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190 Current Immunology Reviews, 2019, 15, 190-206
REVIEW ARTICLE
1573-3955/19 $58.00+.00 © 2019 Bentham Science Publishers
Recent Advances in Metabolites from Medicinal Plants in Cancer Preven-
tion and Treatment
Manzoor A. Mir1,* , Syed S. Hamdani1, Bashir A. Sheikh1 and Umar Mehraj1
1Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
Abstract: Cancer is the second leading cause of death and morbidity in the world among non-
communicable diseases after cardiovascular ailments. With the advancement in science and research, a
number of therapies have been developed to treat cancer, including chemotherapy, radiotherapy and
immunotherapy. Chemo and radiotherapy have been in use since the last two decades, however these
are not devoid of their own intrinsic problems, such as myelotoxicity, cardiotoxicity, nephrotoxicity,
neurotoxicity and immunosuppression. Hence, there is an urgent need to develop alternative methods
for the treatment of cancer. An increase in the cases of various cancers has encouraged the researchers
to discover novel, more effective drugs from plant sources. In this review, fifteen medicinal plants
alongside their products with anticancer effects will be introduced and discussed, as well as the most
important plant compounds responsible for the anticancer activity of the plant. Several phenolic and
alkaloid compounds have been demonstrated to have anticancer effects on various types of cancers.
The most fundamental and efficient role exhibited by these secondary plant metabolites against cancer
involves removing free radicals and antioxidant effects, induction of apoptosis, cell cycle arrest and
inhibition of angiogenesis. Moreover, recent studies have shown that plants and their metabolites may
provide an alternative to the existing approaches, including chemotherapies and radiotherapies, in the
treatment of cancer. In this review, a brief overview of important secondary metabolites having anti-
cancer activity will be given, along with the major molecular mechanisms involved in the disease. In
addition to this, recent advances in secondary metabolites from various medicinal plants in the preven-
tion and treatment of cancer will be explored.
A R T I C L E H I S T O R Y
Received: June 13, 2019
Revised: July 31, 2019
Accepted: October 17, 2019
DOI:
10.2174/1573395515666191102094330
Keywords: Metabolites, phytochemical, anticancer agents, anti-inflammatory, antimicrobial, antioxidant.
1. INTRODUCTION
Cancer has been a constant battle globally with signifi-
cant development in cures and preventive therapies. The
disease is characterized by continuous multiplication of the
cells in the human body with the inability to be controlled or
stopped,consequently forming tumors of malignant cells
with the potential to be metastatic. The traditional use of
plant remedies provides potential indicators of biological
activities. The WHO has estimated that 8 % of the popula-
tion of developing countries rely on traditional medicines,
mostly plant-based drugs, for their primary health care
needs. There are some simple herbs and roots that can be
used by people without a physician’s prescription. Medicinal
plants are a valuable natural resource and are regarded as
potentially safe drugs. They play an important role in allevi-
ating human diseases by contributing herbal medicines to the
primary healthcare systems of rural and remote areas where
more than 70% of the population depends on folk and tradi-
tional systems of medicines [1, 2]. The reason for their
popularity is the high cost and side effects of allopathic
*Address correspondence to this author at the Department of Bioresources,
School of Biological Sciences, University of Kashmir, Srinagar 190006,
India; Tel: 9622901319; E-mail: mirmanzoor110@gmail.com
medicines. The state of Jammu and Kashmir, cradled in the
lap of Himalayas, has been recognized as the heaven on earth
and is also called the biomass state of India, as it harbors a
rich diversity of medicinal plants [3, 4]. This area has a di-
verse variety of plant species, especially the plants of medic-
inal importance, due to its topography and microclimatic
conditions [4, 5]. Since ages, in the need of hour, people in
the valley have learned and practiced the medicinal usage of
plants /herbs growing in their vicinity for the treatment of
various ailments. Many studies have been carried out to doc-
ument the indigenous knowledge of medicinal plants from
different areas of the Kashmir valley. However, no study has
exclusively investigated the effect of plant species on cancer
and the mechanism involved.
Cancer is one of the major causes of death and is the se-
cond leading cause of mortality after cardiovascular diseases
[6]. Cancer starts with the deformation of natural cells
caused by a genetic mutation in the DNA of normal cells. A
few cancer syndromes are caused by inherited mutations of
protooncogenes that cause oncogene to be activated. Mutated
oncogenes are stimulated by the exposure to chemical, envi-
ronmental or viral carcinogens and are wrongly expressed in
the normal cells or expressed in inappropriate tissues which
leads to cellular proliferation, thereby resulting in cancer
Recent Advances in Metabolites from Medicinal Plants Current Immunology Reviews, 2019, Vol. 15, No. 2 191
formation. Tumor suppressor genes are intended to keep
oncogenes in check by halting uncontrolled cellular growth.
When tumor suppressor genes are inactivated or attenuated,
it leads to the promotion or initiation of cancer [9] Table 1.
Since various therapeutic procedures are used for the treat-
ment of cancer, undesirable side effects have been observed
in most cases, such as kidney damage, gastrointestinal disor-
ders, and other complications [7]. Therefore, natural prod-
ucts with higher effectiveness and lower side effects are de-
sirable. Natural products include various formula-
tions/compounds obtained from medicinal plants and herbs
that nature has blessed us with. The compounds include alka-
loids, phenols, monoterpenes, etc. These compounds have
antioxidant properties and cause the inhibition of damage to
DNA, cell cycle arrest (especially at the G2/M), induction of
apoptosis and inhibition of angiogenesis in tumor cells [8].
Therefore, the demand for medicinal plants is increasing in
both developed and developing countries due to the growing
reorganization of non-narcotic natural products having no
side effects, easily available at affordable prices and some-
times the only source of health care available to the poor.
Table 1. Types of cancer and their common oncogenic or
tumor suppressor gene origin.
Cancer Type
Common Oncogenic or Tumor
Suppressor Gene Origin
Leukemia, breast, colon, gastric and
lung
Cancer
c-MYC amplification
Renal cell cancer
Von Hippel-Lindaugene (VHL) dys-
function
Chronic myelogenous leukemia
Bcr-abl proto-oncogene translocation
Childhood neuroblastoma and small
cell lung
Cancer
n-MYC amplification
Follicular lymphoma
Bcl-2 amplification, myc mutation
Sporadic thyroid cancer
Ret mutation
Familial melanoma
P16INK4A mutation
Familial breast and ovarian cancer
BRCA1, BRCA2 mutation
Colorectal and gastric cancer
APC gene mutation
Invasive ductal breast cancer
HER-2 amplification
There are various methods available in the medical field
that are used for the treatment of cancer, such as chemother-
apy, radiotherapy, immunotherapy, CRISPR-Cas. However,
in these methods, there is non-selectivity of medicines due to
which a high percentage of healthy cells are lost with cancer
cells [7]. The most important problem in cancer treatment is
destroying tumor cells in the presence of natural cells, with-
out damaging the natural cells [10]. In order to prepare anti-
cancer medicines from natural resources, such as plants, test-
ing the cytotoxic compounds and screening the raw extracts
of plants are necessary [11]. Therefore, natural products with
higher effectiveness and lower side effects are desired [10].
Various medicinal herbs are important for cancer treatment
due to their multiple chemical compounds for discovering
new active materials against cancer [8]. Plants produce a
wide range of chemical compounds called secondary metab-
olites, such as alkaloids, terpenoids, flavonoids, pigments
and tannins, which have biologic effects, such as anti-
inflammatory, antioxidant, antimicrobial, anticancer, etc.
The development of novel plant derived natural products and
their analogs for anticancer activity requires efforts to syn-
thesize new derivatives based on bioactivity, mechanism of
action-directed isolation and characterization coupled with
rational drug design - based modification [12].
The review will shed light on the role of medicinal plants
in cancer and in the treatment of other human ailments, par-
ticularly those plants that grow in the temperate to tropic
regions of Kashmir valley. Table 2 describes the effects of
different metabolites of plants on cancer. This review will
give insight into the role of plants in human health and why
should we mostly rely on a plant-based diet. The review will
also shed light on the mechanism of action of different plant
products in cancer cells.
2. SAUSSUREA COSTUS
Saussurea costus, belonging to family Asteraceae, is
commonly known as costus and locally known as Kuth. Tra-
ditionally, it has been used to treat joint pain, back pain, sole
ulcers, dysentery, fever and urinary problems. C-17 polyene
alcohol, isolated from S.costus, exhibits moderate cytotoxici-
ty against the human tumor cell lines, A549, SK-OV3, SK-
MEL-2, XF 498 and HCT 15 [13]. Costunolide is a second-
ary metabolite synthesized by the mevalonic acid pathway
(Flow chart 1).
Flow chart 1. showing biosynthetic pathway of Costunolide, a
secondary metabolite derived from Saussurea costus [145].
192 Current Immunology Reviews, 2019, Vol. 15, No. 2 Mir et al.
Table 2. Showing list of some important medicinal plants and their phytochemicals against specific type of cancer.
Plant
Compound or Extract
Effective In
Cell Lines Used
Refs.
S.costus
Costunolide, lappadilactone,
Cynaropicrin
Leukemia, Liver, Gastric, cervical
and ovarian cancer
U937, Eol-1, HepG2, OVCAR-3,
heLa
[13-19]
T. foenum graecum
Quercitin,Squaline,
naringenin
Brain, Liver, breast,
Colorectal and thyroid cancer
MCF7, TCP, FRO,
A431, Hep2
[20-29]
Rosa damascenes
Beta-citronellal,Geranellal
Breast, Lung,
Gastric and cervical cancer
Hela, A549,
MCF7, MKN45
[30-36]
Podophyllum hexan-
drum
Podophyllin
Lung, ovarian and Testicular cancer,
Leukemia
HCT, HL-60,
HeLa, A-549
[37-46]
Papaver somniferum
Morphine, Noscapine,
Narcotine, codeine
Breast, colon,
Prostate, lung, Blood and
Ovarian cancer
HT-29, T47D
[47-54]
Lavatera cashmeria-
na
Protease inhibitors LC-pi-I, II,
III and IV
Lung, colon and blood cancer
NCIH322, Colo205,
HCT-116, THP-1
[55-60]
Achillea wihelmsii
Methanol extract
Colon, Stomach and Breast cancer
HT-29, human melanoma cells
[61-69]
Allium sativum
Allicin, Ajoene
Breast, larynx, colon, bladder, pros-
tate,
Gastric and lung, cancer
SGC-7901
[70-82]
Artemisia absenthium
Artemisisnin,Quercetin, isoham-
netin,Piene
Breast, colon and liver cancer
MDA-MB-231, MCF-7, MB-435,
SKMEL-5,
Du-145, HT-29
[83-91]
Cannabais sativa
Cannabinoid
Breast, Pancreatic,
Lung and Prostate
Cancer
MDA-MB-231
[92-99]
Crocus sativus
Safranal, crocin,
crocetin, picrocrocin
Breast, prostate, lung, pancreatic and
liver cancer
MCF-7, HeLa, HepG2, K562
[100-107]
D. stramonium
Witthanoliodes
Lung, stomach, breast and blood
cancer
A549, BGC-823, K562, MDA-MB231, FaDu
[92,108-112]
Urticadioica
Kaempferol, rutin
Prostate, Breast and esophageal can-
cer
LNCaP, hPCP. MCF 7
[113-121]
Viola odorata
Cycloviolacin O2
Breast, Lung and Ovarian Cancer
4T1, MCF 7
[122-129]
Viscum album
Viscumin
Breast and Cervical Cancer, Leuke-
mia
K562, THP 1, HeLa
[130-144]
Fig. (1). Chemical compound Costunolide, isolated from Saussurea
costus having anticancer activity.
Costunolide, an active compound isolated from the root
of S.costus, has been investigated for its effect on the induc-
tion of apoptosis in HL-60 human leukemia cells and its pu-
tative pathways of action (Fig. 1). It has been shown that
costunolide is a potent inducer of apoptosis, and facilitates
its activity via ROS generation, thereby inducing mitochon-
drial permeability transition (MPT) and cytochrome C re-
lease to the cytosol [14]. Costunolide also shows an anti-
angiogenic effect. This compound selectively inhibits the
endothelial cell proliferation induced by vascular endothelial
growth factor (VEGF). VEGF interacts with its cognate re-
ceptors, KDR/Flk-1 and Flt-1, and exerts its angiogenic ef-
fect. Costunolide inhibits the autophosphorylation of
KDR/Flk-1 without affecting that of Flt-1. These results
suggest that costunolide may prove to be useful for the de-
velopment of a novel angiogenesis inhibitor [15]. Studies
have demonstrated that Saussurea costus induced growth
inhibition and apoptosis of human gastric cancer cells, and
these effects were correlated with the down-regulation and
up-regulation of growth-regulating apoptotic and tumor sup-
Recent Advances in Metabolites from Medicinal Plants Current Immunology Reviews, 2019, Vol. 15, No. 2 193
pressor genes, respectively [16]. It has been shown that the
extracts of the root of S.costus can be used for the treatment
of gastric cancers either by traditional herbal therapy or by
combinational therapy with conventional chemotherapy [17].
Dehydrocostus Lactone (DL) is the major sesquiterpene lac-
tone isolated from the roots of Saussurea costus, which in-
hibits NF-kappa B activation by preventing TNF-alpha in-
duced degradation and phosphorylation of its inhibitory pro-
tein, I-kappa B alpha, in human leukemia HL-60 cells and
that DL renders HL-60 cells susceptible to TNF-alpha in-
duced apoptosis by enhancing caspase-8 and caspase-3 activ-
ities [18]. Cynaropicrin is another active compound isolated
from Saussurea lappa which exhibits immunomodulatory
effects on cytokine release, nitric oxide production and im-
munosuppressive effects. Cynaropicrin potently inhibits the
proliferation of leukocyte cancer cell lines, such as U937,
Eol-1 and Jurkat T cells, through pro-apoptotic activity [19].
3. TRIGONELLA FOENUM-GRAECUM
Trigonella foenum-graecum belongs to the family Legu-
minosae of the plant kingdom. It is commonly known as
Fenugreek and locally known as Meth. Diosgenin is a phy-
tosteroidal saponin and a major bioactive compound found in
the seeds of T. foenum-graecum (Flow chart 2). Several stud-
ies have been carried out to show the diverse biological ac-
tivities of diosgenin, such as hypolipidemic, anti-
inflammatory, anti-proliferative, anti-oxidant and hypogly-
cemic activity [20]. In addition, diosgenin has been found to
inhibit cancer cell proliferation and induced apoptosis in a
variety of cancer cell lines, including colorectal, hepatocellu-
lar, breast, osteosarcoma, and leukemia [21-23]. It has been
studied that the crude extract of fenugreek exhibits selective
cytotoxicity against some cell lines, such as MCF7, TCP
(T-cell lymphoma), FRO (thyroid papillary carcinoma), and
brain tumors [24]. It also shows protective effects against
breast cancer induced by DMBA (7,12-dimethylbenz
(a) anthracene) in mice [25]. In another study, the extract of
this plant showed inhibitory effects on the growth of cancer
cells. The main mechanism of anticancer activity is apoptosis
induction [24, 25]. Diosgenin, either alone, or in combina-
tion with thymoquinone, has been found to inhibit A431 and
Hep2 squamous cell carcinoma cell proliferation, increase
the Bax/Bcl2 ratio, and induce caspase 3-mediated apoptosis
[26]. It has been reported that diosgenin suppressed osteo-
clastogenesis by receptor-activated NFκB ligand (RANK-L)
induction of RAW-264.7 and suppressed TNF-induced inva-
sion of human non-small cell lung cancer H1299 cells [27].
Furthermore, diosgenin arrested chronic myelogenous leuke-
mia KBM-5 cells at the sub-G1 phase of the cell cycle and in-
hibited TNF-dependent NF-κB activation and TNF-induced
degradation and phosphorylation of IκBα (the inhibitory subunit
of NF-κB) [27]. Diosgenin induced differentiation of human
erythroleukemiaTIB-180 (HEL) cells by a mechanism involv-
ing the induction of glycoprotein Ib and suppressed 12-
lipoxygenase activity [28, 29]. Fig. (2) depicts the anticancer
molecule squalene isolated from Trigonella foenum.
4. ROSA DAMASCENA
Rosa damascene, belonging to family Rosaceae, is com-
monly known as rose and locally known as gulab or posh in
Kashmir. The flowers and leaves of the plant have tannin as
an active ingredient. It has gained great importance due to its
pharmacological properties, including anti-diabetic and anti-
HIV, and due to its potential to cure cardiovascular diseases
[22]. The petals of Rosa damascene have been reported to
contain several important chemical compounds, which in-
clude flavonoids, terpenes, anthocyanins, glycosides, car-
boxylic acid, vitamin C, myrcene, kaempferol and quercetin
[30]. The ethanol extract of the plant cell has tumoricidal
effects on cervical cancer cells (HeLa) [31]. It has also been
reported that the essential oil obtained from this plant has
toxic effects on lung cancer cell lines (A549) and breast can-
cer (MCF7) cell lines [31]. The essential oil affects gastric
cancer cells in two specific phases, soluble phase and the
vapor phase: the soluble phase increases cell viability, while
the vapor phase decreases cell survival. Also, by cytometry,
it has been shown that apoptosis is an important mechanism
accompanied by cell death [32]. Studies have been carried
out on gastric cancer cell line, MKN45, to show the anti-
cancer activity of Rosa Damascene, and its mechanism of
action on gastric cancer via flow cytometry [32]. In another
study, the effect of the essential oil of Rosa damascena was
investigated on the colon cancer cell line and normal human
fibroblast cells and it was found to have cytotoxic effects on
both the cell lines in different volumes [33]. Geraniol, syn-
thesized from glucose through the mevalonic acid pathway,
is one of the main compounds of Rosa damascene (Flow
chart 3). It induces the apoptosis of cancer cells,increases the
expression of apoptotic protein, Bak [34], arrests the
G0/G1phase of the cell cycle and reduces cdk2 activity
(Fig. 3) [35]. It has been reported that Geraniol suppresses
the growth of MCF-7 breast cancer cells via the induction of
cell cycle arrest in the G1 phase [36].
5. PODOPHYLLUM HEXANDRUM
Podophyllum hexandrum is a perennial herb belonging to
the plant family, Berberidaceae. It is commonly known as
the Himalayan mayapple and locally known as banwagun.
Podophyllum hexundrum contains a large number of com-
pounds that have significant pharmacological properties.
These compounds include epipodophyllotoxin, podophyllo-
toxone, aryltetrahydronaphthalene lignans, flavonoids, such
as quercetin, quercetin-3-glycoside, podophyllotoxin glyco-
side, kaempferol and kaempferol-3-glucoside. The rhizomes
and roots of the plant contain anti-tumor lignans, such as
podophyllotoxin, 4’-demethyl podophyllotoxin and podo-
phyllotoxin 4-O-glucoside [37, 38]. The biosynthetic mecha-
nism of podophyllotoxin includes the aromatic compound,
phenylalanine, and various other intermediate compounds
(Flow chart 4). Among these lignans, podophyllotoxin is the
most important due to its use in the synthesis of anti-cancer
drugs, such as etoposide, teniposide and etopophos [39].
These compounds are used for the treatment of lung and tes-
ticular cancers as well as certain leukemias [40]. The active
compound of Podophyllum hexundrum, podophyllin, has an
antimitotic effect, as it affects the key factors regulating cell
division and can thus prevent the growth of cells (Fig. 4)
[41]. The isolated compound has been reported to inhibit cell
division of tumor cells. It is, therefore, a possible drug for
the treatment of cancer, especially ovarian cancer [42]. The
semi-synthetic derive reported that teniposide and etoposide,
194 Current Immunology Reviews, 2019, Vol. 15, No. 2 Mir et al.
Flow chart 2. showing biosynthetic pathway of Diosgenin, a sec-
ondary metabolite derived from Trigonella foenum [146].
Fig. (2). Structure of squalene, isolated from Trigonella foenum
having anticancer properties.
Flow chart 3. showing biosynthetic pathway of Geraniol, a second-
ary metabolite derived from Rosa damascene [147].
Fig. (3). Chemical compound Geraniol, isolated from R.damascena
having anticancer activity.
atives of podophyllotoxin, etoposide and teniposide, play
an important role in the treatment of lung cancer, a variety
of leukemia and other solid tumors [43, 44]. In another
study, podophyllotoxin derivatives were found to have
promising cytotoxicities against a number of human cancer
cell lines, HL-60, A-549, HeLa, and HCT-8 [45]. It has been
Recent Advances in Metabolites from Medicinal Plants Current Immunology Reviews, 2019, Vol. 15, No. 2 195
used as chemotherapeutic agents, cause DNA damage by
inhibiting topoisomerase II, potently inhibiting MYB (tran-
scription factor) activity and inducing the degradation of
MYB in Acute Myeloid Leukemia (AML) cell lines [46].
Flow chart 4. showing biosynthetic pathway of Podophyllo-
toxin, a secondary metabolite derived from P. hexundrum
[148].
Fig. (4). Chemical compound Podophyllotoxin, isolated from
P. hexundrum having anticancer activity.
6. PAPAVER SOMNIFERUM
Papaver somniferum, belonging to the family Papavera-
ceae, is commonly known as opium poppy and locally
known as khashkhash. It is widely used for medicinal pur-
poses because it contains various alkaloids, such as mor-
phine, noscapine, narcotine, codeine, papaverine, and others
[47, 48] (Flow chart 5). The alkaloid, noscapine, obtained
from Papaver somniferum, is used in cancer treatment. It
interacts with α-tubulin and has anticancer and antiangioge-
netic properties (Fig. 5) [49]. Noscapine inhibits the progres-
sion of melanoma, lymphoma, leukemia, breast cancer, colon
cancer, ovarian carcinoma, glioblastoma, non-small cell lung
cancer and prostate cancer [49, 50]. Another alkaloid, co-
deinone, obtained from Papaver somniferum, is an oxidative
product of codeine and has been reported to possess apoptot-
ic effects through the fragmentation of DNA [51]. Morphine
is another alkaloid obtained from Papaver somniferum that
shows anticancer activities by inhibiting NF-κB [52]. Studies
have shown that noscapine and papaverine have dose-
dependent cytotoxic effects on cancer cell lines, HT-29 and
T47D, without any cytotoxic effect on noncancerous NIH-3
T3 cells [50]. It has been reported that noscapine induces
G2/M arrest in various types of cancers, such as breast, lung,
and colorectal cancer [53, 54].
7. LAVATERA CASHMERIANA
Lavatera cashmeriana, belonging to the family Malva-
ceae, is commonly known as Kashmiri mallow and locally
known as sazposh. Traditionally, it is used to treat mumps,
throat and skin problems and as a mild laxative. Four prote-
ase inhibitors viz LC-pi I, II, III and IV, which are purified
from the seeds of Lavatera cashmeriana, inhibits trypsin,
chymotrypsin and elastase (Fig. 6) [55] and have antibacteri-
al activity against Klebsiella pnuemoniae and Pseudomonas
aeruginosa in vitro [56]. Proteases play a critical role in can-
cer. Protease signaling pathways are strictly regulated and
the dysregulation of protease activity can lead to pathologies,
especially cancer. The dysregulated proteases cause the
dysregulation of the cell cycle, apoptosis, cell growth and
activation, cell-cell adhesion, cellular interactions and signal
transduction. Thus one possibility of cancer treatment is to
suppress the activity of proteases that play an important role
in tumour invasion and metastasis [57, 58]. Protease inhibi-
tors, found to be special agents in anticancer therapy, have
been isolated from plants [59, 60]. Protease inhibitors are a
family of small proteins that play an integral role in the de-
fense mechanism of plant against herbivory from insects or
microorganisms that may compromise the integrity of the
plant (Flow chart 6). In a study, LC-pi I and II were found to
significantly inhibit the in vitro growth of human acute mon-
ocytic leukemia cell line (THP-1), human lung carcinoma
cell line (NCIH322) and human colon cancer cell lines Co-
lo205, whereas only LC-pi I inhibited the growth of human
colon cancer cell lines (HCT-116) in a dose-dependent man-
ner. Furthermore, LC-pi III and IV could not inhibit the
growth of these cells. Their pharmacological effects may be
mediated through the inhibition of the protease activity and
the subsequent modulation of the protease pro-survival sig-
naling as LC-pi I and II strongly inhibited the in vitro activi-
ty of trypsin, elastase and chymotrypsin [56].
8. ACHILLEA WILHELMSII
Achillea wilhelmsii, belonging to family Asteraceae, is
commonly known as yarrow and locally known as pahal
gaeses. Traditionally, it is used as an antihypertensive and
antihyperlipidemic. The methanol extract of this plant has
demonstrated cytotoxic effects on colon cancer cells (HT-29)
[61]. It has also been found that the methanol extracts of the
leaves of the plant affect the cell lineage of colon cancer,
196 Current Immunology Reviews, 2019, Vol. 15, No. 2 Mir et al.
Flow chart 5. showing biosynthetic pathway of Noscapine, a sec-
ondary metabolite derived from Papaver somniferum [149].
Fig. (5). Chemical compound Noscapine, isolated from Papaver-
somniferum having anticancer activity.
stomach cancer and breast cancer [62]. The plant extract also
contains phenol compounds, especially flavonoids, which
suppress the division of cancer cells by inducing apoptosis
[63, 64]. 1,8-cineole (eucalyptol) is one of the most im-
portant monoterpene compounds synthesized via the meva-
lonic acid pathway (Flow chart 7) that causes apoptosis in
human melanoma cells (Fig. 7) [65]. Another compound
obtained from Achillea wilhelmsii is carvacrol which has
been reported to have an anti-proliferative effect on lung,
breast, and colon cancer cell lines [66-68]. It has been re-
ported that carvacrol significantly inhibits the migration and
invasion of human OSCC cells by blocking the phosphoryla-
tion of FAK and MMP-9 and MMP-2, transcription factor
ZEB1, and β-catenin proteins’ expression. Carvacrol signifi-
cantly reduces the proliferation and induced apoptosis by
regulating the cell cycle-associated proteins (P21, CCND1
and CDK4) and apoptosis-associated proteins (Cox2, Bcl-2,
and Bax) [69].
Flow chart 6. showing Synthesis of protease inhibitor, a polypep-
tide [150].
Fig. (6). Protein inhabitors, isolated from Lavatera cashmeriana
having anticancer activity.
9. ALLIUM SATIVUM
Allium sativum, belonging to family Amaryllidaceae and
subfamily allioideae, is commonly known as garlic and lo-
cally known as rhohun or lahsun. Garlic is used as food due
to its unique taste and odor. It is well established that the
wide variety of dietary and medicinal functions of garlic can
Recent Advances in Metabolites from Medicinal Plants Current Immunology Reviews, 2019, Vol. 15, No. 2 197
Flow chart 7. showing biosynthetic pathway of Eucalptol, a sec-
ondary metabolite derived from Achillea wihelmsii [151].
Fig. (7). Chemical compound Eucalyptol, isolated from Achillea
wihelmsii having anticancer activity.
be attributed to the sulfur compounds present in or generated
from garlic. Although garlic produces more than 20 kinds of
sulfide compounds from a few sulfur-containing amino acids,
their functions are different from one another; e.g., allicin,
methyl allyltrisulfide and diallyl trisulfide have anti bac
terial, antithrombotic and anticancer activities, respectively
Flow chart 8. showing biosynthetic pathway of Allicin, a second-
ary metabolite derived from Allium sativum [152].
Fig. (8). Chemical compound Allicin, isolated from Allium sativum
having anticancer activity
[70]. Allicin is synthesized from glutathione via a number of
intermediate compounds (Flow chart 8). It has been reported
that Allium sativum and organosulfur compounds reduce the
risk of cancer in breast, larynx, colon, skin, womb, gullet,
bladder, and lung [71, 72]. Moreover, allicin has been found
to have antitumor effects on breast and prostate cancer by
inducing apoptosis (Fig. 8) [73, 74]. Allicin is a known pro-
liferation inhibitor of malignant human cells. When human
gastric cancer cell line SGC-7901 were treated with allicin, it
was found that different concentrations of allicin apparently
inhibited gastric cancer SGC7901 cells [75]. Ajoene, another
compound of Allium sativum, suppresses the proliferation of
leukemia and causes apoptosis [76, 77]. It has been reported
that the growth inhibition of gastric cancer by allicin is main-
ly by arresting the cell cycle at the G2/M phase, Endoplas-
mic Reticulum (ER) stress, and mitochondria-mediated
apoptosis, which includes the caspase-dependent/-
independent pathways and death receptor pathway [78, 79].
The antiproliferative effects of garlic on various cells have
been considered as a barrier against the progression of the
198 Current Immunology Reviews, 2019, Vol. 15, No. 2 Mir et al.
cell cycle from the G1 phase to the G2 phase or from the G2
phase to the M phase [80]. It has also been reported that gar-
lic extract prevents oxidative modification of DNA, proteins
and lipids by scavenging ROS, increasing the expression of
cellular antioxidant enzymes and enhancing glutathione lev-
els in normal cells [81]. It has also been studied that garlic
extract increases caspase-3 activity in the human cancer cell
lines, such as hepatic (HepG2), colon (Caco-2), prostate (PC-
3), and breast (MCF-7) [82].
Flow chart 9. showing biosynthetic pathway of Artemisinin, a
secondary metabolite derived from Artemisia absenthium [153].
Fig. (9). Chemical compound Artemisinin, isolated from Artemisia
absenthium having anticancer activity.
10. ARTEMISIA ABSINTHIUM
Artemisia absinthium, belonging to Asteraceae family, is
commonly known as wormwood and sagebrush and in
Kashmir as ‘Tethwen’. In Kashmir, it is traditionally used as
a vermifuge, an insecticide, an antispasmodic, an antiseptic
as well as in the treatment of chronic fevers and inflamma-
tion of the liver [83]. The essential oil obtained from it has
antimicrobial [84] and antifungal activity [85]. The chemical
analysis of the extracts of Artemisia absinthium has shown
that its volatile oil is rich in thujone, which has been reported
as an anthelmintic agent [86]. The main compounds of Arte-
misia absinthium are artemisinin, quercetin, isorhamnetin,
kamfrolinalol, alpha-pinene, limonene, and myrcene. Arte-
misinin is biosynthetically obtained from acetyl- CoA by the
mevalonic acid pathway (Flow chart 9). It has been found
that artemisinin inhibits the proliferation of human breast
cancer MDA-MB-231 and MCF-7 cells through the induc-
tion of apoptosis by regulating Bcl-2 family proteins and
MEK/MAPK signaling (Fig. 9). It has also been found that
p53-independent cell death induced by Artemisia absinthium
is regulated through an MEK–ERK–mitochondria–caspase
cascade that may help in the improvement of the clinical
outcome, which suggests that the extract of Artemisia ab-
sinthium has an anticancer effect that is mediated via the
apoptotic pathway in human breast cancer cell lines [87, 88].
Artemisinin has been shown to inhibit the production of the
angiogenic factor VEGF [89]. Quercetin inhibits the growth
of many cancer cells, such as MCF-7, and isorhamnetin in-
hibits the growth of many cancer cells, such as MB-435,
SKMEL-5, Du-145 and MCF-7 [89]. Other novel com-
pounds from Artemisia absinthium, such as Alpha-pinene,
beta-pinene, limonene, and myrcene, are the probable factors
for inhibiting the growth of human breast cancer,hepatic
cancer and melanoma. Alpha-pinene, beta-pinene, and limo-
nene, available in the methanol and ethanol extracts of this
plant, are the inhibitory factors of HT-29 cells (colon cancer)
[90]. It has been reported that Artemisinin induces apoptosis
by the intrinsic mitochondrial pathway, mediated by caspase
3/9 activation and the release of cytochrome C, following the
permeabilization of the mitochondrial membrane [91].
11. CANNABIS SATIVA
Cannabis sativa is a dioicous plant of the cannabaceae
family, commonly known as hemp and locally known as
bhang. It is used as a psychoactive drug, and as a traditional
medicine to treat ear-ache, scabies and piles [92]. The active
components of Cannabis sativa are cannabinoids which,
along with their derivatives, exert palliative effects on cancer
patients by preventing nausea, vomiting and pain and also by
stimulating the appetite (Fig. 10). Cannabinoids are derived
from acetyl-CoA (Flow chart 10). These compounds have
also been shown to possess anti-tumor activity in cell culture
and animal models by modulating key cell-signaling path-
ways [93]. Various studies have been conducted which sug-
gest that Δ9-THC and other naturally occurring cannabinoids,
synthetic cannabinoid agonists and endocannabinoids have
anti-cancer properties against lung carcinoma, gliomas, thy-
roid epithelioma, lymphoma, skin carcinoma, uterine carci-
noma, breast cancer, prostate carcinoma, pancreatic cancer
and neuroblastoma [94]. Cannabinoids inhibit the migration
and invasion of MDA-MB231 breast cancer cells [95].
Recent Advances in Metabolites from Medicinal Plants Current Immunology Reviews, 2019, Vol. 15, No. 2 199
Flow chart 10. showing biosynthetic pathway of Cannabinoid, a
secondary metabolite derived from Cannabis sativa [154].
Fig. (10). Chemical compound Cannabinoid, isolated from Canna-
bis. sativa having anticancer activity.
Cannabinoid treatment promotes cancer cell death, impairs
tumor angiogenesis and blocks the invasion and metastasis
[96]. It has been studied that cannabinoids inhibit the stimu-
lation of the vascular endothelial growth factor (VEGF)
pathway. Thus, various components of the VEGF-activated
pathway, such as the active forms of its best-established re-
ceptors (VEGFR1 and VEGFR2), have been shown to be
down-regulated in response to the treatment with canna-
binoids in different cancer types [97]. Cannabinoid receptor
activation inhibits the migration and proliferation and induc-
es apoptosis in vascular endothelial cells which might also
contribute to the antiangiogenic effect of cannabinoids [98].
It has been studied that cannabinoids affect various cellular
pathways by binding and activating their specific G-protein-
coupled cannabinoid receptors. They inhibit the adenylyl
cyclase cyclic AMP (cAMP) protein kinase A pathway and
modulate the activity of Ca2+ and K+ channels, which inhibits
neurotransmitter release (BOX 1) [99].
Flow chart 11. showing biosynthetic pathway of Safranal, a sec-
ondary metabolite derived from Crocus sativus [155].
Fig. (11). Chemical compound Safranal, isolated from Crocus sa-
tivus having anticancer activity.
200 Current Immunology Reviews, 2019, Vol. 15, No. 2 Mir et al.
12. CROCUS SATIVUS
Crocus sativus, a perennial plant belonging to family
Iridaceae, is commonly known as saffron and locally known
as kung. Traditionally, it is used to treat asthma, arthritis,
digestive disorders, diuretic, leucorrhoea, etc. The part of the
plant used is stigma which is known as saffron. Various
studies have been carried out on saffron extract showing
anticancer effects in vitro; for example, materials separated
from saffron, such as crocin, crocetin, picrocrocin, and saf-
ranal are known to induce apoptosis in cancer cells (Fig. 11)
[100, 101]. In another study, quercetin, plant substance of
saffron, showed cytotoxic effects on colorectal cancer cells
[102]. Studies have also revealed that C. sativus has an anti-
angiogenic effect on breast cancer cells (MCF-7), as the ex-
tract of this plant inhibits angiogenesis in these cells [103].
Geromichalos et al. performed an experimental work in
which they demonstrated the safranal (SFR) and crocin me-
diate cytotoxic response to K562 cells (human chronic mye-
logenous leukemia cells) [104]. Safranal is synthesized by
the mevalonic acid pathway (Flow chart 11). Saffron can be
used as a chemotherapeutic agent to treat cancer in humans
in the future [103, 105]. It has been reported that crocetin-
mediated inhibition of tumor growth includes the reduction
in the synthesis of DNA, RNA and protein [106]. It has also
been demonstrated that crocetin inhibits RNA polymerase II
activity [107].
13. DATURA STRAMONIUM
Datura stramonium is a wild weed belonging to family
Solanaceae, and its name has been derived from a Sanskrit
word “Dhutra”. It is commonly known as daturas, Jimson
weed or devil’s snare and locally known as datur. Tradition-
ally, datura plant parts are used to treat various disorders,
including asthma, skin disorders, jaundice, piles, diabetes,
rheumatism, frostbite and toothache [92, 108]. In a chemical
investigation of the methanol extract of the flowers of Datu-
ra, it was found that the isolated withanolides exhibit cyto-
toxic activities against various cancer cell lines, including
A549 (lung), BGC-823 (gastric) and K562 (leukemia) (Fig.
12) [109]. Withanolides are mainly derived from acetyl-CoA
(Flow chart 12). In another study, it was found that Datura
stramonium agglutin (DSA (lectin)) induced irreversible
differentiation in C6 glioma cells. The differentiated cells
had long processes, a low rate of proliferation and a high
content of glial fibrillary acidic protein. The proliferation of
four human glial tumor cells was also inhibited by DSA,
which suggests its usefulness as a new therapy for treating
glioma without side effects [110]. When isolated endophytic
fungi from Datura stramonium was tested for the antitumor
activities by the MTT assay in human gastric tumor cell line
BGC-823, it showed a 100% growth inhibition rate [111].
Further studies were carried out on human cancer cell lines
in vitro on MDA-MB231 (breast) and FaDu (neck), which
were treated with Datura stramonium aqueous leaf extract
for 24 and 48 h and showed an increase in GSSG in FaDu
cells indicating oxidative stress in treated cells [112].
14. URTICA DIOICA
Urtica dioica belongs to the family Urticaceae of the
plant kingdom. It is commonly known as stinging nettle and
locally known as soi or sadder. Traditionally, it is used to
induce activity in paralyzed limbs and is also used as a vege-
table. It has been reported to exhibit anti-arthritic, analgesic,
antioxidant, antimicrobial and antiulcer activity [113, 114].
Extracts of stinging nettle have also shown clinical efficacy
in alleviating symptoms of benign prostatic hyperplasia.
Studies have shown that the aqueous and ethanol extracts of
the plant show cell proliferation inhibitory effect on prostate
cancer cells (LNCaP and as hPCPs) [115]. It has also been
found that the extract of this plant has anticancer effects
against esophageal cancer [116]. It has been shown that the
root extract of this plant has an antiproliferative effect on
human prostate cancer cells [117]. Studies have been carried
out on the antiproliferative and apoptotic effects of different
extracts (aqueous, hydroalcoholic, chloroform and ethyl ace-
tate) of U. dioica on KG-1 cell line for acute myelogenous
leukemia [118]. It has been shown that the leaf extract of this
plant exerts antioxidant, antiproliferative and apoptotic ef-
fects on the MCF-7 cell line (human breast cancer cell line)
[119]. It has been reported that Urtica dioica selectively
kills NSCLC cells by promoting ER-mediated apoptosis
[120]. It has also been reported that U. dioica promotes
Endoplasmic Reticulum (ER) stress via the activation of the
growth arrest and DNA damage-inducible gene 153
(GADD153) triggering apoptosis [121]. Phenylalanine acts
as a precursor molecule for the synthesis of Rutin (Fig. 13).
Rutin, a highly anti-proliferative compound isolated from U.
dioica, has demonstrated high potential in inhibiting cancer
growth in vitro (Flow chart 13).
Flow chart 12. showing biosynthetic pathway of Withanolide, a
secondary metabolite derived from Datura stramonium [156].
Recent Advances in Metabolites from Medicinal Plants Current Immunology Reviews, 2019, Vol. 15, No. 2 201
Fig. (12). Chemical compound withanoliode, isolated from Datura
stramonium having anticancer activity.
Flow chart 13. showing biosynthetic pathway of Rutin, a second-
ary metabolite derived from Urtica dioica [157].
Fig. (13). Chemical compound Rutin, isolated from Urtica dioica
having anticancer activity.
15. VIOLA ODORATA
Viola odorata, belonging to family Violaceae, is com-
monly known as garden violet and locally known as
bunufsha. Traditionally, V. odorata has been recognized as a
medicinal herb that is widely used in anxiety, lower blood
pressure, bronchitis, kidney liver disorders and also in reliev-
ing cancer pain [122]. A number of reports have also indicat-
ed the anti-inflammatory, antipyretic, antioxidant and anti-
bacterial activities of V. odorata [123, 124]. All the aerial
parts, including stem, flowers and leaves, are used in cancer.
Viola has been reported as a pharmacological tool and an
antitumor agent [125]. Cycloviolacin O2 (CYO2), a cyclo-
tide from Viola odorata, has antitumor effects and causes
cell death by membrane permeabilization (Fig. 14) [126].
Cyclotides are small disulfide-rich peptides typically con-
taining 28-37 amino acids. They are characterized by their
head-to-tail cyclized peptide backbone and the interlocking
arrangement of their three disulfide bonds (Flow chart 14).
Flow chart 14. showing synthesis of cyclotide, globular micropro-
tein with cyclized backbone, which is stabilized by three disulfide
bonds [158].
Fig. (14). Chemical compound Cycloviolacin, isolated from Viola
odorata having anticancer activity.
202 Current Immunology Reviews, 2019, Vol. 15, No. 2 Mir et al.
Flow chart 15. showing biosynthetic pathway of Caffeic acid, a
secondary metabolite derived from Viscum album [159].
Fig. (15). Chemical compound Caffeic acid, isolated from Viscum
album having anticancer activity.
Cycloviolacin O2 (CYO2), a cyclotide obtained from
Viola odorata, shows selective toxicity against cancer cell
lines relative to normal cells, which indicates the possibility
of its use as an anticancer agent [126]. The analysis of the
proposed mechanism of action shows that the disruption of
cell membranes plays a crucial role in the cytotoxicity of
cycloviolacin O2 (CYO2) because damage to cancer cells
(human lymphoma) can be morphologically distinguished
within a few minutes, indicating necrosis [127]. It has been
reported that Viola odorata hydro-alcoholic extract (VOE)
has cytotoxic effects on 4T1 breast cancer cells and affects
the antioxidant activity and metastasis in breast cancer [128].
It has been shown that cyclotides isolated from several spe-
cies of Viola have cytotoxic activity against various cancers,
including renal adenocarcinoma, T‐cell leukemia, lung can-
cer, myeloma, lymphoma and ovarian cancer [125, 129].
16. VISCUM ALBUM
Viscum album is a hemiparasitic shrub belonging to plant
family Santalaceae that grows on the stems and crowns of
other broad-leaved trees, especially walnut, lime, hawthorn,
and poplar. Viscum album is also commonly known as Eu-
ropean mistletoe and common mistletoe and locally known
as ahul in Kashmir [130]. Traditionally, it is used as a laxa-
tive and to treat fractures and rheumatism. It has hyperten-
sion & anticancer effects. Lectins (ML-I, ML-II, and ML-III)
are the main constituents of mistletoe which are responsible
for its antitumor and immunomodulatory effects [131-133].
A toxic lectin protein, viscumin, is isolated from the extracts
of Viscum album [134]. Viscumin (mistletoe lectin-1 or ML-
1) has been found to be effective in cancer treatment. In vitro
(cell-free and cellular preparations) and animal studies have
shown that it has cytotoxic effects on 3T3 cells, is lethal to
mice and is a protein synthesis inhibitor [135, 136]. Vis-
cumin has been found to induce apoptosis in murine lym-
phocytes (ML-3, ML-2, and ML-1), human peripheral blood
lymphocytes and monocytes, murine thymocytes, human
monocytic leukemia cell line (THP-1 cells), and human er-
thromyeloblastoid leukemia (K562) cell line [137]. Viscumin
also enhances the activity of natural killer cells and granulo-
cyte phagocytosis in patients with breast cancers [138]. It has
been studied that viscum extracts mediate apoptosis induc-
tion by the activation of the PI3K/AKT pathway,
JNK/p38/MAPK signaling and caspase cascades (139-141).
Viscum lectins and viscotoxins are known to stimulate the
immune system by activating leukocytes resulting in cyto-
kine release, inhibition of cell proliferation and induction of
apoptosis by triggering PI3K/Akt-, MAPK- and TLR-
signalling, resulting in the activation of caspases [139, 142-
144]. The chemical compound, Caffeic acid, is synthesized
from tyrosine through various intermediate compounds
(Flow chart 15). This compound from Viscum album demon-
strates high anticancer activity (Fig. 15).
CONCLUSION
Keeping in view the high cost of allopathic medicine and
side effects caused by them, the use of medicinal plants
against different diseases plays a significant role in meeting
the primary health care needs, particularly in developing
countries. Herbs play a vital role in the prevention and treat-
ment of cancer. The photochemical exploration of these
herbs has contributed, to some extent, to the discovery of
new anticancer drugs. Although drug discovery from medic-
inal plants continues to provide an important source of new
drug leads, numerous challenges are encountered, including
the procurement of plant materials and their selection. Be-
sides, the information could prove to be a fruitful source to
the pharmacologists, phytochemists, botanists and those in-
terested in the development of alternative therapies. The uti-
lization of indigenous drug resources will boost the local
industry on one hand and minimize the expenditure incurred
on the purchase of foreign drugs on the other.
This review gives an idea of how compounds from vari-
ous plants can serve as a promising and effective research
Recent Advances in Metabolites from Medicinal Plants Current Immunology Reviews, 2019, Vol. 15, No. 2 203
area in the future. The growing incidence of cancer, and high
cost and toxicity of present anticancer drugs are the most
challenging aspects for cancer treatment, thus prompting
researchers to develop and design an alternative, eco-
friendly, biocompatible and cost-effective strategy for cancer
treatment in a greener way. High biodegradability and bio-
compatibility have increased the efficacy of these phytomol-
ecules in cancer therapy. This review paper provides infor-
mation on medicinal plants and their bioactive compounds
with a potential to cure different types of cancer. Potential
anticancer compounds obtained from various plants of
Kashmir valley described in this review article should be
further researched in clinical trials on different models for
their effectiveness and toxicological profile. Furthermore,
extensive research work should be carried out on these phy-
tochemicals to evaluate their possible applications, toxico-
logical and particularly, genotoxic profiles against a wide
range of cancer both in-vitro and in-vivo. It is also suggested
to document such vital and valuable knowledge for the future
generations as this knowledge is declining with time. There-
fore, the extract and active compounds of the medicinal
plants introduced in this review article can open a way to
conduct clinical trials on cancer and greatly help researchers
and pharmacists to develop new anticancer drugs.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
MAM initiated the study, designed the plan and edited
the manuscript. SSH, UM, BAS, BAB wrote the manuscript
and designed the figures and tables. All the authors read and
approved the final manuscript.
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