Disease can occur due to alterations in many physiological processes. A variety of factorsare known to be involved in the progression of cancer, a chronic diseasethat occurs due to permissible proliferative signaling, avoiding growth suppressors, resisting cell death, allowing replicative immortality, induction of angiogenesis, and inducing invasion and metastasis, along with reprogramming of metabolic pathways involved in energy production and avoiding the host immune response for cell destruction. Treatment of such a multifactorial disease has very less cure rate because of the singular agents tried in the past for targeting. Molecular level studies with deeper insight are urgently neededthat focus on the most promising herbal-derived bioactive substances for which thorough research was carried out in the literature in various data-bases such as PUB-MED, MEDLINE, SCOPUS indexed journals etc. to look for systematic reviews of the protocols or data interpretation, natural drug/immunological properties and validation. As immune system plays avery important role in the proliferation or suppression of cancer and other autoimmune diseases, It is the dire need to study the effect of such natural compound on the immune system so that a possible drug target or epitope can be identified for the treatment of such diseases. In nutshell there are many nonclinical in vitro and in vivo studies on herbal medicines which commonly supports the traditional therapeutic claims. It has been seen from the previos studies in literature that the yield and composition of bioactive compounds derived from plants are dependent upon the production source,culturing conditions and extraction protocols.Therefore appropriate optimization conditions would certainly assist the medical and scientific fraternity to accept herbal products as potential candidates for cancer treatment. In this article we explored the different natural products, their immunological effects concerning cancer with no or negligible side effects. However,one has to look for potential herb–drug or herb-epitope interactions and how immune system responds to such drugs.

1. Page | 902
Anti-cancer potential of natural products: recent trends, scope and relevance
Gobind Ram 1
, Var Ruchi Sharma 2
, Imran Sheikh 3
, Atul Sankhyan 4
, Diwakar Aggarwal 5
,
Anil K. Sharma5,*
1
Department of Biotechnology, LayalpurKhalsa College, Jalandhar,Punjab, India
2
Department of Biotechnology, Sri Guru Gobind Singh College Sector-26, Chandigarh (UT) India
3
Department of Biotechnology, Eternal University, Baru Sahib, Sirmour, Himachal Pradesh,India
4
Department of Dentistry, Swami Devi Dyal Hospital and Dental College, Panchkula (Haryana) India
5
Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala (Haryana)
*corresponding author e-mail address: anibiotech18@gmail.com | Scopus ID 55693618000
ABSTRACT
Disease can occur due to alterations in many physiological processes. A variety of factorsare known to be involved in the progression of
cancer, a chronic diseasethat occurs due to permissible proliferative signaling, avoiding growth suppressors, resisting cell death, allowing
replicative immortality, induction of angiogenesis, and inducing invasion and metastasis, along with reprogramming of metabolic
pathways involved in energy production and avoiding the host immune response for cell destruction. Treatment of such a multifactorial
disease has very less cure rate because of the singular agents tried in the past for targeting. Molecular level studies with deeper insight
are urgently neededthat focus on the most promising herbal-derived bioactive substances for which thorough research was carried out in
the literature in various data-bases such as PUB-MED, MEDLINE, SCOPUS indexed journals etc. to look for systematic reviews of the
protocols or data interpretation, natural drug/immunological properties and validation. As immune system plays avery important role in
the proliferation or suppression of cancer and other autoimmune diseases, It is the dire need to study the effect of such natural compound
on the immune system so that a possible drug target or epitope can be identified for the treatment of such diseases. In nutshell there are
many nonclinical in vitro and in vivo studies on herbal medicines which commonly supports the traditional therapeutic claims. It has
been seen from the previos studies in literature that the yield and composition of bioactive compounds derived from plants are dependent
upon the production source,culturing conditions and extraction protocols.Therefore appropriate optimization conditions would certainly
assist the medical and scientific fraternity to accept herbal products as potential candidates for cancer treatment. In this article we
explored the different natural products, their immunological effects concerning cancer with no or negligible side effects. However,one
has to look for potential herb–drug or herb-epitope interactions and how immune system responds to such drugs.
Keywords: Cancer; therapy; natural products; herbs; nutrition.
1. INTRODUCTION
Natural products (NPs) have tremendous capacity to cure
deadly diseases like cancer. These products are herbs,
Neutraceuticals and dietary phytoconstituents that have the
capacity to produce anti-cancerous activities by interfering with
initiation, development and progression of cancer through
modulation of various mechanisms including cellular proliferation,
differentiation, apoptosis, angiogenesis and metastasis. The natural
products are getting attention for the treatment of such kind of
diseases because of their no side effects and cost effectiveness.
These natural products have different immunological and
anti-cancerous properties because of which these NP are gaining
attention for the treatment of such kind of diseases. (Figure 1)
Approximately 36% of small molecules approved by United State
Food and Drug Administration (US-FDA) from 1999 -2008 were
NPs or NPs derivatives [1] according to a recent analysis of
strategies used in the discovery of new drugs. Similarly, an
analysis of new and approved drugs for cancer by US-FDA over
the period of 1981-2002 showed that 62% of the cancer drugs
were of natural origin [2].
The drug-discovery, biochemical characterization along
with appropriate clinical trials of the drugs derived from the
marine environment are consistently underway as have been seen
previously[3]. But on the other hand there are limited studies as
far as the literature in the field of nature products and medicines
[4].
Figure 1. Wide-spectrum therapeutic potential of natural products.
Approximately more than 600 natural products have been
reported that possess pharmaceutical activity as well as anti-cancer
activity. Curcumin which is also known as diferuloyl methane has
been derived from Curcuma longa,constitutes one of such natural
bioactivecompounds possessing promising anti-cancer and
chemoprevention activities[5]. This phenolic compound has the
ability to influence a wide-variety of cancer signaling pathways
including NF-κB, STAT3, PI3K /Akt pathways. Curcumin has also
been reported to modulate the cancer cell proliferation by
Volume 9, Issue 1, 2020, 902 - 907 ISSN 2284-6808
Open Access Journal
Received: 02.03.2020 / Revised:18.03.2020 / Accepted:18.03.2020 / Published on-line: 21.03.2020
Original Review Article
Letters in Applied NanoBioScience
https://nanobioletters.com/
https://doi.org/10.33263/LIANBS91.902907

2. Anti-cancer potential of natural products: recent trends, scope and relevance
Page | 903
specifically targeting the mTOR (Mammalian target of rapamycin) signaling pathway [6](Table 1).
2. IMMUNOGENIC POTENTIAL OF NATURAL PRODUCTS
2.1. Curcumin.
Curcumin has been reported to contain the spread of the
tumor restricting its outgrowth.Moreover it rejuvenates and
restores the immunological activity against cancer [40].
Curcuminis reportedly known to restore CD4+/CD8+ T-
lymphocyte cell population, skewing the immune response
towards Th-1 type,reducing the regulatory T-cell population and
suppressing the programmed cell death of T-cells.The tumor
immunosurveillanceis further restored resulting the regression of
the tumor.Therefore, it is of paramount interest to further explore
the interactive relationship of cucumin with the host immune
system proving as a vital product having enhanced activity against
cancer [41].
Table 1. Prominent bioactive compounds derived from plants and their targets.
Natural Compounds Gene Specific Targets/Functions Reference No
Curcumin Wnt/β-catenin pathway; MMP2, MMP14, TIMP-1,Gelatinase; EGF, MMP9,VEGF, bFGF,NF-κB,
STAT3; PI3K/AKT,mTOR, JNK, ERK1/2,uPA, VEGF, KDR, Angiopoietin1/2
[7-12]
Sulforaphane (SFN) Wnt/β-catenin pathway, [13,14]
Resveratrol β-catenin, VEGF,Src, NF-κB, AP1, Egr1; MAPKs; AR; AKT; Caspase-9; COX; NOS; IL-1β, PI3K [15, 16]
Caffeic acid phenethyl
ester (CAPE)
Wnt/β-catenin signaling; NF-κB; HER2; AKT; ERK; ER-α;MMP2 [17-21]
Quercetin Wnt/β-catenin signaling; EGF; VEGF; HER2/neu; HER3; VEGF-R2; COX-2;iNOS; TGF-α; c-Raf;
MEK1/2; Elk-1; AKT;mTOR
[22-26]
EGCG Wnt/β-catenin signaling; NF-κB; DNMT [27- 28]
Lycopene NF-κB; MMP9; IGF-1; AKT; β-catenin;cyclin D1; Bad; AR;PSA;pRb; ICAM-1; TNFα; SP-1; IGF-1R
Genistein EGF; FOXO3; NF-κB; Notch-1;uPA; JNK; ERK1/2 [29-31]
13-cis-retinoic acid IL-2; TIMP-1; NF-κB; ATF-2; c-fos [32-33]
Indol-3-carbinol (I3C) IGF1R; IRS-1; ERα [34]
Urolithin, ellagitannins
and punicalagin
PSA; Aromatase; NF-κB [35]
Amentoflavone COX-2; iNOS [36]
Indirubin VEGF-R2; JAK/STAT3 [37]
Salvianolic Acid B (Sal
B)
TGF-β1; Smad2/3; Smad7; MMP2 [38]
Andrographolide Antioxidant enzymatic activity increase, cytotoxic effect against cancer cell lines. [39]
Phyltetralin Cell cycle arrest, Inhibition of topoisomerase I and II activity and cell proliferation among different
cultures.
Bullatacin Cytotoxicagainst tumor cell lines
Camptothecin Inhibits topoisomerase-1, chemotherapy drug against leukemia
2.2. Sulforaphane and indol-3-carbinol (I3C).
Indol-3-carbinol (I3C) formed as a result of hydrolysis of
glucobrassicin present in Cruciferous vegetables, was reported to
have an inhibitory activity towards cancer cells in terms of cell
proliferation.The compound resulted in modulation of expression
of insulin-like growth factor receptor-1 (IGF1R) and insulin
receptor substrate-1 (IRS1) which was further reported to induce
estrogen receptor-alpha (ERα) degradation [42]. Similarly
vegetables belonging to family Crucifera have been known to
possess an organo-sulfur natural compound named as sulforaphane
(SFN).This compound is formed as a result of glucosinolates
undergoing hydrolysis .SFN was reported to have anti-oxidant and
activity against cancer as well. The same study based upon
epidemiological data revealed that the intake of cruciferous
vegetables could be responsible for lowering down the prostate
and colon cancer risk [43]. In vitro and in vivo studies further
supported the action of brassinin,an indole based compound
derived from cruciferous vegetables displaying inhibitory role
against cell proliferation,thus having anti-cancer properties [44].
(Table 1).
2.3. Resveratrol.
Grapes have been reported to have a natural compound
called as 3,4′,5-trihydroxy-trans-stilbene, polyphenolic in nature
which is also known commonly as Resveratrol having wide-
spectrum bioactive properties.This compound was shown to have
anti-cancer chemoprevention property along with cardioprotective,
anti-inflammatory and anti-viral actions [45-48]. More so
Resveratrol displayed anti-proliferatve action along with the
promotion of cell cycle arrest, and apoptosis inducer in cancer
cells.This was mediated through the suppression of ERK1/2 (an
extracellular signaling kinase),tumor suppressor protein
p53,Rb/E2F,cell cyclins and CDKs as well.Moreover
transcriptional factors involved in cell proliferation along with
stress responses including NF-κB, activator protein 1 (AP1) and
Egr1, mitogen-activated protein kinases (MAPKs), tyrosine
kinases (Src) are reported to induce apoptosis. Further Resveratrol
(RV) effects were evaluated on M21 and NXS2 cancer cells
displaying anti-tumorogenic and immunosuppressive properties
evaluated in human and murine models. The RV with a
concentration of ≥ 25mcM was found to inhibit cell
proliferation.The same concentration of RV was reported to arrest
DNA synthesis as well.Moreover it was found to induce G1cell
cycle phase arrest in tumorigenic and immunological cells. RV at
a concentration range of 12–50 mcM was reported to inhibit
antibody dependent cell mediated cytotoxicity (ADCC) in
tumorigenic cells.The above effect wasfacilitated through the
immune-cytokine (IC) hu14.18-IL2. Anti-cancer and
immunomodulatory potential of RV was further assessed in mice
model resulting in growth inhibition of NXS2 tumor in vivo
without interfering with the blood cell count,macrophage or

3. Gobind Ram, Var Ruchi Sharma, Imran Sheikh, Atul Sankhyan, Diwakar Aggarwal, Anil K. Sharma
Page | 904
splenocyte function. Therefore RV seems to be a potential
candidate for combinational immunotherapeutics
[49].
2.4. Epigallocatechingallate (EGCG).
Epigallocatechingallate (EGCG) is a flavonoid present in
green tea along with other polyphenols have been reported to
reduce the incidence of growth and cancer development. This
flavonoid has the potential to suppress the androgen receptor
expression and induce the process of signaling via several growth
factor receptors. Moreover, EGCG has been known to block the
nuclear translocation of the NF-κB transcription factor [50].
In another study, EGCG significantly suppressed the
proliferation of peripheral blood mononuclear cells (PBMC) in
response to stimulation separately with the mitogen, anti-CD3
antibody, and the cancer antigen peptides. In in vitro study it was
shown that the IFN-γ production was also significantly suppressed
by EGCG. It appears that EGCG hasan immunosuppressive effect
on the proliferation of PBMC, indicating that it is worth exploring
for immunomodulatory effects in autoimmune diseases and tissue
transplantation [51].
2.5. Genistein.
One of the isoflavones,Genistein has been reported to uccur
in Soy.This flavonoid has been derived from the hydrolysis of the
glycoside, genistin. The consumption of Soy has been reported to
lower down the incidence of variety of cancers, including the
colon cancer.The studies reveal that this anticancer effect of soy is
mainly mediated through the isoflavonoid, genistein. The negative
effects of epidermal growth factor (EGF) on the fork head box O3
(FOXO3) protein activity were greatly attenuated by this
Genistein molecule and resulting in inhibition of cancer
progression and blocking cell proliferation [52].
2.6. 13-cis-retinoic acid.
Retinoids (RAs) have been known to be quintessential for
the regular maintenance and sustainability of the immune system.
They have been proven to be effective immunomodulators which
play important role in transcriptional activity of degenerative,
normal and tumor cell. The strong relationship between
senescence, immunity and retinoid levels shows the predominat
regulatory role of retinoids in the immune system activity. The
signaling cascade is induced through RAR resulting in its
activation followed by induction of target genes which
subsequently lead to proliferation inhibition, differentiation and
programmed cell death in a wide variety of cell types [53-55].
Therefore any defects or abnormalities associated with RAR may
have serious consequences leading to cancer.
2.7. Urolithin, Ellagitannins and Punicalagin.
Another series of polyphenols have been derived from
berries and pomegranates which have been shown to have
significant bioactivity for e.g. Ellagitannins possess a variety of
activities including strong anti-oxidant, anti-cancer and anti-
atherosclerotic, and anti-inflammatory activity. When it comes to
the metabolism, Ellagitannins have to broken down and
hydrolysed to ellagic acid before being absorbed into the blood
stream. Gut microflora further come into play and convert ellagic
acid into urolithins. Urolithins form conjugates in the liver which
are further excreted out in the urine. Urolithins have been shown
to have variety of bioactivities as reported in earlier studies in
literature for example they have been known to be inhibitory to
cancer cell proliferation. Moreover urolithins act as mediators by
interfering with the activity of the NF-κB pathway. In one of the
clinical studies, the administration of the pomegranate juice was
reported to reduce the level of prostate specific antigen (PSA)
after the patient underwent surgical intervention or radiation
therapy as a primary treatment for prostate cancer [56].
A wide-variety of natural products have been known to
have anti-angiogenic potential in preclinical models, including
Artemisia annua (Chinese wormwood), Viscum album (European
mistletoe), Curcuma longa (curcumin), Scutellariabaicalensis
(Chinese skullcap), resveratrol and proanthocyanidin (grape seed
extract), Magnolia officinalis (Chinese magnolia tree), Camellia
sinensis (green tea), Ginkgo biloba, quercetin, Poriacocos,
Zingiberofficinalis (ginger), Panax ginseng,
Rabdosiarubescenshora(Rabdosia), and Chinese destagnation
herbs (Table 1). Angiogenesis is known to be a physiological
process involving the growth of new blood vessels from pre-
existing vessels and also have a role in wound healing. Whenever
there is a transition of tumors from the dormant to a malignant
state,this process constitutes the initial step. Angiogenesis has
been reported to be induced due to the secretion of various
growth factors by the tumor, such as vascular endothelial growth
factor (VEGF) and basic fibroblast growth factor (bFGF). These
growth factors further induce capillary growth of the tumor and
allow it to grow by supplementing nutrients and oxygen while
removing waste products. Further, newly formed vessels allow the
tumor cells to escape into the circulation and move into other
organs resulting in tumor metastases [ 57-59].
The naturally occurring polysaccharides β-Glucans are
glucose polymers produced by a variety of plants, such as oat,
barley, and seaweed .b-glucan is the most known powerful
immune stimulant and a very powerful antagonist to both benign
and malignant tumors; it lowers cholesterol and triglyceride level,
normalizes blood sugar level, heals and rejuvenates the skin and
has various other benefits.Mushrooms have been known for their
healing and immunostimulating properties for thousands of years.
Approximately 140000 mushroom types only 10% are known and
used for treatment purposes in East countries. These mushrooms
contain biologically active polysaccharides in fruit bodies and
cultured mycelium. These natural products have tremendous
capacity to cure deadly diseases like cancer. It is the need of the
hour to explore natural products as a target molecule for such
diseases.
3. CONCLUSIONS AND FUTURE PERSPECTIVES
There are a number of natural products or dietary
substances that exhibit anticancer activity in in vitro systems
against a variety of cancer cells like leukemia, lymphoma, breast,
prostate, liver, lung, and myeloma cells [60-63]. The anti-cancer
activity of natural products includes the inhibition of proliferation,
induction of apoptosis, induction of cell cycle arrest, inhibition of
invasive behavior, and suppression of tumor angiogenesis in many
experimental systems. In-depth studies are required at the
molecular level focussing on the plant-derived bioactive
substances or secondary metabolites. As immune system plays a

4. Anti-cancer potential of natural products: recent trends, scope and relevance
Page | 905
proactive role in the proliferation or suppression of cancer and
other autoimmune diseases, there is an urgent need to study the
effect of such natural compounds on the immune system so that a
possible drug target or epitope can be identified for the treatment
of such diseases. In a nutshell, variety of plant-derived herbal
drugs tested in vitro and in vivo further support the traditional
therapeutic claims. But, the lacking part is systematic reviews of
the protocols or data interpretation, drug/immunological properties
and validation. To achieve this goal, standardization of purely
natural products or active extracts is an important element.
Because the composition and amount of biologically active
substances depend on sites of production, cultivation conditions,
and extraction procedures, and standardization will help the
acceptance of natural products as suitable candidates for cancer
treatment. The challenge now is to develop personalized
supplements comprised of specific phytochemicals for each
clinical situation and how the host microbiota respond bringing in
the concept of personalized medicine [64]. However, there is a
need for the identification and prediction of potential herb–drug or
herb-epitope interactions and how the immune system responds to
such drugs.
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6. ACKNOWLEDGEMENTS
Authors would like to especially acknowledge Department of Biotechnology at LayalpurKhalsa College, Jalandhar, Punjab, India
and MMDU Mullana,Ambala,India for providing the requisite platform to accomplish this work.
© 2020 by the authors. This article is an open access article distributed under the terms and conditions of the
Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).