxyribonucleic acid (DNA) damage thereby acting as a
chemopreventive agent.
Tulasi exerts radioprotective effects in oral cancer by causing a
significant reduction of glutathione in erythrocytes of oral cancer
patients who were treated with radiotherapy and flavonoids of
O. sanctum in comparison with oral cancer patients who received
only radiotherapy.[5]
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Saranya and Malathi
Allium vegetables
Allium vegetables like onion are used as flavoring and seasoning
agent for food in many countries.[6] Interestingly, two species
of onion viz red onion (Allium cepa) and yellow onion
(Allium flavum) possess medicinal properties.
Bulb of A. cepa contains flavonoids such as anthrocyanins
and dihydroflavonols.[7] The sulfur containing the active
constituent of onion bulb occur mainly in the form of S-alkyl
cysteine sulfoxides which decompose into thiosulfinates and
polysulfides.[8] Thiosulfinates are volatile sulfur compounds
responsible for the pungent odor and medicinal properties.[9]
Onion exerts chemopreventive activity. The ethyl acetate extract
of onion has been shown to induce apoptosis in human breast
cancer cell lines.[10] It also inhibits fatty acid synthase and lipid
accumulation in adipocytes, thereby preventing obesity, one of
the predisposing factors for breast cancer.[11]
Yellow onion (A. flavum) also has anticancer activity
A. flavum extract has significant phenolic content, antioxidant,
antibacterial activity against Staphylococcus aureus, Bacillius
subtilis, and antiproliferative activity against homo sapiens
colorectal carcinoma cell lines.[12]
Pineapple
Annamas cosmous or pineapple is a tropical plant of
Bromadiaceae family. Edible portion of this plant is the fruit
which is made of coalesced berries. Pineapple has been used in
South America, China, South East Asia for the management of
various ailments like inflammation, burns as it exerts medicinal
properties such as anti-inflammatory, antithrombotic,
fibrinolytic, inhibition of platelet aggregation, and skin
debridement. In 1957, Bromelain was identified as the active
principle present in the stem and unripe fruits of pineapple
exerting the above-mentioned activities. Bromelain is a
mixture of proteases.[13] Bromelain alters molecular pathways
of carcinogenesis, tumor microenvironment hence could be
used as an anticancer agent. Bromelain also exerts anticancer
effects by immunomodulation and hemostatic mechanism.[14]
Pineapple extract in stage 2 mouse skin tumorigenesis model
cause reduction in tumor size (65%) and volume. Molecular
analysis revealed up-regulation of p53, bax, caspase 3, 9 and
down-regulation of Bcl2, inhibition of cyclooxygenase 2,
inactivation of NF kappa B, MAP, extracellular-signal-regulated
kinases, and protein kinase B.[15,16]
Cruciferous vegetables
Brassica oleracea belongs to the family Brassiaceae, which are
commonly known as cruciferous vegetables. In uncultivated
form, it is called as wild cabbage and is native to Europe. Cabbage
(B. oleracea capita), Cauliflower (B. oleracea botrytis), Brocoli
(Brassica oleraceaitalica) are some of the varieties of wild cabbage
developed by various cultivars. These cruciferous vegetables are
a part of the diet in many countries including India. Recently,
research has been carried out to assess the phytochemical
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Saranya and Malathi
constituents and medicinal properties of these vegetables.[17] The
leaves of cabbage contain two pyrolidinone which has been isolated
and identified by gas chromatography, mass spectrometry, and
high-performance liquid chromatography. This active constituent
induces apoptosis and cell cycle arrest in GO/G1 phase in
cervical cancer cell line taken from Henrietta Lacks (HeLa)
and body cavity-based lymphoma cell line (BC-3 cell lines),
hence possesses antitumor activity.[18] B. oleracea also contains
glucosinoates which on hydrolysis yields isothicyanates that exerts
antineoplastic effects. Surforaphane is one such isothiocyanate
that causes down-regulation of Bcl2 and up-regulation of p53, bax,
caspase 3 in HeLa derivative (Hep 2 cell lines).[19] Isothicyanates
has chemopreventive effects. These isothiocyanates modulate
carcinogen metabolizing enzymes, thereby limit formation of
reactive intermediates that from DNA adducts. Both intact
glucosinolates and isothiocyantes modulate Phase II detoxification
enzymes such as Quinone reductases, Glutathione-S-transferases,
Epoxide hydrolase, Uridine 5’-diphospho-glucuronosyltransferase.
Intact glucosinolates modulate cytochrome P450 enzymes line
ethoxyresorufin-O-deethylase, ethoxyresorufin O-deethylase.
Isothicyanates and glucosinolates such as Phenyl isothiocyanates,
erucin, sulforaphone are antagonists of aryl hydrocarcobon
receptor hence aid in cancer prevention.[17]
Apple
Apple, the pomaceous fruit of Malus domestica tree belongs
to the family Rosaceae. Malas sieversi, ancestor of this
species is native to the mountains of Central Asia. It is one
of the oldest known fruits that prevents lung cancer, chronic
obstructive pulmonary disease, cardiovascular disease,
thrombosis, and stroke. Polyphenols and flavonoids, the
phytochemical constituents of apple fruit have antioxidant
properties. The phytochemical components of apple can
act as a chemopreventive agent due to the antioxidant and
the antiproliferative property.[20] Triterpenoids of apple
peel possess antitumor activity. 2R-hydroxy-3â-([(2E)3-phenyl-1-oxo-2-propenyl]oxy)olean-12-en-28-oic
acid,
2R-hydroxyursolic acid, and 3â-trans-p-coumaroyloxy-2Rhydroxyolean-12-en-28-oic acid, the triterpenoids isolated
from apple peel exerts higher antitumor activity against
HepG2 cell lines. Ursolic acid, 3â-transp-coumaroyloxy-2Rhydroxyolean-12-en-28-oic acid, and 2R-hydroxyursolic acid
are the terpenoids that have higher antineoplastic activity
against Michigan Cancer Foundation-7 (MCF-7) cancer cells.
Terpenoids such as 2R-hydroxy-3â-([(2E)-3-phenyl-1-oxo2-propenyl]oxy)olean-12-en-28-oic acid, 2R-hydroxyursolic
acid, maslinic acid, and 3â-trans-p-coumaroyloxy-2Rhydroxyolean-12-en-28-oic acid have higher anticancer
effects against heterogeneous human epithelial colorectal
adenocarcinoma cells cancer cells. Apple peel extracts
exert anticancer effects by causing Go/G1 cell cycle arrest,
decreasing expression of proliferating cell nuclear antigen
(PCNA), increasing the levels of the tumor suppressor protein
maps in human prostate and breast carcinoma cells.[21,22]
Anticancer effects of commonly used herbs
Papaya
Carcia papaya commonly known as papaya of the family
Caricaceae, is cultivated throughout India. Leaves of papaya
have been used to treat diseases and aliments such as jaundice,
asthma, colic, fever, beriberi. Recent studies have demonstrated
that papaya leaf extracts could be used for cancer management.
Significant growth inhibitory activity of C. papaya leaf extract
on a couple of cell lines including Raji and Ramos (Burkitt’s
lymphoma cell lines), Jurkat (T cell Lymphoma cell line),
HepG2 and Huh-7 (hepatocellular carcinoma cell lines),
K562 (chronic myelogenous leukemia cell line) PC14 (lung
adenocarcinoma cell line), HeLa (cervical carcinoma cell line,
Panc-1 (pancreatic epithelioid carcinoma cell line), Capan1
(pancreatic adenocarcinoma cell line), ARH77 (plasma cell
leukemia cell line), H2452 (mesothelioma cell line), Karpas-299
(anaplastic large cell lymphoma cell line), and MCF-7 (breast
adenocarcinoma cell line). Treatment of peripheral blood
mononuclear cells (PBMC) with the extract caused increased
production of antitumor cytokines with no change in viability
of the cells. In addition, the PBMC treated with the extract
had increased cytotoxic activity against chronic myelogenous
leukemia cell line.[23] Thus, C. papaya exterts antitumor
activity through growth inhibitory and immunomodulatory
mechanisms. This property could be attributed to the active
constituent carpaine present in papaya leaves. Papaya leaf also
contains a remarkable protein-dissolving enzyme called papain
that degrades fibrin that makes up the protective layer of cancer
cells, making the cancer cells more susceptible to immune
response or chemotherapy. Studies have revealed that mice
immunized with papain possess serum antibodies which crossreact with cathepsin-B-and cathepsin-H-like endopeptidases
isolated from B16 melanoma cells along with inhibition of
growth rate, invasion and metastasis in B16 melanoma, and
the Lewis lung carcinoma. Thus, the compound hinders tumor
growth and prevents it from spreading to other parts of the
body.[24] In addition, papaya leaf has antioxidants such as betacarotene, flavonols, and vitamin C that scavenge free radicals
which are responsible for carcinogenesis, which act as an
adjuvant for cancer therapy. Papaya seed has been used for the
management of worm infestations in the gastrointestinal tract
due to its antihelminthic activity. Papaya seeds contain benzyl
isothiocyanate which exhibits antineoplastic effects by inhibiting
of carcinogen-activating cytochrome P450 mono-oxygenases
and cell cycle progression; inducing carcinogen-detoxifying
phase two enzyme and apoptosis. Higher concentration
of benzylisothiocyanate has a better inhibition rate of cell
proliferation on H69 cell, with IC (50) value of 6.5 μmol/L.[25]
Tomato
Lycopersecon ecsculentum or tomato belongs to the nightshade
family called Solanaceae. Fleshy fruit of this plant is red in
color which is classified based on size and shape as slicing
or globe tomato, beefsteak, oxheart, plum, pear, cherri,
carpari. Lycopene is the chief active constituent having
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Anticancer effects of commonly used herbs
antibiotic, anti-inflammatory, antioxidant, cardiovascular and
immunomodulatory effects.[26] Lycopene is a better singlet
oxygen scavenger than other carotenoids. Interestingly, tomato
leaves have anticancer activity. Extracts of tomato leaves have
been shown to exert antineoplastic activity in MCF breast
cancer cell lines by causing genetic alterations.[27] Lycopene
promotes cell adhesion by increasing E-cadherin expression,
reduces cell proliferation by decreasing PCNA expression, and
confines proliferating cells to the basal and parabasal layer in
4-nitroquinoline-1-oxide-induced tongue carcinogenesis model
in mice. Thus, Lycopene could be used as a chemopreventive
agent.[28] Bifunctional nucleases from tomato RTBN1 also have
antitumor activity.[29]
Conclusion
Along with attempts to improve cure rate of cancer, concerted
efforts to prevent the disease continuity should be undertaken.
This is particularly true for the high-risk population and highrisk individuals. A targeted prevention in high-risk individuals
with high-risk lesions using agents targeted to key molecules in
the carcinogenesis process should have an impact in lowering
the disease morbidity and mortality. Advances in molecular
biology have helped to define these high-risk individuals with
high-risk lesions and novel chemopreventive targets. In this
regard, targeted approach using medicinal properties of plants
should overcome some of the earlier setbacks observed in cancer
prevention and therapeutic research.
References
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA
Cancer J Clin 2013;63:11-30.
2. Arumugam A, Agullo P, Boopalan T, Nandy S, Lopez R,
Gutierrez C, et al. Neem leaf extract inhibits mammary
carcinogenesis by altering cell proliferation, apoptosis, and
angiogenesis. Cancer Biol Ther 2014;15:26-34.
3. Barik S, Banerjee S, Mallick A, Goswami KK, Roy S, Bose A,
et al. Normalization of tumor microenvironment by neem
leaf glycoprotein potentiates effector T cell functions and
therapeutically intervenes in the growth of mouse sarcoma.
PLoS One 2013;8:e66501.
4. Baliga MS, Jimmy R, Thilakchand KR, Sunitha V, Bhat NR,
Saldanha E, et al. Ocimum sanctum L (Holy Basil or Tulsi) and
its phytochemicals in the prevention and treatment of cancer.
Nutr Cancer 2013;65 Suppl 1:26-35.
5. Reshma K, Ashalatha VR, Dinesh M, Vasudevan D. Effect of
ocimum flavonoids as a radioprotector on the erythrocyte
antioxidants in oral cancer. Indian J Clin Biochem 2005;20:160-4.
6. Sengupta A, Ghosh S, Bhattacharjee S. Allium vegetables in cancer
prevention: An overview. Asian Pac J Cancer Prev 2004;5:237-45.
7. Slimestad R, Fossen T, Vågen IM. Onions: A source of unique
dietary flavonoids. J Agric Food Chem 2007;55:10067-80.
8. Augusti KT. Therapeutic values of onion (Allium cepa L.) and
garlic (Allium sativum L.). Indian J Exp Biol 1996;34:634-40.
9. Lanzotti V. The analysis of onion and garlic. J Chromatogr A
2006;1112:3-22.
76
Saranya and Malathi
10.Xiao H, Parkin KL. Isolation and identification of potential
cancer chemopreventive agents from methanolic extracts of
green onion (Allium cepa). Phytochemistry 2007;68:1059-67.
11.Wang Y, Tian WX, Ma XF. Inhibitory effects of onion
(Allium cepa L.) extract on proliferation of cancer cells and
adipocytes via inhibiting fatty acid synthase. Asian Pac J Cancer
Prev 2012;13:5573-9.
12.Curcic MG, Stankovic MS, Radojevic ID, Stefanovic OD,
Comic LR, Topuzovic MD, et al. Biological effects, total phenolic
content and flavonoid concentrations of fragrant yellow onion
(Allium flavum L.). Med Chem 2012;8:46-51.
13.Taussig SJ, Batkin S. Bromelain, the enzyme complex of
pineapple (Ananas comosus) and its clinical application. An
update. J Ethnopharmacol 1988;22:191-203.
14.Chobotova K, Vernallis AB, Majid FA. Bromelain’s activity
and potential as an anti-cancer agent: Current evidence and
perspectives. Cancer Lett 2010;290:148-56.
15.Bhui K, Prasad S, George J, Shukla Y. Bromelain inhibits COX-2
expression by blocking the activation of MAPK regulated NFkappa B against skin tumor-initiation triggering mitochondrial
death pathway. Cancer Lett 2009;282:167-76.
16.Kalra N, Bhui K, Roy P, Srivastava S, George J, Prasad S, et al.
Regulation of p53, nuclear factor kappaB and cyclooxygenase-2
expression by bromelain through targeting mitogen-activated
protein kinase pathway in mouse skin. Toxicol Appl Pharmacol
2008;226:30-7.
17.Abdull Razis AF, Noor NM. Cruciferous vegetables: Dietary
phytochemicals for cancer prevention. Asian Pac J Cancer Prev
2013;14:1565-70.
18.Thangam R, Suresh V, Rajkumar M, Vincent JD, Gunasekaran P,
Anbazhagan C, et al. Antioxidant and in vitro anticancer effect
of 2-pyrrolidinone rich fraction of Brassica oleracea var. capitata
through induction of apoptosis in human cancer cells. Phytother
Res 2013;27:1664-70.
19.Devi JR, Thangam EB. Mechanisms of anticancer activity of
sulforaphane from Brassica oleracea in HEp-2 human epithelial
carcinoma cell line. Asian Pac J Cancer Prev 2012;13:2095-100.
20.Ribeiro FA, Gomes de Moura CF, Aguiar O Jr, de Oliveira F,
Spadari RC, Oliveira NR, et al. The chemopreventive activity of
apple against carcinogenesis: Antioxidant activity and cell cycle
control. Eur J Cancer Prev 2014;23:477-80.
21.He X, Liu RH. Triterpenoids isolated from apple peels
have potent antiproliferative activity and may be partially
responsible for apple’s anticancer activity. J Agric Food Chem
2007;55:4366-70.
22.
Reagan-Shaw S, Eggert D, Mukhtar H, Ahmad N.
Antiproliferative effects of apple peel extract against cancer cells.
Nutr Cancer 2010;62:517-24.
23.Otsuki N, Dang NH, Kumagai E, Kondo A, Iwata S, Morimoto C.
Aqueous extract of Carica papaya leaves exhibits anti-tumor
activity and immunomodulatory effects. J Ethnopharmacol
2010;127:760-7.
24.Bellelli A, Mattioni M, Rusconi V, Sezzi ML, Bellelli L. Inhibition
of tumor growth, invasion and metastasis in papain-immunized
mice. Invasion Metastasis 1990;10:142-69.
25.Li ZY, Wang Y, Shen WT, Zhou P. Content determination of
benzyl glucosinolate and anti-cancer activity of its hydrolysis
product in Carica papaya L. Asian Pac J Trop Med 2012;5:231-3.
26.Friedman M. Anticarcinogenic, cardioprotective, and other
health benefits of tomato compounds lycopene, a-tomatine, and
Journal of Advanced Clinical & Research Insights ● Vol. 1:2 ● Sep-Oct 2014
Saranya and Malathi
tomatidine in pure form and in fresh and processed tomatoes.
J Agric Food Chem 2013;61:9534-50.
27.Amid A, Wan Chik WD, Jamal P, Hashim YZ. Microarray
and quantitative PCR analysis of gene expression profiles in
response to treatment with tomato leaf extract in mcf-7 breast
cancer cells. Asian Pac J Cancer Prev 2012;13:6319-25.
28.
El-Rouby DH. Histological and immunohistochemical
evaluation of the chemopreventive role of lycopene in tongue
carcinogenesis induced by 4-nitroquinoline-1-oxide. Arch Oral
Anticancer effects of commonly used herbs
Biol 2011;56:664-71.
29.Podzimek T, Matoušek J, Lipovová P, Poucková P, Spiwok V,
Santrucek J. Biochemical properties of three plant nucleases
with anticancer potential. Plant Sci 2011;180:343-51.
How to cite this article: Saranya V, Malathi N. Evidence-based
review on anticancer effects of commonly used herbs. J Adv
Clin Res Insights 2014;1:73-77.
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