Content uploaded by Mohd Suhail
Author content
All content in this area was uploaded by Mohd Suhail on Jul 16, 2022
Content may be subject to copyright.
Citation: Muhammad, N.; Usmani,
D.; Tarique, M.; Naz, H.; Ashraf, M.;
Raliya, R.; Tabrez, S.; Zughaibi, T.A.;
Alsaieedi, A.; Hakeem, I.J.; et al. The
Role of Natural Products and Their
Multitargeted Approach to Treat
Solid Cancer. Cells 2022,11, 2209.
https://doi.org/10.3390/
cells11142209
Academic Editor: Natália
Cruz-Martins
Received: 21 June 2022
Accepted: 13 July 2022
Published: 15 July 2022
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
cells
Review
The Role of Natural Products and Their Multitargeted
Approach to Treat Solid Cancer
Naoshad Muhammad 1, †, Darksha Usmani 2, Mohammad Tarique 3, Huma Naz 4, Mohammad Ashraf 5,
Ramesh Raliya 6, Shams Tabrez 7,8 , Torki A. Zughaibi 7,8 , Ahdab Alsaieedi 8,9, Israa J. Hakeem 10
and Mohd Suhail 7, 8,*,†
1
Department of Radiation Oncology, School of Medicine, Washington University, Saint Louis, MO 63130, USA;
nmuhammad@wustl.edu
2G-Bioscience, 9800 Page Ave., St. Louis, MO 63132, USA; darksha97@gmail.com
3Department of Child Health, University of Missouri, Columbia, MO 65211, USA;
tariqueunmatched@gmail.com
4Department of Internal Medicine, University of Missouri, Columbia, MO 65211, USA;
huma.7biotech@gmail.com
5Department of Chemistry, Bundelkhand University Jhansi, Jhansi 284128, Uttar Pradesh, India;
ashrafm035@gmail.com
6IFFCO Nano Biotechnology Research Center, Kalol 382423, Gujarat, India; rameshraliya@iffco.in
7King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
shamstabrez1@gmail.com (S.T.); taalzughaibi@kau.edu.sa (T.A.Z.)
8
Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University,
Jeddah 21589, Saudi Arabia; aalsaieedi@kau.edu.sa
9Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University,
Jeddah 21589, Saudi Arabia
10 Department of Biochemistry, College of Science, University of Jeddah, Jeddah 21959, Saudi Arabia;
ijhakeem@uj.edu.sa
*Correspondence: suhaildbt@gmail.com
† These authors contributed equally to this work.
Abstract:
Natural products play a critical role in the discovery and development of numerous
drugs for the treatment of various types of cancer. These phytochemicals have demonstrated anti-
carcinogenic properties by interfering with the initiation, development, and progression of cancer
through altering various mechanisms such as cellular proliferation, differentiation, apoptosis, an-
giogenesis, and metastasis. Treating multifactorial diseases, such as cancer with agents targeting
a single
target, might lead to limited success and, in many cases, unsatisfactory outcomes. Various
epidemiological studies have shown that the steady consumption of fruits and vegetables is intensely
associated with a reduced risk of cancer. Since ancient period, plants, herbs, and other natural
products have been used as healing agents. Likewise, most of the medicinal ingredients accessible
today are originated from the natural resources. Regardless of achievements, developing bioactive
compounds and drugs from natural products has remained challenging, in part because of the
problem associated with large-scale sequestration and mechanistic understanding. With significant
progress in the landscape of cancer therapy and the rising use of cutting-edge technologies, we
may have come to a crossroads to review approaches to identify the potential natural products and
investigate their therapeutic efficacy. In the present review, we summarize the recent developments
in natural products-based cancer research and its application in generating novel systemic strategies
with a focus on underlying molecular mechanisms in solid cancer.
Keywords: medicinal plants; natural products; phytochemicals and solid cancer
1. Introduction
Cancer is a not only a genetic but also a challenging disease and, the main cause of
mortality globally. In 2020, there have been a projected 18.1 million cancer cases worldwide.
Cells 2022,11, 2209. https://doi.org/10.3390/cells11142209 https://www.mdpi.com/journal/cells
Cells 2022,11, 2209 2 of 20
According to the prediction, it is likely to record seven out of ten deaths in Central and
South America, Africa, and Asia due to cancer [
1
,
2
]. This could be a panic situation that
most developing countries prerequisite to upgrade and develop more tactical preparation
that limits reconnaissance, early recognition, and active treatment for cancer patients.
Several factors such as growing populations, aging, and prompt socioeconomic growth are
associated with the rise in cancer burden throughout the world. There is a probability that
the cancer maladies rise with increase in age due to the accumulated DNA damage and
multi-stage carcinogenesis [
3
–
5
]. In recent years, due to improvements in novel therapeutics
not only diagnosis rate has been increased but also over-all life expectancy of cancer patients
has improved [6,7].
Presently, the National Cancer Institute (NCI) enlisted 8 categories for treatment of
cancer including surgery, radiation, chemotherapy, targeted therapy, immunotherapy, stem
cell transplant, and precision medicine [
8
]. However, the customary approaches for cancer
treatment include surgery, radiotherapy, and chemotherapy [
9
,
10
]. Conversely, regardless
of the various types of chemotherapeutic drugs utilized for the cancer treatment and the
remedial triumph of several management programs, the main therapies have not achieved
the desired result [
11
,
12
]. Some early targeted therapies have shown a positive clinical
response, however, frequent drug resistance was observed after an initial positive response
in cancer patients. This alteration in the treatment is known as acquired drug resistance,
as contrasting to intrinsic resistance, which occurs earlier to any cancer therapy. Acquired
drug resistance is developed due to both cytotoxic chemotherapies and targeted therapies
with different molecular mechanisms. In most of the cancer, these molecular mechanisms
can incorporate compensatory and redundant molecular signaling, targeting mutations
developed during treatment, modulation in the expression of the targeted proteins, inhibi-
tion of pro-apoptotic pathways, activation of pro-survival signaling, inactivation of DNA
repair mechanisms, and upregulation of tumor cell efflux transporters [
13
,
14
]. Despite of
the progress, resistance to cancer chemotherapy and common side effects are the main
issues in patients who have received first-line treatment. Targeted therapy employs a range
of small molecules and inhibitors that play an important role in targeting key signaling
pathways, result in development of resistance in a rare instance even from first doses. Drug
resistance develops in the patient as a result of tumor or cancer cells being certainly chosen
for molecular mechanisms that can compensate for the precisely targeted pathway. In light
of this, there is an urgent necessity to pursue more selective and active compounds or
natural products that have fewer side effects, have more medicinal elements, cost-effective,
and have a least level of disease resistance for the management of cancer. However, less
evidence exists in the scientific literature about the utilization of such natural products and
their mechanism of action against solid cancers.
Throughout the history, natural products played an important and crucial role in
the treatment of human illnesses. Furthermore, traditional remedies, mainly based on
native plants, still govern therapeutic practices globally, and natural products cover a huge
portion of current-day pharmaceutical tools, especially in the field of antibiotic and cancer
therapies. For the management of cancer, timely diagnosis and definitive tumor removal
by radiation therapy or surgical resection is the greatest anticipation. Conversely, in case
of dealing with malignant and metastatic disease, chemotherapy is usually required. As
defined herein, most of the significant improvements that have been recognized for the
management of cancer are directly or indirectly associated with the discovery of natural
product based chemotherapeutic approach. In past few decades, cumulative evidence
has demonstrated the remarkable amplification or utilization of plant-based remedies. As
compared with the high cost and side effects of most modern drugs, medical plants have
shown significant therapeutic potential with minimal side effects and low cost, such as
epigallocatechin gallate (EGCG), resveratrol, curcumin, sugiol etc. EGCG is a polyphenol
found in green tea [15–18].
Cells 2022,11, 2209 3 of 20
2. Natural Products
Plant-derived natural products are the primary source of biologically active com-
pounds. Moreover, their nontoxic or less toxic nature to normal cells and better toleratation
has gained attention from the scientific community and clinicians in the modern drug
discovery area [
19
,
20
]. The untapped structural diversity of natural compounds is long-
lasting importance in drug discovery. It is estimated that the plant kingdom includes
at least 250,000 species, of which only 10 percent have been explored for pharmacologi-
cal
applications [21]
. Several natural compounds have shown potential activities against
metastasis and tumor invasion [
16
,
20
,
22
]. Some plant-derived FDA-approved phyto-
molecules, such as tetrandrine, lycobetaine, curdione, vincristine, vinblastine, cur-
cumol, monocrotaline, elliptinium, etoposide, gossypol, ipomeanol, taxol, indirubin,
10-hydroxycamptothecin, homoharringtonine, and colchicinamide have shown significant
antitumor potential [
23
]. Approximately more than 600 natural compounds have reported
as an anticancer agent. However, keeping in mind the content’s limitation and inability to
cover every natural product in a single article, we have briefly discussed some common
well-known anticancer compounds such as curcumin, indol-3-carbinol (I3C), resveratrol,
kaempferol, epigallocatechin gallate (EGCG), and genistein (Figure 1).
Cells 2022, 11, x FOR PEER REVIEW 3 of 21
epigallocatechin gallate (EGCG), resveratrol, curcumin, sugiol etc. EGCG is a polyphenol
found in green tea [15–18].
2. Natural Products
Plant-derived natural products are the primary source of biologically active com-
pounds. Moreover, their nontoxic or less toxic nature to normal cells and better tolerata-
tion has gained attention from the scientific community and clinicians in the modern drug
discovery area [19,20]. The untapped structural diversity of natural compounds is long-
lasting importance in drug discovery. It is estimated that the plant kingdom includes at
least 250,000 species, of which only 10 percent have been explored for pharmacological
applications [21]. Several natural compounds have shown potential activities against me-
tastasis and tumor invasion [16,20,22]. Some plant-derived FDA-approved phytomole-
cules, such as tetrandrine, lycobetaine, curdione, vincristine, vinblastine, curcumol, mono-
crotaline, elliptinium, etoposide, gossypol, ipomeanol, taxol, indirubin, 10-hydroxycamp-
tothecin, homoharringtonine, and colchicinamide have shown significant antitumor po-
tential [23]. Approximately more than 600 natural compounds have reported as an anti-
cancer agent. However, keeping in mind the content's limitation and inability to cover
every natural product in a single article, we have briefly discussed some common well-
known anticancer compounds such as curcumin, indol-3-carbinol (I3C), resveratrol,
kaempferol, epigallocatechin gallate (EGCG), and genistein (Figure 1).
Figure 1. Schematic representation of cancer types that could be prevented/managed by natural
products (phytochemicals). IC3, Indol-3-carbinol.
Figure 1.
Schematic representation of cancer types that could be prevented/managed by natural
products (phytochemicals). IC3, Indol-3-carbinol.
2.1. Curcumin
Curcumin has been suggested as the most potent natural product among the
600 natural
products. It is a yellow spice and a phenolic compound derived from the plant Curcuma
longa. Curcumin has shown promising chemopreventive and anticancer activity in different
cancer models, such as prostate cancer, lung cancer, breast cancer, brain tumors, head and
neck squamous cell carcinoma [
24
,
25
]. The scientific literatures report the modulation in
Cells 2022,11, 2209 4 of 20
various signaling pathways by curcumin that results into its antitumor activity [
24
,
26
]. The
active JAK2 / STAT3 signaling pathway plays a vital role in the initiation and development
of various cancers [
27
]. Thus, JAK2/STAT3 pathway is a well-known therapeutic target
for curcumin inhibiting tumor initiation. In primary effusion lymphoma cells, curcumin
significantly suppresses the JAK/STAT3 pathway in a dose-dependent manner, which
inhibits cell proliferation and induces caspase-dependent apoptosis [
28
]. Furthermore,
curcumin is a more potent inhibitor than a selective inhibitor of AG490 a selective inhibitor
of STAT3 phosphorylation of the JAK2/STAT3 signaling pathway in multiple myeloma
cells [
29
]. Scientific studies suggest that curcumin inhibits cell proliferation in numerous
cancer cell lines, such as malignant gliomas [
30
], pancreatic [
31
,
32
], hepatocellular [
33
],
ovarian, and endometrial carcinoma [
34
] by down-regulating the JAK-STAT3 pathway.
An in-vivo
study reveals that curcumin injected with tumorspheres of lung cancer NCI-
H460 cells in nude mice suppressed the tumor growth via repressing the JAK2/STAT3
signaling pathway [35].
2.2. Indol-3-Carbinol (I3C)
Another natural product, indol-3-carbinol, mainly present in cruciferous vegetables
such as cabbage, cauliflower, and broccoli, also exhibit anticancer activity [
36
]. It has
been reported to inhibit cancer cell proliferation by modulating the expression of insulin
receptor substrate-1 (IRS1) and insulin-like growth factor receptor-1 (IGF1R) [
37
]. A recent
study suggested that I3C induces apoptosis in H1299 cells by activating apoptosis signal-
regulating kinase 1 (ASK1) [
38
]. Furthermore, I3C has been reported to exert its anticancer
effects through a different mechanism that include decreased cell proliferation, increased
apoptosis, and reduced mammosphere formation in MCF-10AR-Her2 cells [
39
]. Nuclear
factor-kappa B (NF-
κ
B) is a master regulator of more than five hundred genes. It plays
a crucial
role in cancer cell survival by mediating the transcription of several antiapoptotic
genes such as p53,p21,survivin,Bcl-2, and Bcl-xL [
40
]. I3C and diindolylmethane (DIM)
inhibit the activation of NF-
κ
B in SW480 colon cancer cells [
41
]. Earlier studies also reported
that I3C and DIM inhibit the cell cycle in the G1 phase in breast and prostate cancer cell
lines [
42
,
43
]. Recently it has been shown that I3C decreases cell proliferation and induces
apoptosis in the inflammatory breast cancer model. However, this result could not be
adequate to evade the development of tumor embolization and metastasis [
44
]. A study
showed that I3C could induce apoptosis in osteosarcoma cells by upregulating the FOXO3
signaling pathway [45].
2.3. Resveratrol
Resveratrol is a well-known naturally occurring polyphenol and commonly present
in grapes, wine, nuts, berries, and many other human diets [
46
]. Several studies reported
a wide
range of pharmacological activities associated with resveratrol such as antiviral,
antifungal, anti-inflammatory, antiaging, anticancer, and antioxidant effects [
46
,
47
]. Resver-
atrol has shown anticancer effects in renal carcinoma cells such as ACHN and A498. It
reduced cell proliferation, migration, and invasion through inhibition or inactivation of the
Akt and ERK1/2 signaling pathways in a concentration-dependent manner [
48
]. It has also
been reported to exert anti-cell proliferation effects through modulation in VEGF expression
in an osteosarcoma cell line [
49
]. In colorectal adenocarcinoma cells (CaCo-2), resveratrol
has shown significant growth inhibition at 25
µ
M due to S/G2 phase arrest through the
inhibition of ornithine decarboxylase activity [
50
]. A study reported that
a combination
of resveratrol and docetaxel treatment induced apoptosis in prostate cancer cells (C4–2B
and DU-145) by inhibiting the cell cycle at the G2/M phase and inducing the expression of
pro-apoptotic genes, such as Bax, Bid, and Bak [33].
2.4. Kaempferol
Kaempferol, a yellow color compound, is an aglycone type of flavonoid that is made
up of glycosides. It contains four hydroxy groups on 3, 5, 7, and 4 positions [
51
]. The
Cells 2022,11, 2209 5 of 20
primary sources of kaempferol are fruits, seeds, flowers, leaves, green vegetables, and
different plants [
52
]. It has been reported to be involved in various activities, including
anticancer, anti-inflammatory, antioxidant, antitumor, antimicrobial, neuroprotective, and
cardioprotective [
53
]. In addition, kaempferol exerts an anticancer effect in different human
cancer cell lines such as SW480, HCT-15, HCT116, HT-29, and LS174-R colon
cells [54–56]
.
A study has also shown that treatment of Huh7 cells with kaempferol in hypoxic conditions
could inhibit tumor growth through the inactivation of p44/42 MAPK pathways by in-
hibiting HIF-1
α
protein [
51
]. Moreover, kaempferol induced apoptosis in colon cancer cells
by activating the upregulation of death receptor 5 and TRAIL receptors [
57
]. Moreover,
a study
reported that kaempferol inhibited triclosan and E2-induced breast cancer progres-
sion by playing an antagonist role against estrogen receptor and IGF1R signaling [
58
]. In
addition, it also induces apoptosis naturally in MCF-7 cells through the activation of poly
ADP-ribose polymerase and via the mitochondrial caspase-9 signaling pathway [
58
,
59
].
In vivo
study suggests that kaempferol has shown inhibitory activity against metasta-
sis of murine melanoma B16F10 cells and could downregulate the expression of matrix
metalloproteinase-9 (MMP-9) and its activity. Therefore it might be a potential anticancer
agent for cancer metastasis [60].
2.5. Epigallocatechin Gallate (EGCG)
Green tea is a refreshing drink that is used globally. The green tea catechins such
as EGCG and other polyphenols showed anticancer activity in different cancer models.
EGCG is the most abundant and well-studied catechin found in green tea [
40
,
61
,
62
]. The
anti-carcinogenic properties of green tea include controlling cell proliferation, cell death
of tumor cells, induction of apoptosis, induction of proapoptotic genes, inhibition of anti-
apoptotic genes, rise in ROS production and vascular angiogenesis [
63
]. These catechins
modulate the gene expression by directly affecting the transcription factor or indirectly
through epigenetic mechanisms [
64
]. A study revealed that EGCG (10–100
µ
M) inhibits
the receptor activator of nuclear factor-
κ
B ligand (RANKL) and induces NF-kB activity
in a murine preosteoclast cell-line RAW 264.7 [
65
]. Scientific studies have shown signifi-
cant growth inhibitory potential of EGCG (40–80
µ
M) in different cancer models, such as
prostate, colorectal and liver cancer [
66
–
68
]. An
in vitro
study has shown that EGCG and
nano-EGCG treatment increases the expression of AMPK phosphorylation in H1299 lung
cancer cells [
69
]. Another study reported the inhibition of cell proliferation and migration
in oral cancer cells (H400 and H357) by EGCG treatment through reduced expression of
phosphorylated epidermal growth factor receptor (EGFR) [
70
]. The nano-EGCG regulates
various biological activities, including suppressing cell proliferation, inhibiting cell mi-
gration, colony formation, and invasion by activating the AMPK signaling pathway in
H1299 lung cancer cells [
69
]. Recently, we have also reported the significant anticancer
potential of nano-EGCG in prostate cell lines, viz. 22Rv1 and PC3 [
71
]. Treating rats with
(50 mg/kg) catechin exhibits the downregulation of endotoxin-mediated activation of
initial signaling molecule NF-
κ
B, TNF
α
, nitric oxide, and reactive oxygen species due to
catechin’s antioxidant effect [
72
,
73
]. In addition, studies have reported that EGCG treat-
ment induced the natural killer (NK) cell activity, triggered the proliferation of B-cell and T
cells, and increased NK-cell mediated cytotoxicity in murine leukemia and bladder cancer
model [74,75].
2.6. Genistein
A naturally occurring compound, genistein is an isoflavone belongs to the flavonoid
family. It is derived from legumes such as soybeans, lupin and fava beans [
17
,
76
]. The
consumption of soybeans, lupin, and fava beans is associated with many beneficial effects
including lower incidence of some cancers, such as colon cancer, reduction in the cardio-
vascular disease risk, protection against osteoporosis, and alleviation of postmenopausal
symptoms [
77
,
78
]. A study reported that genistein inhibits tumor growth and cell prolif-
eration by downregulating the negative effect of epidermal growth factor (EGF) on the
Cells 2022,11, 2209 6 of 20
activity of forkhead box O3 (FOXO3) in a colon cancer model [
79
]. In addition, it is also
observed that genistein reduces breast cancer stem cells (CSCs) and mammospheres by
downregulating the hedgehog-signaling pathway that subsequently regulates cell prolif-
eration, self-renewal ability, stem cell, and progenitor cell maintenance [
80
,
81
]. Based on
the scientific studies, it is believed that genistein regulates miRNAs expression to stop cell
proliferation and up-regulates miR-200 expression, also regulate the essential targets such
as vimentin, zinc finger E-box binding homeobox 1 (ZEB1), and slug, which help in the
epithelial-mesenchymal transition (EMT) process [
82
,
83
]. Genistein could inhibit the tumor
development in estrogen receptor alpha (ER
α
) negative breast cancer through remodeling
the chromatin structure in the ER
α
promoter to reactivate the ER
α
expression [
84
]. In the
below-mentioned section, we have focused various signaling pathways that are affected by
these natural products.
3. Cellular Signaling Pathways as a Therapeutic Target for Cancer Therapy
Cellular signaling are multifaceted communication system consist of three-dimensional
molecular cascades containing various signaling proteins. The precious molecular mech-
anism associated with these proteins are very specific to cell type, cell site, and intra-
molecular interactions. Modulation in the homeostasis of these proteins leads to the diverse
pathological diseased conditions. However, in case of cancer, alternation in cell signaling
and cell communication leads to modulation in the expression of various critical genes
associated with the normal functioning of the cells [
13
]. A series of mutation in numer-
ous cancers associated genes, such as tumor-suppressor and oncogenes lead to cancer
proliferation [85]
. Early discovery of many oncogenes such as RAS, RAF, MYC, and KIT
and several other tumor suppressor genes TP53, PTEN, and BRCA1 have led to the identi-
fication of several cancer-associated genetic lesions [
86
,
87
]. Currently, cellular signaling
pathways and its associated molecular networks are documented for their important roles
in regulation of pro-survival cellular processes and are thus predominantly involved in
the onset of cancer, and in its prospective management. Many signaling pathways are
associated with the development of cancer such as VEGF receptor pathway that activate
RAS/RAF/MEK/ERK pathway, and the fibroblast growth factor (FGF) receptor pathway
that stimulates multiple pathways, including the PI3K/Akt/mTOR, RAS/RAF/MEK/ERK
and act as signal transducer and activator of transcription (STAT) pathways [
88
,
89
]. In this
review, we have emphasized not only some signaling pathways involved in solid cancer
but also highlighted targeted strategies which helps to improve the clinical outcomes.
Specifically, two pathways, the PI3K/AKT/mTOR signaling pathway and Ras/MAPK
pathway, are repeatedly activated, or mutated in many solid cancers.
PI3K/Akt/mTOR pathway plays an important role in the regulation of several normal
cellular activities that are also important for tumorigenesis such as cell survival, migration,
cell cycle progression, angiogenesis, and EMT [
16
,
90
]. Aberrant regulation or activation of
the PI3K/Akt/mTOR cascade is mainly involved in the development of various human
cancers such as acute lymphoma (AML), T cell acute lymphoblastic leukemia (T-ALL),
breast cancer, ovarian cancer, prostate cancer, and mantle cell lymphoma [
91
–
94
]. The
activation of the PI3K/Akt/mTOR pathway begins in the response of extracellular stim-
uli and growth factors leading to the activation of receptor tyrosine kinases (RTKs) that
make the autophosphorylation of tyrosine residues and transphosphorylation of adaptor
proteins [
94
]. The phosphatidylinositol (PI)-3-kinase (PI3K) class Ia activation occurs as
its Src homology (SH2) domains bind with the p85 regulatory unit to specific phosphoty-
rosine residues on the activated receptor or associated adaptor proteins, which helps the
enzyme to move from cytosol to the plasma membrane and activates the p110 catalytic
unit [
16
,
95
]. Activated PI3Ks acts as lipid kinase and phosphorylate phosphatidylinosi-
tol 4,5-bisphosphate (PIP2) to produce the phosphatidylinositol-3,4,5-triphosphate (PIP3)
which further plays a crucial role in the form of second cellular messenger to control the cell
growth, proliferation, and cell survival [
16
,
96
]. PIP3 starts the Akt activation through the
recruitment of PDK-1 and the PKB on the plasma membrane, where PDK-1 makes the phos-
Cells 2022,11, 2209 7 of 20
phorylation at Threonine(T)308 residue of Akt in the activation loop [
97
,
98
]. Consequently,
Akt gets activated and moves to the cytosol and nucleus where it phosphorylates the differ-
ent substrate downstream proteins including Bcl-2 associated agonist of cell death (BAD),
forkhead box class O (FoxO) and glycogen synthase kinase-3 (GSK3)
α
/
β
to support the
cell growth, survival, and other cellular effects [
99
]. Furthermore, Akt indirectly activates
its downstream target mTOR by phosphorylating and inhibiting tuberous sclerosis complex
1 and 2 (TSC1/2) at S939 and T1462 residues (Figure 2). Thus, mTOR positively regulates
different cellular functions by promoting protein synthesis and inhibition of autophagy by
releasing its inhibitory effects on Ras-related GTPase Rheb complex [100,101].
Cells 2022, 11, x FOR PEER REVIEW 7 of 21
adaptor proteins [94]. The phosphatidylinositol (PI)-3-kinase (PI3K) class Ia activation oc-
curs as its Src homology (SH2) domains bind with the p85 regulatory unit to specific phos-
photyrosine residues on the activated receptor or associated adaptor proteins, which helps
the enzyme to move from cytosol to the plasma membrane and activates the p110 catalytic
unit [16,95]. Activated PI3Ks acts as lipid kinase and phosphorylate phosphatidylinositol
4,5-bisphosphate (PIP2) to produce the phosphatidylinositol-3,4,5-triphosphate (PIP3)
which further plays a crucial role in the form of second cellular messenger to control the
cell growth, proliferation, and cell survival [16,96]. PIP3 starts the Akt activation through
the recruitment of PDK-1 and the PKB on the plasma membrane, where PDK-1 makes the
phosphorylation at Threonine(T)308 residue of Akt in the activation loop [97,98]. Conse-
quently, Akt gets activated and moves to the cytosol and nucleus where it phosphorylates
the different substrate downstream proteins including Bcl-2 associated agonist of cell
death (BAD), forkhead box class O (FoxO) and glycogen synthase kinase-3 (GSK3) α/β to
support the cell growth, survival, and other cellular effects [99]. Furthermore, Akt indi-
rectly activates its downstream target mTOR by phosphorylating and inhibiting tuberous
sclerosis complex 1 and 2 (TSC1/2) at S939 and T1462 residues (Figure 2). Thus, mTOR
positively regulates different cellular functions by promoting protein synthesis and inhi-
bition of autophagy by releasing its inhibitory effects on Ras-related GTPase Rheb com-
plex [100,101].
Figure 2. Schematic overview of PI3K/Akt/mTOR pathway. BAD, BCL2 associated agonist of cell
death; FOXO1, Forkhead box O1 protein; IRS1, Insulin receptor substrate 1; 4EBP1, Eukaryotic trans-
lation initiation factor 4E-binding protein 1; p70S6K1, p70 Ribosomal S6 kinase 1; PIP2, Phosphati-
dylinositol 4,5-bisphosphate; PTEN, Phosphatase, and tensin homolog deleted on chromosome 10;
PDK1, 3-Phosphoinositide-dependent kinase 1; PP2A, Protein phosphatase 2A; Rheb GDP, Ras
homolog enriched in brain GDP; Rheb GTP, Ras homolog enriched in brain GTP and TSC, Tuberous
sclerosis complex.
Figure 2.
Schematic overview of PI3K/Akt/mTOR pathway. BAD, BCL2 associated agonist of cell
death; FOXO1, Forkhead box O1 protein; IRS1, Insulin receptor substrate 1; 4EBP1, Eukaryotic
translation initiation factor 4E-binding protein 1; p70S6K1, p70 Ribosomal S6 kinase 1; PIP2, Phos-
phatidylinositol 4,5-bisphosphate; PTEN, Phosphatase, and tensin homolog deleted on chromosome
10; PDK1, 3-Phosphoinositide-dependent kinase 1; PP2A, Protein phosphatase 2A; Rheb GDP, Ras
homolog enriched in brain GDP; Rheb GTP, Ras homolog enriched in brain GTP and TSC, Tuberous
sclerosis complex.
Another signaling pathway, the mitogen-activated protein kinase (MAPK) is com-
prised of different signaling cascade components and has been observed to be deregulated
in various human cancer. The hyperactivation of Ras/RAF/MEK/ERK (MAPK) pathways
is noted in more than 40% of human cancer cases [
102
]. A series of activated kinases send
the extracellular signals to regulate the various cellular activities, including cell prolifera-
tion, differentiation, apoptosis, cell growth, and cell migration. It is reported that abnormal
or aberrant activation of RTKs or gain-of-function mutations in the RAS or RAF genes are
the leading causes of alteration in RAS-MAPK in human cancer. For these reasons, the
RAS-MAPK pathway is a well-established therapeutic target for cancer treatment and its
management [
103
,
104
]. In resting cells, plasma membrane-associated Ras-GDP remains
Cells 2022,11, 2209 8 of 20
inactive with RAF, MEK, and ERK in the cytosol. However, in response to the exposure to
extracellular stimuli (growth factors, hormones, and cytokines), RTK autophosphorylation
begins to generate the binding sites for SHC and GRB2 adaptor molecules that recruit SOS
and RasGEF (GTPase exchange factor) to the plasma membrane (Figure 3) to trigger the
activation of RAF/MEK/ERK kinase cascade [
105
]. Furthermore, activated ERKs stay in
the cytoplasm or move into the nucleus where they regulate the various physiological
processes by phosphorylation of several substates [105–107].
Cells 2022, 11, x FOR PEER REVIEW 8 of 21
Another signaling pathway, the mitogen-activated protein kinase (MAPK) is com-
prised of different signaling cascade components and has been observed to be deregulated
in various human cancer. The hyperactivation of Ras/RAF/MEK/ERK (MAPK) pathways
is noted in more than 40% of human cancer cases [102]. A series of activated kinases send
the extracellular signals to regulate the various cellular activities, including cell prolifera-
tion, differentiation, apoptosis, cell growth, and cell migration. It is reported that abnor-
mal or aberrant activation of RTKs or gain-of-function mutations in the RAS or RAF genes
are the leading causes of alteration in RAS-MAPK in human cancer. For these reasons, the
RAS-MAPK pathway is a well-established therapeutic target for cancer treatment and its
management [103,104]. In resting cells, plasma membrane-associated Ras-GDP remains
inactive with RAF, MEK, and ERK in the cytosol. However, in response to the exposure
to extracellular stimuli (growth factors, hormones, and cytokines), RTK autophosphory-
lation begins to generate the binding sites for SHC and GRB2 adaptor molecules that re-
cruit SOS and RasGEF (GTPase exchange factor) to the plasma membrane (Figure 3) to
trigger the activation of RAF/MEK/ERK kinase cascade [105]. Furthermore, activated
ERKs stay in the cytoplasm or move into the nucleus where they regulate the various
physiological processes by phosphorylation of several substates [105–107].
Figure 3. Schematic representation of Ras/MAPK pathway. ERK, Extracellular signal-regulated ki-
nase; GAP, GTPase-activating protein; PKC; Protein kinase C; PM, Phorbol 12-myristate 13-acetate;
RSK, Ribosomal s6 kinase.
These pathways are prominently interconnected in facilitating upstream signals from
receptor tyrosine kinases (RTKs) to intracellular effector proteins and cell cycle regulators
[108]. Interestingly, the signals transmitted from the extracellular space into the cytoplas-
mic and nuclear compartments, the PI3K and MAPK pathways are intensely connected
Figure 3.
Schematic representation of Ras/MAPK pathway. ERK, Extracellular signal-regulated
kinase; GAP, GTPase-activating protein; PKC; Protein kinase C; PM, Phorbol 12-myristate 13-acetate;
RSK, Ribosomal s6 kinase.
These pathways are prominently interconnected in facilitating upstream signals
from receptor tyrosine kinases (RTKs) to intracellular effector proteins and cell cycle
regulators [108]
. Interestingly, the signals transmitted from the extracellular space into
the cytoplasmic and nuclear compartments, the PI3K and MAPK pathways are intensely
connected via several positive and negative axis. Additionally, other signaling pathways
linked with the process of EGFR activation are phospholipase C-g and the JNK. These
molecular pathways participate primarily in processes of cell proliferation, cell migration,
and transformation. Together, these signaling pathways regulates gene transcription, cell
proliferation, cell cycle progression, survival, adhesion, angiogenesis, and cell migration in
solid cancer [
102
,
109
]. Various kinases have been observed to be meticulously participate in
the processes of tumor cell proliferation and survival [
110
]. Modulation in the RTK activity
is the key mechanism of the tumor cells to escape from physiological controls on survival
and growth. Atypical activation of RTK takes place due to receptor over-expression, gene
amplification, mutations, and abnormal receptor regulation associated with the develop-
ment of various forms of cancer in human [
111
]. In many solid cancers, the family of RTKs
has been observed to be deregulated, leading to not only overexpression and amplifica-
Cells 2022,11, 2209 9 of 20
tion of EGFR but also unsuitable cellular stimulation. Receptor overexpression has been
associated with a more aggressive clinical outcomes in numerous solid tumor types [
112
].
Most of the drug resistant and many chemotherapy-naive tumors are characterized by
deregulated RTK signaling. Furthermore, pan-cancer analyses have exhibited rearrange-
ments in chromosome due genomic instability, as the initial events in many cancer types
like melanoma, glioblastoma, breast, and adenocarcinoma [
86
]. Moreover, the survival
of cancers expressing hormonal receptors, such as prostate, breast, and ovarian cancers
essentially depend on the growth signal induced by their relative hormones, such as estro-
gen and androgen. For the treatment per se of solid cancer a variety of anticancer drugs
have been developed. These chemo drugs include the cytotoxic, cytostatic agents, and
newer compound that interfere or impede with intracellular processes of solid cancer [
113
].
Some essential cancer-causing pathways and targets of natural products are presented
in Figure 4.
Cells 2022, 11, x FOR PEER REVIEW 9 of 21
via several positive and negative axis. Additionally, other signaling pathways linked with
the process of EGFR activation are phospholipase C-g and the JNK. These molecular path-
ways participate primarily in processes of cell proliferation, cell migration, and transfor-
mation. Together, these signaling pathways regulates gene transcription, cell prolifera-
tion, cell cycle progression, survival, adhesion, angiogenesis, and cell migration in solid
cancer [102,109]. Various kinases have been observed to be meticulously participate in the
processes of tumor cell proliferation and survival [110]. Modulation in the RTK activity is
the key mechanism of the tumor cells to escape from physiological controls on survival
and growth. Atypical activation of RTK takes place due to receptor over-expression, gene
amplification, mutations, and abnormal receptor regulation associated with the develop-
ment of various forms of cancer in human [111]. In many solid cancers, the family of RTKs
has been observed to be deregulated, leading to not only overexpression and amplifica-
tion of EGFR but also unsuitable cellular stimulation. Receptor overexpression has been
associated with a more aggressive clinical outcomes in numerous solid tumor types [112].
Most of the drug resistant and many chemotherapy-naive tumors are characterized by
deregulated RTK signaling. Furthermore, pan-cancer analyses have exhibited rearrange-
ments in chromosome due genomic instability, as the initial events in many cancer types
like melanoma, glioblastoma, breast, and adenocarcinoma [86]. Moreover, the survival of
cancers expressing hormonal receptors, such as prostate, breast, and ovarian cancers es-
sentially depend on the growth signal induced by their relative hormones, such as estro-
gen and androgen. For the treatment per se of solid cancer a variety of anticancer drugs
have been developed. These chemo drugs include the cytotoxic, cytostatic agents, and
newer compound that interfere or impede with intracellular processes of solid cancer
[113]. Some essential cancer-causing pathways and targets of natural products are pre-
sented in Figure 4.
Figure 4.
Depiction of important cellular pathways regulated by natural products that could be
utilized for therapeutic purpose in solid cancer.
4. Scientific Principles Related with Cancer Chemoprevention
Chemoprevention is the application of pharmacological or natural compounds for the
inhibition of invasive cancer. It integrates the concept of delay which infers several years,
or decades that might be added to human life cycle. Scientific interest in cancer biology
research, especially in the area of chemoprevention has significantly improved with the ad-
vancement in the understanding of carcinogenesis and identification of potential molecular
targets associated with this process. The process of carcinogenesis has been recognized as a
clonal propagation and accumulation of genetic damage over the period. Chemopreventive
compounds are potent to interrupt clonal propagation in abnormal cells by delaying DNA
damage, impeding, or reversing the malignant phenotype, or promoting apoptosis in the
Cells 2022,11, 2209 10 of 20
impaired cells of premalignant lesions [
114
]. The importance of chemoprevention further
improved by achieving the control of breast, colon, and prostate cancer. There are more
than 10 natural product-based medications are approved by USFDA for the decline in
cancer risk [
115
]. Recently, the concept of chemoprevention was considered as a vital and
enthusiastic strategy for controlling solid cancer. It does not only play
an essential
role in
preventing the growth of the invasive and metastatic potential of cancer (neoplasm) but
also lowers the cancer prevalence rate. Chemoprevention strategy can be categorized into
three parts: (1) primary prevention, impeding the growth of tumors in healthy individu-
als; (2) secondary prevention, inhibiting the growth of tumors in those individuals with
precancerous lesions like invasion; (3) tertiary prevention, inhibiting recurrence or relapse
of cancers in target patients [
116
]. Besides rigorous biomolecular validation, chemopre-
ventive compounds must retain very less or no toxicity because they will be applied by
an essentially healthy people at high cancer riskof. Numerous classes of compounds like
cyclooxygenase (COX) inhibitors, retinoids, and sex hormone antagonists are very useful
in the prevention of various epithelial cancers [
117
–
119
]. Similarly, various molecular
mechanisms of action have been defined and efforts have been made to broadly classify
the chemopreventive compounds according to different stages of carcinogenesis [
120
].
Nonetheless, it is likely that many compound, mainly derived from dietary ingredient have
multi-targeted effects throughout the carcinogenic process. Agents that prevent cancer
initiation are customarily termed ‘blocking agents’. They work by reducing the interac-
tion between chemical carcinogens and DNA, thus reducing the level of damage [
121
].
Once beginning has arisen, chemopreventive compounds might impact on the promotion
and progression of initiated cells; such compounds are frequently termed ‘suppressing
agents’ [
110
]. Recent studies demonstrated that intervention in tumor metabolism and
energy homoeostasis through AMPK and mTOR signaling pathways may be a striking tool
for chemopreventive agents [122].
5. Role of Natural Products in the Management of Cancer
Since ancient times, local communities consume natural products and herbs in health
care system for preventing several diseases, including cancer [
20
]. Approximately
40% of
alternative therapies including natural product based herbal medicine were used for pre-
venting various disease in the United States of America (USA). Generally natural products,
as part of complementary medicine in the USA, have provided a basis to conduct the re-
search for discovering novel plant-based medicinal agents, and more than half of currently
existing drugs are based on natural products [
123
]. The epidemiological data also suggested
that more than 50% of the approved anticancer agents are either natural compounds or
natural product derivatives derived from herbal medicine [124,125].
Despite substantial development in the prevention and treatment of cancer, major
gaps still exist, and further progresses are still required. Various studies have suggested
that substantial application of plant-based therapeutics with ability to regulate physiolog-
ical functions including flavonoids, phenolics, alkaloids, and organosulfur compounds,
have been recognized to inhibit cancer in several
in vivo
and
in vitro
cancer models via
different mechanisms [
126
–
133
]. However, very few evidence-based studies exist in the sci-
entific literature regarding the application of biological natural agents and their associated
molecular mechanism against solid cancer. Using modern technology and novel research
strategies, more plant-derived components have been discovered for the management of
advanced-stage cancer without significant collateral damage.
Natural product acquired from diverse sources indicates the ability to modulate
numerous physiological signaling pathways such as apoptosis, metastasis, angiogenesis,
and drug resistance (Figure 5), necessary for the treatment of cancer [127,134–136].
Cells 2022,11, 2209 11 of 20
Cells 2022, 11, x FOR PEER REVIEW 11 of 21
that substantial application of plant-based therapeutics with ability to regulate physiolog-
ical functions including flavonoids, phenolics, alkaloids, and organosulfur compounds,
have been recognized to inhibit cancer in several in vivo and in vitro cancer models via
different mechanisms [126–133]. However, very few evidence-based studies exist in the
scientific literature regarding the application of biological natural agents and their associ-
ated molecular mechanism against solid cancer. Using modern technology and novel re-
search strategies, more plant-derived components have been discovered for the manage-
ment of advanced-stage cancer without significant collateral damage.
Natural product acquired from diverse sources indicates the ability to modulate nu-
merous physiological signaling pathways such as apoptosis, metastasis, angiogenesis,
and drug resistance (Figure 5), necessary for the treatment of cancer [127,134–136].
Figure 5. Schematic diagram of cellular process regulated by different phytochemicals against var-
ious cancer forms.
Therefore, it is imperative to apply various strategies for the management of this
deadly diseases by using natural products, especially phytochemicals [137,138]. Various
studies suggested the anticancer activity of natural products-based extract and its active
ingredients in in-vitro cancer cell line models and pre-clinical animal models of many
solid cancers [139–151]. Nature remains to be a rich source of biologically active and di-
verse chemotypes. Unfortunately, a small percentage of natural products are being devel-
oped into clinically (Table 1) effective drugs via exploitation of chemical techniques such
as metabolomics, alteration of their biosynthetic pathways, and total or combinatorial fab-
rication [16,152].
Figure 5.
Schematic diagram of cellular process regulated by different phytochemicals against various
cancer forms.
Therefore, it is imperative to apply various strategies for the management of this
deadly diseases by using natural products, especially phytochemicals [
137
,
138
]. Various
studies suggested the anticancer activity of natural products-based extract and its active
ingredients in in-vitro cancer cell line models and pre-clinical animal models of many
solid cancers [
139
–
151
]. Nature remains to be a rich source of biologically active and
diverse chemotypes. Unfortunately, a small percentage of natural products are being
developed into clinically (Table 1) effective drugs via exploitation of chemical techniques
such as metabolomics, alteration of their biosynthetic pathways, and total or combinatorial
fabrication [16,152].
Table 1. A list of phytochemicals as anticancer agents for different cancer in clinical trial.
Phytochemicals Clinical Trial Type
and Phase Cancer/Conditions Type References
Quercetin
For prevention, Phase
not applicable Prostate cancer [84]
For prevention, Phase II Squamous cell carcinoma [84]
Green tea catechins
For prevention, Phase II High breast density and
postmenopausal in women [150]
For treatment, Phase II Neoplasm and multiple myeloma [150]
For treatment, Phase II Oral premalignant lesion [153]
For treatment, Phase II Bladder cancer [150]
For prevention, Phase II Tobacco use disorder [150]
For treatment, Phase I lung carcinoma [150]
Cells 2022,11, 2209 12 of 20
Table 1. Cont.
Phytochemicals Clinical Trial Type
and Phase Cancer/Conditions Type References
Green tea polyphenon E
and Erlotinib For prevention, Phase I Lesions of head and neck cancer [154]
Curcumin
For prevention, Phase II Familial adenomatous polyposis [155]
For treatment, Phase I Advanced osteosarcoma [150,156]
For treatment, Phase II Advanced pancreatic cancer [157]
For prevention, Phase I Colon cancer [150,158]
Indole-3-carbinol/
3,3-diindolylmethane (IC3/DIM)
For prevention, Phase II Prostate cancer progression [159]
For treatment, Phase II Breast cancer [150]
For prevention, Phase I Women carrying BRCA1 mutation [160]
(IC3/DIM) + Radical
prostatectomy For treatment, Phase I Prostate cancer [150,161]
Genistein For prevention, Phase II Patients with bladder cancer [162]
Resveratrol For prevention, Phase II Colorectal cancer [163]
Betulinic acid For treatment, Phase I/II Dysplastic nevi that can be change
into melanoma [164]
Ingenol mebutate For prevention, phase I/II Human non-melanoma skin cancer [164]
Moreover, recent developments in the formulation strategies of novel biological active
compounds may results in the more efficient application of drugs to the cancer patients.
There are several tools such as fusion of toxic natural molecules to monoclonal antibodies
and polymeric carriers precisely targeting epitopes on the membrane of targeted tumor cell
result in the discovery and development of more active antitumor drugs [
165
]. Additionally,
the scientific inputs and multidisciplinary alliances among various researchers around the
globe are also required to optimize the most active biological compounds at the molecular
level ultimately leading to significant control of cancer progression [147–149].
6. Conclusions and Future Perspectives
The high rate of mortality and morbidity in solid cancers remain a primary task
for scientific investigation. Still conventional tools, such as surgery, radiotherapy, and
chemotherapy are effective in some patients but five-year survival rate in solid cancer
patients is usually miserable. In most of the cases chemotherapy causes drug resistance
and unwanted toxic side effects in the patients. In last decade, plant-derived natural
compounds have been used as a potent candidate for the management of cancer. This
review provides a deep understanding about the role of plant derived natural products in
the treatment of cancer by modulating various signaling pathways. Natural compounds
are evolving as a prospective therapeutic tool in cancer biology research owing to their
easy accessibility and cost-effectiveness. Various natural agents are used in preclinical or
clinical settings for the management of cancer [
75
,
76
]. Several epidemiological data suggest
that high nutritional intake of fruits and vegetables reduce the risk of cancer [
77
]. The
scientific evidence described in this article highlight the uninterrupted development and
advancement in the field of plants based natural products research, demonstrating that it
occupies a critical position in the use of chemopreventive compounds. The discovery and
development of anticancer agents have steadily shifted from all those drugs having a single
target and robust side effects to natural plant-based drugs with less or no toxicity. Most
of the natural medicine typically affects more than one pathway (for instance triggering
apoptosis, inhibiting cell proliferation, etc.). The multitarget potential of natural products
allows them to efficiently offset the biological complication in cancer and offer favorable
resources for cancer chemoprevention. Better understanding of cellular signaling pathways
Cells 2022,11, 2209 13 of 20
and its regulation may demonstrate a valuable strategy in cancer therapy. To discover
the effective treatment approaches with least side effects and low cost, the researchers
are encouraged to conduct research on natural resources, exclusively on plants and their
active constituents. Therefore, it is essential to enhance the mechanistic and clinical based
studies to discover novel and effective natural chemopreventive compounds. We believe
that natural antitumor active ingredients and precursor drugs could provide an alternative
or adjuvant treatment strategies in clinical medicine for the cure of solid cancer.
Author Contributions:
Conceptualization, methodology, original draft preparation, article writing,
visualization, review, and editing, N.M.; software work, validation, data curation, review, and editing,
D.U., M.T., H.N., M.A., R.R., S.T., T.A.Z., A.A. and I.J.H.; resources, review and editing, supervision,
project administration, and funding acquisition, M.S. and T.A.Z. All authors have read and agreed to
the published version of the manuscript.
Funding:
This research work was funded by the Institutional Fund Projects under grant
no. (IFPDP-8-22)
.
Therefore, the authors gratefully acknowledge technical and financial support from Ministry of Education
and Deanship of Scientific Research (DSR), King Abdulaziz University (KAU), Jeddah, Saudi Arabia.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
Akt Protein kinase B
ASK1 Apoptosis signal-regulating kinase 1
BAD BCL2 associated agonist of cell death
EGF Epidermal growth factor
EGFR Epidermal growth factor receptor
ERK Extracellular signal-regulated kinases
4EBP1 Eukaryotic translation initiation factor 4E-binding protein 1
FOXO1 Forkhead box O1 protein
GAP GTPase-activating protein
IRS1 Insulin receptor substrate 1
MEK MAPK/ERK kinase
MMP-9 Matrix metalloproteinase-9
NF-κB Nuclear Factor-κB
PDK1 3-Phosphoinositide-dependent kinase 1
PKC Protein kinase C
PMA Phorbol 12-myristate 13-acetate
p70S6K1 p70 Ribosomal S6 kinase 1
PTEN Phosphatase and tensin homolog deleted in chromosome 10
VEGF Vascular endothelial growth factor
PIP2 Phosphatidylinositol 4, 5-bisphosphate
PI3K Phosphoinositide 3-kinases
mTOR Mammalian target of rapamycin
Raf Rapidly accelerated aibrosarcoma
Rheb GDP Ras homolog enriched in brain GDP
Rheb GTP Ras homolog enriched in brain GTP and.
RTK Receptor tyrosine kinases
RSK Ribosomal s6 kinase
TSC Tuberous sclerosis complex
ZEB1 Zinc finger E-box binding homeobox 1
References
1. World Health Organization. International Agency for Research on Cancer; World Health Organization: Geneva, Switzerland, 2019.
Cells 2022,11, 2209 14 of 20
2.
Nagai, H.; Kim, Y.H. Cancer prevention from the perspective of global cancer burden patterns. J. Thorac. Dis.
2017
,9, 448–451.
[CrossRef] [PubMed]
3. Cho, W.C. Molecular Connections of Aging and Cancer. Aging Dis. 2017,8, 685–687. [CrossRef] [PubMed]
4.
Bouvard, V.; Baan, R.; Straif, K.; Grosse, Y.; Secretan, B.; El Ghissassi, F.; Benbrahim-Tallaa, L.; Guha, N.; Freeman, C.;
Galichet, L.; et al. A review of human carcinogens–Part B: Biological agents. Lancet Oncol. 2009,10, 321–322. [CrossRef]
5.
Lombard, D.B.; Chua, K.F.; Mostoslavsky, R.; Franco, S.; Gostissa, M.; Alt, F.W. DNA repair, genome stability, and aging. Cell
2005
,
120, 497–512. [CrossRef] [PubMed]
6.
Sharifi-Rad, J.; Quispe, C.; Patra, J.K.; Singh, Y.D.; Panda, M.K.; Das, G.; Adetunji, C.O.; Michael, O.S.; Sytar, O.; Polito, L.; et al.
Paclitaxel: Application in Modern Oncology and Nanomedicine-Based Cancer Therapy. Oxid. Med. Cell. Longev.
2021
,2021,
3687700. [CrossRef]
7.
Docea, A.O.; Mitru¸t, P.; Grigore, D.; Pirici, D.; Călina, D.C.; Gofi¸tă, E. Immunohistochemical expression of TGF beta (TGF-
β
),
TGF beta receptor 1 (TGFBR1), and Ki67 in intestinal variant of gastric adenocarcinomas. Rom. J. Morphol. Embryol.
2012
,
53 (Suppl. S3), 683–692.
8. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011,144, 646–674. [CrossRef]
9.
Housman, G.; Byler, S.; Heerboth, S.; Lapinska, K.; Longacre, M.; Snyder, N.; Sarkar, S. Drug resistance in cancer: An overview.
Cancers 2014,6, 1769–1792. [CrossRef]
10.
International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature
2004
,
431, 931–945. [CrossRef]
11.
The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature
2020
,
578, 82–93. [CrossRef]
12.
Li, L.; Zhao, G.-D.; Shi, Z.; Qi, L.-L.; Zhou, L.-Y.; Fu, Z.-X. The Ras/Raf/MEK/ERK signaling pathway and its role in the
occurrence and development of HCC. Oncol. Lett. 2016,12, 3045–3050. [CrossRef] [PubMed]
13.
Farooq, M.; Khan, A.W.; Kim, M.S.; Choi, S. The Role of Fibroblast Growth Factor (FGF) Signaling in Tissue Repair and
Regeneration. Cells 2021,10, 3242. [CrossRef]
14.
Mendoza, M.C.; Er, E.E.; Blenis, J. The Ras-ERK and PI3K-mTOR pathways: Cross-talk and compensation. Trends Biochem Sci.
2011,36, 320–328. [CrossRef] [PubMed]
15.
Alharthy, S.A.; Tabrez, S.; Mirza, A.A.; Zughaibi, T.A.; Firoz, C.K.; Dutta, M. Sugiol Suppresses the Proliferation of Human
U87 Glioma Cells via Induction of Apoptosis and Cell Cycle Arrest. Evid. Based Complement. Altern. Med.
2022
,2022, 7658899.
[CrossRef] [PubMed]
16.
Zughaibi, T.A.; Suhail, M.; Tarique, M.; Tabrez, S. Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer
Chemopreventive Approach. Int. J. Mol. Sci. 2021,22, 12455. [CrossRef] [PubMed]
17.
Badar Ul Islam, n.; Khan, M.S.; Husain, F.M.; Rehman, M.T.; Zughaibi, T.A.; Abuzenadah, A.M.; Urooj, M.; Kamal, M.A.;
Tabrez, S.
mTOR Targeted Cancer Chemoprevention by Flavonoids. Curr. Med. Chem. 2021,28, 8068–8082. [CrossRef]
18.
Islam, B.; Suhail, M.; Khan, M.; Ahmad, A.; Zughaibi, T.; Husain, F.; Rehman, M.T.; Tabrez, S. Flavonoids and PI3K/Akt/mTOR
signaling cascade: A potential crosstalk in anticancer treatment. Curr. Med. Chem. 2021,28, 8083–8097. [CrossRef]
19.
Najmi, A.; Javed, S.A.; Al Bratty, M.; Alhazmi, H.A. Modern Approaches in the Discovery and Development of Plant-Based
Natural Products and Their Analogues as Potential Therapeutic Agents. Molecules 2022,27, 349. [CrossRef]
20.
Islam, B.U.; Suhail, M.; Khan, M.K.; Zughaibi, T.A.; Alserihi, R.F.; Zaidi, S.K.; Tabrez, S. Polyphenols as anticancer agents:
Toxicological concern to healthy cells. Phytother. Res. 2021,35, 6063–6079. [CrossRef]
21.
Veeresham, C. Natural products derived from plants as a source of drugs. J. Adv. Pharm. Technol. Res.
2012
,3, 200–201. [CrossRef]
22.
Bracke, M.E.; Vanhoecke, B.W.A.; Derycke, L.; Bolca, S.; Possemiers, S.; Heyerick, A.; Stevens, C.V.; De Keukeleire, D.;
Depypere, H.T.;
Verstraete, W.; et al. Plant polyphenolics as anti-invasive cancer agents. Anti-cancer. Agents Med. Chem.
2008,8, 171–185. [CrossRef]
23.
Singh, S.; Sharma, B.; Kanwar, S.S.; Kumar, A. Lead Phytochemicals for Anticancer Drug Development. Front Plant Sci.
2016
,
7, 1667. [CrossRef] [PubMed]
24. Sultana, S.; Munir, N.; Mahmood, Z.; Riaz, M.; Akram, M.; Rebezov, M.; Kuderinova, N.; Moldabayeva, Z.; Shariati, M.A.; Rauf,
A.; et al. Molecular targets for the management of cancer using Curcuma longa Linn. phytoconstituents: A Review. Biomed.
Pharmacother. 2021,135, 111078. [CrossRef] [PubMed]
25.
Tomeh, M.A.; Hadianamrei, R.; Zhao, X. A Review of Curcumin and Its Derivatives as Anticancer Agents. Int. J. Mol. Sci.
2019
,
20, 1033. [CrossRef]
26.
Hoda, N.; Naz, H.; Jameel, E.; Shandilya, A.; Dey, S.; Hassan, M.I.; Ahmad, F.; Jayaram, B. Curcumin specifically binds to the
human calcium–calmodulin-dependent protein kinase IV: Fluorescence and molecular dynamics simulation studies. J. Biomol.
Struct. Dyn. 2016,34, 572–584. [CrossRef]
27.
Mengie Ayele, T.; Tilahun Muche, Z.; Behaile Teklemariam, A.; Bogale Kassie, A.; Chekol Abebe, E. Role of JAK2/STAT3 Signaling
Pathway in the Tumorigenesis, Chemotherapy Resistance, and Treatment of Solid Tumors: A Systemic Review. J. Inflamm. Res.
2022,15, 1349–1364. [CrossRef]
28.
Sun, Y.; Liu, L.; Wang, Y.; He, A.; Hu, H.; Zhang, J.; Han, M.; Huang, Y. Curcumin inhibits the proliferation and invasion of
MG-63 cells through inactivation of the p-JAK2/p-STAT3 pathway. Oncol. Targets Ther. 2019,12, 2011–2021. [CrossRef]
Cells 2022,11, 2209 15 of 20
29.
Zhou, Y.; Sun, Y.; Hou, W.; Ma, L.; Tao, Y.; Li, D.; Xu, C.; Bao, J.; Fan, W. The JAK2/STAT3 pathway inhibitor, AG490, suppresses
the abnormal behavior of keloid fibroblasts in vitro. Int. J. Mol. Med. 2020,46, 191–200. [CrossRef]
30.
Pagliuca, A.; Valvo, C.; Fabrizi, E.; di Martino, S.; Biffoni, M.; Runci, D.; Forte, S.; De Maria, R.; Ricci-Vitiani, L. Analysis of the
combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene
repression. Oncogene 2013,32, 4806–4813. [CrossRef]
31.
Liu, Y.; Sun, H.; Makabel, B.; Cui, Q.; Li, J.; Su, C.; Ashby Jr, C.R.; Chen, Z.; Zhang, J. The targeting of non-coding RNAs by
curcumin: Facts and hopes for cancer therapy (Review). Oncol. Rep. 2019,42, 20–34. [CrossRef]
32.
Zhang, Y.; Yu, X.; Chen, L.; Zhang, Z.; Feng, S. EZH2 overexpression is associated with poor prognosis in patients with glioma.
Oncotarget 2016,8, 565–573. [CrossRef] [PubMed]
33.
Hashem, S.; Ali, T.A.; Akhtar, S.; Nisar, S.; Sageena, G.; Ali, S.; Al-Mannai, S.; Therachiyil, L.; Mir, R.; Elfaki, I.; et al. Targeting
cancer signaling pathways by natural products: Exploring promising anti-cancer agents. Biomed. Pharmacother.
2022
,150, 113054.
[CrossRef] [PubMed]
34.
Adiwidjaja, J.; McLachlan, A.J.; Boddy, A.V. Curcumin as a clinically-promising anti-cancer agent: Pharmacokinetics and drug
interactions. Expert Opin. Drug Metab. Toxicol. 2017,13, 953–972. [CrossRef]
35.
Wu, L.; Guo, L.; Liang, Y.; Liu, X.; Jiang, L.; Wang, L. Curcumin suppresses stem-like traits of lung cancer cells via inhibiting the
JAK2/STAT3 signaling pathway. Oncol. Rep. 2015,34, 3311–3317. [CrossRef]
36.
Katz, E.; Nisani, S.; Chamovitz, D.A. Indole-3-carbinol: A plant hormone combatting cancer. F1000Res
2018
,7, F1000-Faculty
Rev-689. [CrossRef] [PubMed]
37.
Marconett, C.N.; Singhal, A.K.; Sundar, S.N.; Firestone, G.L. Indole-3-carbinol disrupts estrogen receptor-alpha dependent
expression of insulin-like growth factor-1 receptor and insulin receptor substrate-1 and proliferation of human breast cancer cells.
Mol. Cell Endocrinol. 2012,363, 74–84. [CrossRef]
38.
Lim, H.M.; Park, S.-H.; Nam, M.J. Induction of apoptosis in indole-3-carbinol-treated lung cancer H1299 cells via ROS level
elevation. Hum. Exp. Toxicol. 2021,40, 812–825. [CrossRef]
39.
Tin, A.S.; Park, A.H.; Sundar, S.N.; Firestone, G.L. Essential role of the cancer stem/progenitor cell marker nucleostemin for
indole-3-carbinol anti-proliferative responsiveness in human breast cancer cells. BMC Biol. 2014,12, 72. [CrossRef]
40.
Suhail, M.; Mohammad, T.; Naoshad, M.; Huma, N.; Abdul, H.; Torki, A.Z.; Mohammad, A.K.; Mohd, R. A Critical Transcription
Factor NF-
κ
B as a Cancer Therapeutic Target and its Inhibitors as Cancer Treatment Options. Curr. Med. Chem.
2021
,28, 4117–4132.
[CrossRef]
41.
Fadlalla, K.; Elgendy, R.; Gilbreath, E.; Pondugula, S.R.; Yehualaeshet, T.; Mansour, M.; Serbessa, T.; Manne, U.; Samuel, T.
3-(2-Bromoethyl)-indole inhibits the growth of cancer cells and NF-κB activation. Oncol. Rep. 2015,34, 495–503. [CrossRef]
42.
Hong, C.; Kim, H.A.; Firestone, G.L.; Bjeldanes, L.F. 3,3
0
-Diindolylmethane (DIM) induces a G1 cell cycle arrest in human breast
cancer cells that is accompanied by Sp1-mediated activation of p21WAF1/CIP1 expression. Carcinogenesis
2002
,23, 1297–1305.
[CrossRef] [PubMed]
43.
Vivar, O.I.; Lin, C.-L.; Firestone, G.L.; Bjeldanes, L.F. 3,3
0
-Diindolylmethane Induces a G1 Arrest in Human Prostate Cancer Cells
Irrespective of Androgen Receptor and p53 Status. Biochem. Pharmacol. 2009,78, 469–476. [CrossRef] [PubMed]
44.
Martín-Ruiz, A.; Peña, L.; González-Gil, A.; Díez-Córdova, L.T.; Cáceres, S.; Illera, J.C. Effects of indole-3-carbinol on steroid
hormone profile and tumor progression in a mice model of canine inflammatory mammarycancer. BMC Cancer
2018
,18, 626.
[CrossRef] [PubMed]
45.
Lee, C.M.; Lee, J.; Nam, M.J.; Park, S.-H. Indole-3-Carbinol Induces Apoptosis in Human Osteosarcoma MG-63 and U2OS Cells.
Biomed. Res. Int. 2018,2018, e7970618. [CrossRef]
46.
Chedea, V.S.; Vica¸s, S.I.; Sticozzi, C.; Pessina, F.; Frosini, M.; Maioli, E.; Valacchi, G. Resveratrol: From diet to topical usage. Food
Funct. 2017,8, 3879–3892. [CrossRef]
47.
Nawaz, W.; Zhou, Z.; Deng, S.; Ma, X.; Ma, X.; Li, C.; Shu, X. Therapeutic Versatility of Resveratrol Derivatives. Nutrients
2017
,
9, 1188. [CrossRef]
48.
Zhao, Y.; Tang, H.; Zeng, X.; Ye, D.; Liu, J. Resveratrol inhibits proliferation, migration and invasion via Akt and ERK1/2 signaling
pathways in renal cell carcinoma cells. Biomed. Pharmacother. 2018,98, 36–44. [CrossRef]
49.
Liu, Z.; Li, Y.; Yang, R. Effects of resveratrol on vascular endothelial growth factor expression in osteosarcoma cells and cell
proliferation. Oncol. Lett. 2012,4, 837–839. [CrossRef]
50.
Rauf, A.; Imran, M.; Butt, M.S.; Nadeem, M.; Peters, D.G.; Mubarak, M.S. Resveratrol as an anti-cancer agent: A review. Crit. Rev.
Food Sci. Nutr. 2018,58, 1428–1447. [CrossRef]
51.
Imran, M.; Salehi, B.; Sharifi-Rad, J.; Aslam Gondal, T.; Saeed, F.; Imran, A.; Shahbaz, M.; Tsouh Fokou, P.V.; Umair Arshad, M.;
Khan, H.; et al. Kaempferol: A Key Emphasis to Its Anticancer Potential. Molecules 2019,24, 2277. [CrossRef]
52.
Sharifi-Rad, M.; Fokou, P.V.T.; Sharopov, F.; Martorell, M.; Ademiluyi, A.O.; Rajkovic, J.; Salehi, B.; Martins, N.; Iriti, M.;
Sharifi-Rad, J
. Antiulcer Agents: From Plant Extracts to Phytochemicals in Healing Promotion. Molecules
2018
,23, 1751.
[CrossRef] [PubMed]
53.
Kashyap, D.; Sharma, A.; Tuli, H.S.; Sak, K.; Punia, S.; Mukherjee, T.K. Kaempferol—A dietary anticancer molecule with multiple
mechanisms of action: Recent trends and advancements. J. Funct. Foods 2017,30, 203–219. [CrossRef] [PubMed]
Cells 2022,11, 2209 16 of 20
54.
Riahi-Chebbi, I.; Souid, S.; Othman, H.; Haoues, M.; Karoui, H.; Morel, A.; Srairi-Abid, N.; Essafi, M.; Essafi-Benkhadir, K. The
Phenolic compound Kaempferol overcomes 5-fluorouracil resistance in human resistant LS174 colon cancer cells. Sci. Rep.
2019
,
9, 195. [CrossRef]
55.
Choi, J.-B.; Kim, J.-H.; Lee, H.; Pak, J.-N.; Shim, B.S.; Kim, S.-H. Reactive Oxygen Species and p53 Mediated Activation of p38
and Caspases is Critically Involved in Kaempferol Induced Apoptosis in Colorectal Cancer Cells. J. Agric. Food Chem.
2018
,
66, 9960–9967. [CrossRef]
56.
Lee, H.S.; Cho, H.J.; Yu, R.; Lee, K.W.; Chun, H.S.; Park, J.H.Y. Mechanisms Underlying Apoptosis-Inducing Effects of Kaempferol
in HT-29 Human Colon Cancer Cells. Int. J. Mol. Sci. 2014,15, 2722–2737. [CrossRef] [PubMed]
57.
Yoshida, T.; Konishi, M.; Horinaka, M.; Yasuda, T.; Goda, A.E.; Taniguchi, H.; Yano, K.; Wakada, M.; Sakai, T. Kaempferol
sensitizes colon cancer cells to TRAIL-induced apoptosis. Biochem. Biophys. Res. Commun.
2008
,375, 129–133. [CrossRef]
[PubMed]
58.
Kim, S.-H.; Hwang, K.-A.; Choi, K.-C. Treatment with kaempferol suppresses breast cancer cell growth caused by estrogen and
triclosan in cellular and xenograft breast cancer models. J. Nutr. Biochem. 2016,28, 70–82. [CrossRef] [PubMed]
59.
Tabrez, S.; Hoque, M.; Suhail, M.; Khan, M.I.; Zughaibi, T.A.; Khan, A.U. Identification of anticancer bioactive compounds derived
from Ficus sp. by targeting Poly[ADP-ribose]polymerase 1 (PARP-1). J. King Saud Univ.-Sci. 2022,34, 102079. [CrossRef]
60.
Li, C.; Zhao, Y.; Yang, D.; Yu, Y.; Guo, H.; Zhao, Z.; Zhang, B.; Yin, X. Inhibitory effects of kaempferol on the invasion of human
breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-9. Biochem. Cell Biol.
2015
,
93, 16–27. [CrossRef]
61.
Suhail, M.; Parveen, A.; Husain, A.; Rehan, M. Exploring Inhibitory Mechanisms of Green Tea Catechins as Inhibitors of a Cancer
Therapeutic Target, Nuclear Factor-κB (NF-κB). Biosci. Biotechnol. Res. Asia 2019,16, 715–723. [CrossRef]
62.
Reygaert, W.C. Green Tea Catechins: Their Use in Treating and Preventing Infectious Diseases. Biomed. Res. Int.
2018
,2018,
9105261. [CrossRef] [PubMed]
63.
Sanna, V.; Singh, C.K.; Jashari, R.; Adhami, V.M.; Chamcheu, J.C.; Rady, I.; Sechi, M.; Mukhtar, H.; Siddiqui, I.A. Targeted
nanoparticles encapsulating (-)-epigallocatechin-3-gallate for prostate cancer prevention and therapy. Sci. Rep.
2017
,7, 41573.
[CrossRef] [PubMed]
64.
Naponelli, V.; Ramazzina, I.; Lenzi, C.; Bettuzzi, S.; Rizzi, F. Green Tea Catechins for Prostate Cancer Prevention: Present
Achievements and Future Challenges. Antioxidants 2017,6, 26. [CrossRef] [PubMed]
65.
Lin, R.-W.; Chen, C.-H.; Wang, Y.-H.; Ho, M.-L.; Hung, S.-H.; Chen, I.-S.; Wang, G.-J. (
−
)-Epigallocatechin gallate inhibition of
osteoclastic differentiation via NF-kappaB. Biochem. Biophys. Res. Commun. 2009,379, 1033–1037. [CrossRef]
66.
Johnson, J.J.; Bailey, H.H.; Mukhtar, H. Green tea polyphenols for prostate cancer chemoprevention: A translational perspective.
Phytomedicine 2010,17, 3–13. [CrossRef]
67.
Wei, R.; Wirkus, J.; Yang, Z.; Machuca, J.; Esparza, Y.; Mackenzie, G.G. EGCG sensitizes chemotherapeutic-induced cytotoxicity
by targeting the ERK pathway in multiple cancer cell lines. Arch. Biochem. Biophys. 2020,692, 108546. [CrossRef]
68.
Shirakami, Y.; Shimizu, M. Possible Mechanisms of Green Tea and Its Constituents against Cancer. Molecules
2018
,23, 2284.
[CrossRef]
69.
Chen, B.-H.; Hsieh, C.-H.; Tsai, S.-Y.; Wang, C.-Y.; Wang, C.-C. Anticancer effects of epigallocatechin-3-gallate nanoemulsion on
lung cancer cells through the activation of AMP-activated protein kinase signaling pathway. Sci. Rep.
2020
,10, 5163. [CrossRef]
70.
Belobrov, S.; Seers, C.; Reynolds, E.; Cirillo, N.; McCullough, M. Functional and molecular effects of a green tea constituent on
oral cancer cells. J. Oral. Pathol. Med. 2019,48, 604–610. [CrossRef]
71.
Alserihi, R.F.; Mohammed, M.R.S.; Kaleem, M.; Khan, M.I.; Sechi, M.; Sanna, V.; Zughaibi, T.A.; Abuzenadah, A.M.;
Tabrez, S.
Development of (
−
)-epigallocatechin-3-gallate-loaded folate receptor-targeted nanoparticles for prostate cancer treatment.
Nanotechnol. Rev. 2022,11, 298–311. [CrossRef]
72.
Bharrhan, S.; Koul, A.; Chopra, K.; Rishi, P. Catechin Suppresses an Array of Signalling Molecules and Modulates Alcohol-Induced
Endotoxin Mediated Liver Injury in a Rat Model. PLoS ONE 2011,6, e20635. [CrossRef] [PubMed]
73.
Tang, G.; Xu, Y.; Zhang, C.; Wang, N.; Li, H.; Feng, Y. Green Tea and Epigallocatechin Gallate (EGCG) for the Management of
Nonalcoholic Fatty Liver Diseases (NAFLD): Insights into the Role of Oxidative Stress and Antioxidant Mechanism. Antioxidants
2021,10, 1076. [CrossRef] [PubMed]
74.
Calgarotto, A.K.; Longhini, A.L.; Pericole de Souza, F.V.; Duarte, A.S.S.; Ferro, K.P.; Santos, I.; Maso, V.; Olalla Saad, S.T.;
Torello, C.O
. Immunomodulatory Effect of Green Tea Treatment in Combination with Low-dose Chemotherapy in Elderly Acute
Myeloid Leukemia Patients with Myelodysplasia-related Changes. Integr. Cancer Ther.
2021
,20, 15347354211002647. [CrossRef]
[PubMed]
75.
Huang, A.-C.; Cheng, H.-Y.; Lin, T.-S.; Chen, W.-H.; Lin, J.-H.; Lin, J.-J.; Lu, C.-C.; Chiang, J.-H.; Hsu, S.-C.; Wu, P.-P.; et al.
Epigallocatechin gallate (EGCG), influences a murine WEHI-3 leukemia model
in vivo
through enhancing phagocytosis of
macrophages and populations of T- and B-cells. In Vivo 2013,27, 627–634.
76.
Tuli, H.S.; Tuorkey, M.J.; Thakral, F.; Sak, K.; Kumar, M.; Sharma, A.K.; Sharma, U.; Jain, A.; Aggarwal, V.; Bishayee, A. Molecular
Mechanisms of Action of Genistein in Cancer: Recent Advances. Front. Pharmacol. 2019,10, 1336. [CrossRef]
77.
Goh, Y.X.; Jalil, J.; Lam, K.W.; Husain, K.; Premakumar, C.M. Genistein: A Review on its Anti-Inflammatory Properties. Front.
Pharmacol. 2022,13, 820969. [CrossRef]
Cells 2022,11, 2209 17 of 20
78.
Irrera, N.; Pizzino, G.; D’Anna, R.; Vaccaro, M.; Arcoraci, V.; Squadrito, F.; Altavilla, D.; Bitto, A. Dietary Management of Skin
Health: The Role of Genistein. Nutrients 2017,9, 622. [CrossRef]
79.
Qi, W.; Weber, C.R.; Wasland, K.; Savkovic, S.D. Genistein inhibits proliferation of colon cancer cells by attenuating a negative
effect of epidermal growth factor on tumor suppressor FOXO3 activity. BMC Cancer 2011,11, 219. [CrossRef]
80.
Deldar Abad Paskeh, M.; Asadi, S.; Zabolian, A.; Saleki, H.; Khoshbakht, M.A.; Sabet, S.; Naghdi, M.J.; Hashemi, M.;
Hushmandi, K.
; Ashrafizadeh, M.; et al. Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strat-
egy against Human Malignancies. Int. J. Mol. Sci. 2021,22, 11669. [CrossRef]
81.
Park, S.; Kim, H.; Kim, K.; Roh, S. Sonic hedgehog signalling regulates the self-renewal and proliferation of skin-derived precursor
cells in mice. Cell Prolif. 2018,51, e12500. [CrossRef]
82.
Javed, Z.; Khan, K.; Herrera-Bravo, J.; Naeem, S.; Iqbal, M.J.; Sadia, H.; Qadri, Q.R.; Raza, S.; Irshad, A.; Akbar, A.; et al. Genistein
as a regulator of signaling pathways and microRNAs in different types of cancers. Cancer Cell Int.
2021
,21, 388. [CrossRef]
[PubMed]
83.
Hsieh, P.-L.; Liao, Y.-W.; Hsieh, C.-W.; Chen, P.-N.; Yu, C.-C. Soy Isoflavone Genistein Impedes Cancer Stemness and Mesenchymal
Transition in Head and Neck Cancer through Activating miR-34a/RTCB Axis. Nutrients 2020,12, 1924. [CrossRef] [PubMed]
84.
Dehelean, C.A.; Marcovici, I.; Soica, C.; Mioc, M.; Coricovac, D.; Iurciuc, S.; Cretu, O.M.; Pinzaru, I. Plant-Derived Anticancer
Compounds as New Perspectives in Drug Discovery and Alternative Therapy. Molecules 2021,26, 1109. [CrossRef] [PubMed]
85.
Pons-Tostivint, E.; Thibault, B.; Guillermet-Guibert, J. Targeting PI3K Signaling in Combination Cancer Therapy. Trends Cancer
2017,3, 454–469. [CrossRef]
86.
van Krieken, J.H.J.M.; Jung, A.; Kirchner, T.; Carneiro, F.; Seruca, R.; Bosman, F.T.; Quirke, P.; Fléjou, J.F.; Plato Hansen, T.;
de Hertogh, G.; et al.
KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: Proposal for
an European quality assurance program. Virchows Arch. 2008,453, 417–431. [CrossRef]
87.
Rastogi, C.; Rajanna, S.; Puri, N. Current Molecularly Targeted Therapies against EGFR for Cancer. J. Cancer Sci.
2013
,6, e131.
[CrossRef]
88.
Zhang, J.; Yang, P.L.; Gray, N.S. Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer
2009
,9, 28–39. [CrossRef]
89.
Hojjat-Farsangi, M. Small-molecule inhibitors of the receptor tyrosine kinases: Promising tools for targeted cancer therapies. Int.
J. Mol. Sci. 2014,15, 13768–13801. [CrossRef]
90.
Zeng, L.; Tang, M.; Pi, C.; Zheng, J.; Gao, S.; Chabanne, T.; Chauvin, R.; Cheng, W.; Lin, H.; Xu, R.; et al. Novel Ferrocene
Derivatives Induce Apoptosis through Mitochondria-Dependent and Cell Cycle Arrest via PI3K/Akt/mTOR Signaling Pathway
in T Cell Acute Lymphoblastic Leukemia. Cancers 2021,13, 4677. [CrossRef]
91.
Huang, T.-T.; Lampert, E.J.; Coots, C.; Lee, J.-M. Targeting the PI3K pathway and DNA damage response as a therapeutic strategy
in ovarian cancer. Cancer Treat. Rev. 2020,86, 102021. [CrossRef]
92.
Owusu-Brackett, N.; Shariati, M.; Meric-Bernstam, F. Role of PI3K/AKT/mTOR in Cancer Signaling. In Predictive Biomarkers in
Oncology: Applications in Precision Medicine; Badve, S., Kumar, G.L., Eds.; Springer International Publishing: Cham, Switzerland,
2019; pp. 263–270.
93.
Popova, N.V.; Jücker, M. The Role of mTOR Signaling as a Therapeutic Target in Cancer. Int. J. Mol. Sci.
2021
,22, 1743. [CrossRef]
[PubMed]
94.
Miricescu, D.; Totan, A.; Stanescu-Spinu, I.-I.; Badoiu, S.C.; Stefani, C.; Greabu, M. PI3K/AKT/mTOR Signaling Pathway in
Breast Cancer: From Molecular Landscape to Clinical Aspects. Int. J. Mol. Sci. 2020,22, 173. [CrossRef] [PubMed]
95.
Yang, J.; Nie, J.; Ma, X.; Wei, Y.; Peng, Y.; Wei, X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol. Cancer
2019,18, 26. [CrossRef]
96. Mandal, K. Review of PIP2 in Cellular Signaling, Functions and Diseases. Int. J. Mol. Sci. 2020,21, 8342. [CrossRef] [PubMed]
97.
Toker, A.; Marmiroli, S. Signaling specificity in the Akt pathway in biology and disease. Adv. Biol. Regul.
2014
,55, 28–38.
[CrossRef]
98.
Truebestein, L.; Hornegger, H.; Anrather, D.; Hartl, M.; Fleming, K.D.; Stariha, J.T.B.; Pardon, E.; Steyaert, J.; Burke, J.E.;
Leonard, T.A
. Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation. Proc. Natl. Acad. Sci. USA
2021
,
118, e2101496118. [CrossRef] [PubMed]
99. Manning, B.D.; Toker, A. AKT/PKB Signaling: Navigating the Network. Cell 2017,169, 381–405. [CrossRef]
100. Manning, B.D.; Cantley, L.C. Rheb fills a GAP between TSC and TOR. Trends Biochem. Sci. 2003,28, 573–576. [CrossRef]
101.
Ballesteros-Álvarez, J.; Andersen, J.K. mTORC2: The other mTOR in autophagy regulation. Aging Cell
2021
,20, e13431. [CrossRef]
102.
Yuan, J.; Dong, X.; Yap, J.; Hu, J. The MAPK and AMPK signalings: Interplay and implication in targeted cancer therapy. J.
Hematol. Oncol. 2020,13, 113. [CrossRef]
103.
Santarpia, L.; Lippman, S.M.; El-Naggar, A.K. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin.
Ther. Targets 2012,16, 103–119. [CrossRef] [PubMed]
104.
Lee, S.; Rauch, J.; Kolch, W. Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity. Int. J. Mol. Sci.
2020,21, 1102. [CrossRef] [PubMed]
105.
Wojnowski, L.; Stancato, L.F.; Larner, A.C.; Rapp, U.R.; Zimmer, A. Overlapping and specific functions of Braf and Craf-1
proto-oncogenes during mouse embryogenesis. Mech. Dev. 2000,91, 97–104. [CrossRef]
106.
Kong, T.; Liu, M.; Ji, B.; Bai, B.; Cheng, B.; Wang, C. Role of the Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway in
Ischemia-Reperfusion Injury. Front. Physiol. 2019,10, 1038. [CrossRef] [PubMed]
Cells 2022,11, 2209 18 of 20
107.
Degirmenci, U.; Wang, M.; Hu, J. Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy. Cells
2020
,9, 198.
[CrossRef] [PubMed]
108.
Mahipal, A.; Kothari, N.; Gupta, S. Epidermal growth factor receptor inhibitors: Coming of age. Cancer Control
2014
,21, 74–79.
[CrossRef] [PubMed]
109. Shukla, Y.; Pal, S.K. Dietary Cancer Chemoprevention: An Overview. Int. J. Hum. Genet. 2004,4, 265–276. [CrossRef]
110.
Vincent, T.L.; Gatenby, R.A. An evolutionary model for initiation, promotion, and progression in carcinogenesis. Int. J. Oncol.
2008,32, 729–737.
111.
Mohan, S.; Epstein, J.B. Carcinogenesis and cyclooxygenase: The potential role of COX-2 inhibition in upper aerodigestive tract
cancer. Oral. Oncol. 2003,39, 537–546. [CrossRef]
112.
Uray, I.P.; Dmitrovsky, E.; Brown, P.H. Retinoids and rexinoids in cancer prevention: From laboratory to clinic. Semin. Oncol.
2016
,
43, 49–64. [CrossRef]
113.
Brook, N.; Brook, E.; Dass, C.R.; Chan, A.; Dharmarajan, A. Pigment Epithelium-Derived Factor and Sex Hormone-Responsive
Cancers. Cancers 2020,12, 3483. [CrossRef] [PubMed]
114.
Abate-Shen, C.; Brown, P.H.; Colburn, N.H.; Gerner, E.W.; Green, J.E.; Lipkin, M.; Nelson, W.G.; Threadgill, D. The untapped
potential of genetically engineered mouse models in chemoprevention research: Opportunities and challenges. Cancer Prev. Res.
2008,1, 161–166. [CrossRef] [PubMed]
115.
Din, F.V.N.; Valanciute, A.; Houde, V.P.; Zibrova, D.; Green, K.A.; Sakamoto, K.; Alessi, D.R.; Dunlop, M.G. Aspirin inhibits mTOR
signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology
2012
,142,
1504–1515.e3. [CrossRef]
116. Gordaliza, M. Natural products as leads to anticancer drugs. Clin. Transl. Oncol. 2007,9, 767–776. [CrossRef] [PubMed]
117.
Karikas, G.A. Anticancer and chemopreventing natural products: Some biochemical and therapeutic aspects. J. BUON
2010
,15,
627–638. [PubMed]
118.
Newman, D.J.; Cragg, G.M.; Snader, K.M. Natural products as sources of new drugs over the period 1981-2002. J. Nat. Prod.
2003
,
66, 1022–1037. [CrossRef]
119.
Ma, X.; Wang, Z. Anticancer drug discovery in the future: An evolutionary perspective. Drug Discov. Today
2009
,14, 1136–1142.
[CrossRef]
120.
Widmer, N.; Bardin, C.; Chatelut, E.; Paci, A.; Beijnen, J.; Levêque, D.; Veal, G.; Astier, A. Review of therapeutic drug monitoring
of anticancer drugs part two–targeted therapies. Eur. J. Cancer 2014,50, 2020–2036. [CrossRef]
121.
Abuzenadah, A.M.; Al-Sayes, F.; Mahafujul Alam, S.S.; Hoque, M.; Karim, S.; Hussain, I.M.R.; Tabrez, S. Identification of
Potential Poly (ADP-Ribose) Polymerase-1 Inhibitors Derived from Rauwolfia serpentina: Possible Implication in Cancer Therapy.
Evid.-Based Complement. Altern. Med. Ecam 2022,2022, 3787162. [CrossRef]
122.
Wu, X.; Patterson, S.; Hawk, E. Chemoprevention–history and general principles. Best Pract. Res. Clin. Gastroenterol.
2011
,
25, 445–459. [CrossRef]
123.
Muhammad, N.; Steele, R.; Isbell, T.S.; Philips, N.; Ray, R.B. Bitter melon extract inhibits breast cancer growth in preclinical model
by inducing autophagic cell death. Oncotarget 2017,8, 66226–66236. [CrossRef] [PubMed]
124.
Bhattacharya, S.; Muhammad, N.; Steele, R.; Kornbluth, J.; Ray, R.B. Bitter Melon Enhances Natural Killer-Mediated Toxicity
against Head and Neck Cancer Cells. Cancer Prev. Res. 2017,10, 337–344. [CrossRef] [PubMed]
125.
Bhattacharya, S.; Muhammad, N.; Steele, R.; Peng, G.; Ray, R.B. Immunomodulatory role of bitter melon extract in inhibition of
head and neck squamous cell carcinoma growth. Oncotarget 2016,7, 33202–33209. [CrossRef]
126.
Naz, H.; Tarique, M.; Khan, P.; Luqman, S.; Ahamad, S.; Islam, A.; Ahmad, F.; Hassan, M.I. Evidence of vanillin binding to
CAMKIV explains the anti-cancer mechanism in human hepatic carcinoma and neuroblastoma cells. Mol. Cell Biochem.
2018
,
438, 35–45. [CrossRef]
127.
Naz, H.; Tarique, M.; Ahamad, S.; Alajmi, M.F.; Hussain, A.; Rehman, M.T.; Luqman, S.; Hassan, M.I. Hesperidin-CAMKIV
interaction and its impact on cell proliferation and apoptosis in the human hepatic carcinoma and neuroblastoma cells. J. Cell
Biochem. 2019,120, 15119–15130. [CrossRef] [PubMed]
128. Balunas, M.J.; Kinghorn, A.D. Drug discovery from medicinal plants. Life Sci. 2005,78, 431–441. [CrossRef]
129. Cragg, G.M.; Newman, D.J. Plants as a source of anti-cancer agents. J. Ethnopharmacol. 2005,100, 72–79. [CrossRef]
130.
Burns, J.; Yokota, T.; Ashihara, H.; Lean, M.E.J.; Crozier, A. Plant foods and herbal sources of resveratrol. J. Agric. Food Chem.
2002
,
50, 3337–3340. [CrossRef]
131.
Park, S.-H.; Kim, M.; Lee, S.; Jung, W.; Kim, B. Therapeutic Potential of Natural Products in Treatment of Cervical Cancer:
A Review. Nutrients 2021,13, 154. [CrossRef]
132. Li, Y.; Li, S.; Meng, X.; Gan, R.-Y.; Zhang, J.-J.; Li, H.-B. Dietary Natural Products for Prevention and Treatment of Breast Cancer.
Nutrients 2017,9, 728. [CrossRef]
133.
Khan, N.; Mukhtar, H. Dietary agents for prevention and treatment of lung cancer. Cancer Lett.
2015
,359, 155–164. [CrossRef]
[PubMed]
134.
Man, S.; Luo, C.; Yan, M.; Zhao, G.; Ma, L.; Gao, W. Treatment for liver cancer: From sorafenib to natural products. Eur. J. Med.
Chem. 2021,224, 113690. [CrossRef] [PubMed]
135.
Chinembiri, T.N.; du Plessis, L.H.; Gerber, M.; Hamman, J.H.; du Plessis, J. Review of natural compounds for potential skin
cancer treatment. Molecules 2014,19, 11679–11721. [CrossRef] [PubMed]
Cells 2022,11, 2209 19 of 20
136.
Abuzenadah, A.M.; Al-Sayes, F.; Mahafujul Alam, S.S.; Hoque, M.; Karim, S.; Hussain, I.M.R.; Tabrez, S. Elucidating Antiangio-
genic Potential of Rauwolfia serpentina: VEGFR-2 Targeting-Based Molecular Docking Study. Evid. Based Complement Alternat
Med. 2022,2022, 6224666. [CrossRef]
137.
Rajamanickam, S.; Agarwal, R. Natural products and colon cancer: Current status and future prospects. Drug Dev Res
2008
,
69, 460–471. [CrossRef]
138.
Cardona-Mendoza, A.; Olivares-Niño, G.; Díaz-Báez, D.; Lafaurie, G.I.; Perdomo, S.J. Chemopreventive and Anti-tumor Potential
of Natural Products in Oral Cancer. Nutr. Cancer 2022,74, 779–795. [CrossRef]
139.
Park, M.N.; Song, H.S.; Kim, M.; Lee, M.-J.; Cho, W.; Lee, H.-J.; Hwang, C.-H.; Kim, S.; Hwang, Y.; Kang, B.; et al. Review of
Natural Product-Derived Compounds as Potent Antiglioblastoma Drugs. Biomed. Res. Int. 2017,2017, 8139848. [CrossRef]
140.
Hwang, D.; Kim, M.; Park, H.; Jeong, M.I.; Jung, W.; Kim, B. Natural Products and Acute Myeloid Leukemia: A Review
Highlighting Mechanisms of Action. Nutrients 2019,11, 1010. [CrossRef]
141.
Fontana, F.; Raimondi, M.; Marzagalli, M.; Di Domizio, A.; Limonta, P. Natural Compounds in Prostate Cancer Prevention and
Treatment: Mechanisms of Action and Molecular Targets. Cells 2020,9, 460. [CrossRef]
142.
Haque, I.; Subramanian, A.; Huang, C.H.; Godwin, A.K.; Van Veldhuizen, P.J.; Banerjee, S.; Banerjee, S.K. The Role of Compounds
Derived from Natural Supplement as Anticancer Agents in Renal Cell Carcinoma: A Review. Int. J. Mol. Sci.
2017
,19, 107.
[CrossRef]
143.
Pistollato, F.; Calderón Iglesias, R.; Ruiz, R.; Aparicio, S.; Crespo, J.; Dzul Lopez, L.; Giampieri, F.; Battino, M. The use of natural
compounds for the targeting and chemoprevention of ovarian cancer. Cancer Lett. 2017,411, 191–200. [CrossRef] [PubMed]
144.
Cragg, G.M.; Grothaus, P.G.; Newman, D.J. Impact of natural products on developing new anti-cancer agents. Chem. Rev.
2009
,
109, 3012–3043. [CrossRef] [PubMed]
145.
Basmadjian, C.; Zhao, Q.; Bentouhami, E.; Djehal, A.; Nebigil, C.G.; Johnson, R.A.; Serova, M.; de Gramont, A.; Faivre, S.;
Raymond, E.; et al. Cancer wars: Natural products strike back. Front. Chem. 2014,2, 20. [CrossRef] [PubMed]
146.
Cragg, G.M.; Newman, D.J. Nature: A vital source of leads for anticancer drug development. Phytochem Rev.
2009
,8, 313–331.
[CrossRef]
147.
Cragg, G.M.; Newman, D.J. Natural products: A continuing source of novel drug leads. Biochim. Biophys. Acta
2013
,1830,
3670–3695. [CrossRef] [PubMed]
148.
Dutta, S.; Sadhukhan, P.; Saha, S.; Sil, P.C. Regulation of Oxidative Stress by Different Naturally Occurring Polyphenolic
Compounds: An Emerging Anticancer Therapeutic Approach. React. Oxyg. Species 2017,3, 81–95. [CrossRef]
149.
Zamora-Ros, R.; Béraud, V.; Franceschi, S.; Cayssials, V.; Tsilidis, K.K.; Boutron-Ruault, M.-C.; Weiderpass, E.; Overvad, K.;
Tjønneland, A.; Eriksen, A.K.; et al. Consumption of fruits, vegetables and fruit juices and differentiated thyroid carcinoma risk in
the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Int. J. Cancer 2018,142, 449–459. [CrossRef]
150.
Wang, J.; Jiang, Y.-F. Natural compounds as anticancer agents: Experimental evidence. World J. Exp. Med.
2012
,2, 45–57.
[CrossRef]
151.
Grothaus, P.G.; Cragg, G.M.; Newman, D.J. Plant Natural Products in Anticancer Drug Discovery. Curr. Org. Chem.
2010
,14,
1781–1791. [CrossRef]
152.
Tabrez, S.; Khan, A.U.; Mirza, A.A.; Suhail, M.; Jabir, N.R.; Zughaibi, T.A.; Alam, M. Biosynthesis of copper oxide nanoparticles
and its therapeutic efficacy against colon cancer. Nanotechnol. Rev. 2022,11, 1322–1331. [CrossRef]
153.
Iriti, M.; Varoni, E.M. Chemopreventive Potential of Flavonoids in Oral Squamous Cell Carcinoma in Human Studies. Nutrients
2013,5, 2564–2576. [CrossRef] [PubMed]
154.
Shin, D.M.; Nannapaneni, S.; Patel, M.R.; Shi, Q.; Liu, Y.; Chen, Z.; Chen, A.Y.; El-Deiry, M.W.; Beitler, J.J.; Steuer, C.E.; et al. Phase
Ib Study of Chemoprevention with Green Tea Polyphenon E and Erlotinib in Patients with Advanced Premalignant Lesions
(APL) of the Head and Neck. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2020,26, 5860–5868. [CrossRef] [PubMed]
155.
Cruz-Correa, M.; Hylind, L.M.; Marrero, J.H.; Zahurak, M.L.; Murray-Stewart, T.; Casero, R.A.; Montgomery, E.A.;
Iacobuzio-Donahue, C.
; Brosens, L.A.; Offerhaus, G.J.; et al. Efficacy and Safety of Curcumin in Treatment of Intestinal Adenomas
in Patients With Familial Adenomatous Polyposis. Gastroenterology 2018,155, 668–673. [CrossRef] [PubMed]
156.
Luo, Z.; Li, D.; Luo, X.; Li, L.; Gu, S.; Yu, L.; Ma, Y. Curcumin may serve an anticancer role in human osteosarcoma cell line U-2
OS by targeting ITPR1. Oncol. Lett. 2018,15, 5593–5601. [CrossRef]
157.
Pastorelli, D.; Fabricio, A.S.C.; Giovanis, P.; D’Ippolito, S.; Fiduccia, P.; Soldà, C.; Buda, A.; Sperti, C.; Bardini, R.;
Da Dalt, G.; et al.
Phytosome complex of curcumin as complementary therapy of advanced pancreatic cancer improves
safety and efficacy of gemcitabine: Results of a prospective phase II trial. Pharmacol. Res. 2018,132, 72–79. [CrossRef]
158.
Pricci, M.; Girardi, B.; Giorgio, F.; Losurdo, G.; Ierardi, E.; Di Leo, A. Curcumin and Colorectal Cancer: From Basic to Clinical
Evidences. Int. J. Mol. Sci. 2020,21, 2364. [CrossRef]
159.
Williams, D.E. Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3’-Diindolylmethane.
Front. Nutr. 2021,8, 691. [CrossRef]
160.
Yerushalmi, R.; Bargil, S.; Ber, Y.; Ozlavo, R.; Sivan, T.; Rapson, Y.; Pomerantz, A.; Tsoref, D.; Sharon, E.; Caspi, O.; et al.
3,3-Diindolylmethane (DIM): A nutritional intervention and its impact on breast density in healthy BRCA carriers. A prospective
clinical trial. Carcinogenesis 2020,41, 1395–1401. [CrossRef]
Cells 2022,11, 2209 20 of 20
161.
Hwang, C.; Sethi, S.; Heilbrun, L.K.; Gupta, N.S.; Chitale, D.A.; Sakr, W.A.; Menon, M.; Peabody, J.O.; Smith, D.W.;
Sarkar, F.H.; et al.
Anti-androgenic activity of absorption-enhanced 3,3
0
-diindolylmethane in prostatectomy patients. Am. J. Transl.
Res. 2016,8, 166–176.
162.
Messing, E.; Gee, J.R.; Saltzstein, D.R.; Kim, K.; diSant’Agnese, A.; Kolesar, J.; Harris, L.; Faerber, A.; Havighurst, T.;
Young, J.M.; et al
. A phase 2 cancer chemoprevention biomarker trial of isoflavone G-2535 (genistein) in presurgical bladder
cancer patients. Cancer Prev. Res. 2012,5, 621–630. [CrossRef]
163.
Honari, M.; Shafabakhsh, R.; Reiter, R.J.; Mirzaei, H.; Asemi, Z. Resveratrol is a promising agent for colorectal cancer prevention
and treatment: Focus on molecular mechanisms. Cancer Cell Int. 2019,19, 180. [CrossRef] [PubMed]
164.
Seca, A.M.L.; Pinto, D.C.G.A. Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic
Application. Int. J. Mol. Sci. 2018,19, 263. [CrossRef] [PubMed]
165.
Gowd, V.; Ahmad, A.; Tarique, M.; Suhail, M.; Zughaibi, T.A.; Tabrez, S.; Khan, R. Advancement of cancer immunotherapy using
nanoparticles-based nanomedicine. Semin. Cancer Biol. 2022, in press. [CrossRef]
