cancers

Review
Research Trend and Detailed Insights into the Molecular
Mechanisms of Food Bioactive Compounds against Cancer:
A Comprehensive Review with Special Emphasis on Probiotics
Manas Yogendra Agrawal 1,2 , Shreyas Gaikwad 1,2 , Sangeeta Srivastava 3 and Sanjay K. Srivastava 1,2, *

1 Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center,
Abilene, TX 79601, USA
2 Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center,
Abilene, TX 79601, USA
3 Department of Chemistry, Lucknow University, Lucknow 226007, India
* Correspondence: [email protected]; Tel.: +1-325-696-0464; Fax: +1-325-676-3875

Simple Summary: Cancer is one of the leading causes of death worldwide. Treatment of cancer has
long been a challenge. While researchers have been searching for many options for the cure, mother
nature has blessed us with natural bioactive components with anticancer potential. Since the 1800s,
scientists have been studying the efficacy of the bioactive agents present in our food for the treatment
of cancer. This review summarizes the molecular mechanisms responsible for these effects. Moreover,
owing to the increased intake of probiotics in daily diets, this review also explains how they can be
helpful in cancer prevention and treatment.

Abstract: In an attempt to find a potential cure for cancer, scientists have been probing the efficacy
Citation: Agrawal, M.Y.; Gaikwad, S.;
of the food we eat and its bioactive components. Over the decades, there has been an exponen-
Srivastava, S.; Srivastava, S.K.
tially increasing trend of research correlating food and cancer. This review explains the molecular
Research Trend and Detailed Insights
mechanisms by which bioactive food components exhibit anticancer effects in several cancer models.
into the Molecular Mechanisms of
These bioactive compounds are mainly plant based or microbiome based. While plants remain the
Food Bioactive Compounds against
Cancer: A Comprehensive Review
primary source of these phytochemicals, little is known about probiotics, i.e., microbiome sources,
with Special Emphasis on Probiotics. and their relationships with cancer. Thus, the molecular mechanisms underlying the anticancer effect
Cancers 2022, 14, 5482. https:// of probiotics are discussed in this review. The principal mode of cell death for most food bioactives is
doi.org/10.3390/cancers14225482 found to be apoptosis. Principal oncogenic signaling axes such as Akt/PI3K, JAK/STAT, and NF-κB
seem to be modulated due to these bioactives along with certain novel targets that provide a platform
Academic Editors: Claudio Luparello
for further oncogenic research. It has been observed that probiotics have an immunomodulatory
and Rita Ferreira
effect leading to their chemopreventive actions. Various foods exhibit better efficacy as complete
Received: 6 October 2022 extracts than their individual phytochemicals, indicating an orchestrated effect of the food compo-
Accepted: 4 November 2022 nents. Combining bioactive agents with available chemotherapies helps synergize the anticancer
Published: 8 November 2022
action of both to overcome drug resistance. Novel techniques to deliver bioactive agents enhance
Publisher’s Note: MDPI stays neutral their therapeutic response. Such combinations and novel approaches are also discussed in this review.
with regard to jurisdictional claims in Notably, most of the food components that have been studied for cancer have shown their efficacy
published maps and institutional affil- in vivo. This bolsters the claims of these studies and, thus, provides us with hope of discovering
iations. anticancer agents in the food that we eat.

Keywords: cancer; bioactive; phytochemicals; cruciferous vegetables; probiotics; nanoformulation;

chemotherapy; apoptosis; oncogene; chemoprevention; curcumin; ROS
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
1. Introduction
Attribution (CC BY) license (https:// The American Cancer Society states, “Cancer is a group of diseases characterized by
creativecommons.org/licenses/by/ uncontrolled growth and spread of abnormal cells” [1]. The multifaceted adverse effects
4.0/). of cancer are the reasons for its mention as a “group of diseases”, as it leads to several

Cancers 2022, 14, 5482. https://doi.org/10.3390/cancers14225482 https://www.mdpi.com/journal/cancers

Cancers 2022, 14, 5482 2 of 40

physiological adversities, which, if not treated, lead to death. Humans have been fighting
a long-lasting battle with this disease with few positive results, even though cancer has
been studied extensively by researchers. Cancer research encompasses (1) the study of the
mechanisms by which it initiates and progresses, and (2) the study of the mechanisms by
which anti-cancer agents act. Successful and in-depth studies of these aspects bolster the
foundation for further discoveries of potential anti-cancer agents. Scientists have not been
able to find any absolute cure for cancer. Several direct and indirect approaches have been
attempted to treat cancer. The use of antioxidants [2] and anti-inflammatory agents [3]
reduce the tumor-friendly environment and thereby alleviate cancer. Repurposing the
existing FDA-approved non-cancer drugs to treat cancer is another promising strategy
and has been studied rigorously [4–7]. This approach could reduce the long wait times
and avoid the millions of dollars needed for new drug development. Strategies such as
radiotherapy and surgery are used to eliminate the majority of the tumor. The remainder
of the tumor can further be treated using chemotherapies.
In an effort to discover agents with anti-cancer efficacy, bioactive compounds found in
nature have been studied extensively. Moreover, regular vegetables have phytochemicals
that exhibit anti-neoplastic properties [8]. As the available chemotherapies exhibit signifi-
cantly high toxicity, there is a good rationale to identify non-toxic chemicals from fruits and
vegetables for the treatment of cancer. As seen in Figure 1, over the years, researchers have
been studying the association between food and cancer. The number of scientific publica-
tions in the decade from 1980 to 1990 was equal to the total number of publications in the
century from 1880 to 1980. These publications are only increasing with time. The number of
review articles has been increasing exponentially with time, signifying a growing interest
among researchers in deciphering the anticancer potential of food bioactives. Probiotics
have become an essential part of the modern daily diet. Their potential against cancer has
been studied since 1982 and has been at its peak since the last decade (Figure 1). 3Thus,
Cancers 2022, 14, x FOR PEER REVIEW of 42
this review not only focuses on plant-based food bioactives but also probes the molecular
mechanisms by which probiotics help combat cancer.

Figure 1. Research
Figure 1. Research trend
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cancer over
over the
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research trend
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years (right). The data related to the
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(Figure created with Biorender.com (https://biorender.com/, accessed on 1 June 2022) and GraphPad
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It has beenFood
2. Plant-Based observed in several studies that the food matrix as a whole, rather than the
Components
individual phytochemicals,
Plants serve as the major exerts
sourcesynergistic effects.
of food for living This is because
beings and thusofhave
the been
orchestrated
studied
effect of the entire food matrix compared with the physiological effects of chemotherapies
the most for their anti-cancer potential. Plants have evolved over centuries to produce
and drugs. metabolites
secondary This narrative review
such showcases terpenoids,
as flavonoids, several of such
andexamples.
alkaloids Although there
with diverse is a
func-
tions. Plant-based foods belonging to different categories and their active phytochemicals
are discussed below.

2.1. Peppers and Other Nightshade Vegetables

Cancers 2022, 14, 5482 3 of 40

huge variety of foods with anti-cancer potential, those covered in this review have been
studied both in vitro and in vivo. A summary of the list of functional foods covered in this
review is provided in Appendix A.

2. Plant-Based Food Components

Plants serve as the major source of food for living beings and thus have been studied
the most for their anti-cancer potential. Plants have evolved over centuries to produce
secondary metabolites such as flavonoids, terpenoids, and alkaloids with diverse functions.
Plant-based foods belonging to different categories and their active phytochemicals are
discussed below.

2.1. Peppers and Other Nightshade Vegetables

Different kinds of peppers, tomatoes, and eggplant fall under the category of night-
shade vegetables belonging to the Solanaceae family. Peppers are an essential part of almost
all cuisines around the world. Several phytochemicals that exert the pungent and hot taste
in peppers have also been found to exhibit anti-cancer effects in several cancer models.
Eggplant and tomatoes have also shown anticancer effects in different experimental models.
The molecular mechanisms involved in the anti-cancer effects of nightshade vegetables are
elaborated below.

2.1.1. Black Pepper (Piper nigrum)

Piperine and piperidine are the alkaloids in black pepper, making it pungent. Both
alkaloids show a strong anti-cancer effect, as discussed below.

Piperine
Piperine exhibits a wide range of physiological activities such as anti-depressant,
anti-arthritic, and anti-inflammatory effects, along with neurological activities such as
mood elevation and treatment of cognitive disorders [9,10]. Due to the promising phys-
iological effects of this alkaloid, piperine has also been studied for cancer. It is effec-
tive against melanoma [11], breast cancer [12], ovarian cancer [13], gastric cancer [14],
glioblastoma [15,16], lung cancer [17], oral squamous carcinoma [18–20], prostate can-
cer [21–24], rectal cancer [25–27], cervical cancer [28], pancreatic cancer, and leukemia [29].
PI3K/Akt signaling has been recognized as the clinical target for breast cancer treat-
ment [30]. Piperine decreased the phosphorylation of Akt at the Ser473 residue, leading
to apoptosis [31]. Also, it was able to reduce the mitochondrial membrane integrity
with the release of mitochondrial cytochrome c and Smac/DIABLO into the cytosol. Cy-
tochrome c in the cytosol forms apoptosome activating caspase-9, the initiator caspase [32].
Smac/DIABLO inhibits the inhibitors of apoptosis (IAP) proteins, which are responsible
for the inhibition of caspase activity, thereby making apoptosis-mediated cell-death even
stronger [33]. MMP-2 and MMP-9, responsible for tumor metastasis, were inhibited by
piperine treatment as well. Piperine also inhibits signal transducer and activator of tran-
scription 3 (STAT3), p65, and IκBα, leading to the downregulation of Bcl-2 and thus causing
apoptosis [31].
Si et al. studied the molecular mechanism underlying the antiproliferative effects
of piperine on ovarian cancer cells (A2780). They confirmed apoptosis as the mode of
cell death by confirming the increase in cytochrome c levels. Cytochrome c is released
by mitochondria due to damage to the mitochondrial membrane potential. Further, they
observed an increase in caspase-3 and caspase-9 levels, along with an increase in the
expression of cleaved PARP, confirming the activation of the intrinsic apoptotic machinery.
Unchanged levels of caspase-8, which plays a role in activating the extrinsic apoptotic
pathway [34], indicated that cell death occurred via the intrinsic apoptosis pathway. JNK
and p38 MAPK signaling axes were also modulated due to piperine, thus proposing the
inhibition of JNK and p38 MAPK to be the probable mechanism of action [13].
Cancers 2022, 14, 5482 4 of 40

It is known that IL6 is responsible for gastric cancer induction and leads to cancer
cell invasion by activating the c-Src/RhoA/ROCK axis. STAT3 activation also leads to an
increase in the production of IL-6. Apart from STAT3, IL-1ß also induces IL-6 production
through PI3 K-dependent Akt/IκB signaling. In gastric cancer cells, IL-1ß activates the
major MAPK pathways, viz, p38 MAPK, ERK 1/2, and JNK/SAPK [35–38]. The antipro-
liferative effect of piperine against gastric cancer cells (TMK-1) was found to be due to
inhibition of IL-6, along with the inhibition of STAT3 and p38 MAPK pathways [14].
Piperine was found to increase caspase-3, -8, and -9 expressions, resulting in the
induction of apoptosis in glioblastoma (GBM) cells. Piperine also inhibits the expression
of CDK2-cyclin-E and CDK-4/6-cyclin D complexes, suggesting a G1/S cell-cycle arrest.
It also increases the phosphorylation of the JNK/p38 MAPK signaling pathway, thereby
curbing glioma development [16]. Thus, piperine inhibits glioblastoma tumor growth by
modulating the JNK/p38 signaling axis.
Lin et al. found an increase in the expression of tumor suppressor p53 gene by piperine
treatment in human lung cancer cells (A549). As p53 is responsible for inducing G2/M
cell-cycle arrest [39,40], the authors proposed that piperine might possibly cause G2/M cell-
cycle arrest in lung cancer cells. Increased caspase-3 and -9 activity, along with increased
Bax and decreased Bcl-2, confirmed apoptosis as the cell death mode. Unchanged caspase-8
confirmed the apoptotic pathway to be intrinsic [17]. Thus, piperine alleviates lung cancer
by increasing p53 expression and arresting them in the G2/M phase along with the intrinsic
apoptosis of cells.
Researchers have shown that piperine inhibits the proliferation of leukemic cells (HL60
and K-562), inducing both extrinsic and intrinsic apoptosis [29,41]. Piperine increased the
expression of caspase-3, -8, and -9 with an increase in Bax and a decrease in Bcl-2.
Piperine modulates STAT-3 and NF-κB signaling in cervical cancer cells [42]. Inhibition
of rectal cancer by piperine can be attributed to the modulation of Wnt/catenin signaling
along with an increase in ROS production [43]. Piperine has also been studied against
pancreatic, oral squamous, and prostate cancers.

Piperidine
Piperidine is another strong alkaloid in black pepper that has been studied broadly for
its anti-cancer potential. A study showed the antiproliferative effects of piperidine against
both estrogen receptor-negative and -positive MDA-MB-231 and MCF-7 cells, respectively.
It restricted the cell cycle in the G0/G1 phase [44]. Piperidine also inhibited prostate cancer
cell growth by the induction of apoptosis [45]. It increased the levels of pro-apoptotic Bax
and decreased the expression of BcL-2 and XIAP [24]. Epithelial–mesenchymal transition
(EMT), a regulatory step in prostate cancer, is activated during the migration of cancer.
A piperidine derivative, 17a, has been shown to hinder the cell migration of prostate
cancer cells. E-cadherin, a marker of epithelial cells, was seen to be upregulated, whereas
N-cadherin and vimentin, markers of mesenchymal cells, were downregulated. Moreover,
17a inhibited tubulin polymerization by binding to colchicine binding sites [24]. The
piperidine derivative 2-amino-4-(1-piperidine) pyridine has shown anti-proliferative effects
against HT29 and DLD-1 colon cancer cells, with G0/G1 cell cycle phase arrest [46,47]. It
downregulated FOXA2 mRNA, responsible for the proliferation and metastasis of colon
cancer cells. Moreover, the expression of mesenchymal cell marker vimentin decreased,
suggesting a decrease in the epithelial–mesenchymal transition (EMT) by the piperidine
derivative treatment [47]. Thus, piperidine has exhibited significant anti-cancer activity
against breast, prostate, colon, lung, and ovarian cancers.

2.1.2. Long Pepper (Piper longum)

Long pepper is a spice that hails from India. The word pepper derives from the Sanskrit
name pippali. Later, this spice spread to Greece, followed by Rome and greater Europe.
Today, long pepper is used worldwide. Long pepper has been shown to be effective against
renal cancer. Piperlongumine (PL), also known as piplartine, is the principal alkaloid
Cancers 2022, 14, 5482 5 of 40

present in long pepper. It acts through the downregulation of c-Met protein. Hepatocyte
growth factor (HGF) is the ligand for c-Met and is responsible for cancer cell proliferation,
growth, motility, and migration. Piperlongumine exerts its effect via the ROS-dependent
mechanism. Moreover, the c-Met depletion by PL coincides with the downregulation of
downstream signaling pathways such as STAT3, NF-κB, PI3K/Akt, and ERK/MAPK. The
study also discovered that the PL derivatives, PL-fluorophenyl (PL-FPh) and PL-dimer
(PL-Di), exhibited much better efficacy than PL alone. The subcutaneous xenograft model
of the PNX0010 cells showed inhibition of tumor growth by PL treatment, which increased
with PL-Di. Thus, these findings strengthen the claim of the efficacy of long pepper against
renal cell carcinoma [48]. In a study by Conde et al., PL inhibited the glioblastoma tumor
progression in vivo in the orthotopic models of U87- and U251-injected mice. There was
also a decrease in malignant cells derived from the patient’s primary tumors. The study
found that hTRPV2 was responsible for the sensitivity of PL’s effect. Knockdown of hTRPV2
led to decreased sensitivity of PL and the production of ROS. Thus, PL’s anti-tumor effect
can be attributed to the upregulation of hTRPV2 [49]. Harshbarger et al. found GSTP1 to
be another target for cancer inhibition by PL. GST is an antioxidant enzyme. It has various
isozymes. Expression of GSTP1 in cancer cells correlated with resistance to chemotherapy. It
was observed that PL underwent hydrolysis intracellularly to form the hydrolysis product
of PL (hPL), which binds to GSH. This hPL–GSH complex binds to the GSTP1 site leading
to the blockade of GSTP1 and thereby its enzymatic activity. Also, this study showed that
PL acts as a prodrug to elicit its action. The hPL–GSH complex further leads to a decrease
in GSH levels and an increase in ROS, leading to apoptosis. These observations were
made in the cervical (HeLa), pancreatic (PANC1), and colorectal (SW620) cancer cells [50].
Altogether, piperlongumine can be considered as a promising anti-cancer bioactive agent
that acts through the downregulation of c-Met, STAT3, NF-κB, PI3K/Akt, and ERK/MAPK
signaling pathways, inhibition of GSTP1, and upregulation of hTRPV2.

2.1.3. Chili Pepper (Capsicum annuum)

Chili peppers consist of an alkaloid, capsaicin, a potent physiologically active natural
compound. Although capsaicin’s anti-cancer potential was controversial in the initial
phase [51,52], current research has provided a solid basis to confirm that capsaicin exhibits
anti-cancer potential [53–58].
Zhang et al. observed significant inhibition of the growth of pancreatic cancer cells
(AsPC-1 and BxPC-3) by capsaicin treatment. This effect was attributed to the induction of
apoptosis, ROS generation, and mitochondrial membrane potential disruption. Apoptosis
was confirmed by the up-regulatory effect of capsaicin on Bax along with the downregu-
lation of Bcl-2 and survivin. The release of cytochrome c and apoptosis-inducing factor
(AIF) in the cytosol was also observed. Capsaicin enhanced the expression of JNK, thus
suggesting that its action is through the JNK signaling axis. Inhibition of ß-catenin is
also a mechanism by which capsaicin inhibits pancreatic tumor growth. The authors also
confirmed these findings in vivo, wherein they observed that oral administration of cap-
saicin leads to the significant inhibition of AsPC-1 pancreatic tumor xenografts in athymic
nude mice without any side effects [53]. Pramanik et al. delineated the mechanism of
ROS generation by capsaicin. The authors found that ROS generation was associated with
the inhibition of mitochondrial complex-I and complex-III by capsaicin in BxPC-3 and
AsPC-1 human pancreatic cancer cells. The findings were confirmed when the authors
observed no ROS generation in BxPC3-rho (ρ0) cells with a dysfunctional mitochondrial
oxidative phosphorylation system. These results were also reproduced in vivo [54]. Thus,
to summarize, capsaicin inhibits pancreatic tumor growth both in vitro and in vivo by the
modulation of JNK signaling and ROS generation and leads to inhibition of mitochondrial
complexes I and III. Capsaicin has also been effective in other cancer models such as bladder,
renal, hepatic, breast, and oral carcinoma. Capsaicin’s anti-cancer effect has been observed
through the binding to transient receptor potential cation channel subfamily V member
1 (TRPV1), which leads to an increase in intracellular calcium and thus apoptosis [59]. Acti-
Cancers 2022, 14, 5482 6 of 40

vator protein 1 (AP-1), nuclear factor kappa B (NF-κB), and STAT3 are signaling pathways
responsible for tumor growth. Studies have shown that capsaicin inhibits AP1, NF-κB, and
STAT3 in cancer cells [60]. Islam et al. have also shown that capsaicin binds to sirtuin 1
(SIRT1), leading to down-regulation of SIRT1 deacetylase, which reduces the migration of
bladder cancer cells [61]. Thus, chili pepper compounds exhibit significant antineoplastic
effects in several cancers.

2.1.4. Other Nightshade Vegetables

Eggplant (Solanum melongena)
Eggplant has been shown to exert anti-cancer effects in fibrosarcoma as well as ovarian,
skin, lung, gastric adenocarcinoma, and liver cancer models [62–66]. Eggplant consists of
glycoalkaloids such as solasodine, solasonine, and solamargine, which exhibit anti-cancer
effects [67]. Downregulation of the matrix metalloproteases and miR-21 is the mechanism
by which food bioactives in eggplant exhibit anti-cancer effects [65]. Although there are
not many molecular studies available on the efficacy of eggplant on skin cancer, several
clinical trials have been conducted, testing the efficacy of eggplant on skin cancer.

Tomato (Solanum lycopersicum)

Tomato is the second-most important fruit or vegetable after potato in the cuisine
world. Tomatidine, an alkaloid present in the leaf of tomatoes, has been shown to be
useful against gastric cancer via the regulation of interferon-stimulated genes (ISGa) [68].
Carotenoids present in tomatoes are strong antioxidants and thus help in preventing the
damage caused to the DNA. Lycopene, a carotenoid, is another antioxidant from tomato
that has been effective against prostate cancer. It enhances the sensitivity of prostate
cancer to the anti-cancer drug enzalutamide by modulating the AKT/EZH2/androgen
receptor-signaling pathway. The in vivo findings indicated a significant inhibition of the
tumor growth by carotenoid treatment as compared to control, along with a reduction
in bone metastasis [69]. It was also observed that whole tomato powder (10% in diet),
which contained other carotenoids, was more effective in alleviating prostate cancer than
lycopene alone (0.025%) [70]. Lycopene’s activity has also been studied in vivo. Gupta et al.
observed that lycopene at a dose of 5 mg/kg was able to downregulate cyclin D1, HIF-
1α, and PCNA, thus reducing hepatocellular carcinoma growth [71]. Tomatoes and their
bioactive components have shown promise in suppressing lung and breast cancers as
well [72,73]. There are a few studies that have observed almost no effect of tomatoes on
prostate cancer [74]. However, the tomato–lycopene–prostate cancer triad has been studied
extensively with promising outcomes from most of the studies [75].
Thus, solanaceous nightshade vegetables, including peppers, exhibit promising anti-
cancer potential in different types of cancers. This effect is exerted via the modulation of
several proto-oncogenic pathways, both in vitro and in vivo.

2.2. Spices
Spices have been known to exert numerous physiological functions useful against
different diseases along with strong anti-cancer potential. Clove and turmeric are the spices
with strong anti-cancer potential and are discussed below.

2.2.1. Cloves (Syzygium aromaticum)

Clove oil extract has shown antiproliferative effects in breast cancer cells (MCF-7 and
MDA-MB231), cervical cancer cells (HeLa), prostate cancer cell metastasis of the brain
(DU145), and esophageal cancer cells (TE-13) [76,77]. Helicobacter pylori (HP), a Gram-
negative bacterium, is known to cause gastric cancer. The methanolic extract from the
leaves of cloves inhibits the growth of all the strains of HP. The authors extrapolated these
finding to the Thai population that is less susceptible to gastric cancer despite having a
higher incidence of HP infections, as the Thai cuisine abundantly uses cloves [78]. This
shows that the use of cloves can serve as a preventive measure for gastric cancer by inhibit-
Cancers 2022, 14, 5482 7 of 40

ing HP growth. Liu et al. found that oleanolic acid (OA), a phytoconstituent present in
cloves, exhibit anti-cancer properties. However, a comparative study found that the whole
extract of cloves was more effective than the bioactive constituents alone. This indicates
that natural food components exert their effect in an orchestrated fashion, where all the
phytoconstituents work in synergy to achieve the desired effects. However, the identifica-
tion of a particular phytochemical will be helpful for further drug development processes.
The study also strengthened the claim by showing that an ethyl acetate cloves extract at a
50 mg/kg dose exerted maximum inhibition of subcutaneous colorectal adenocarcinoma
tumors (HT29) in mice. The effect was better than the individual treatments of oleanolic
acid and standard therapy 5-fluorouracil. The cloves extract arrested the cell growth in
the G0/G1 phase and also exhibited an increase in apoptosis in a dose-dependent fashion.
The cloves extract and OA treatment led to the downregulation of cell-cycle proteins such
as E2F1 and increased the protein expression of p21 WAF1/Cip1 and γ-H2AX. Down-
regulation of thymidylate synthase hints towards DNA damage [79]. Kubatka et al. saw
a significant inhibition in breast tumor growth in mice following cloves administration
compared to the control. Enhanced caspase-3 and Bax confirmed apoptosis as the mode
of cell death. Cloves treatment also increased the population of cells with depleted MMP,
thus showing that cloves also acts through the mitochondrial apoptosis pathway. Ki67, a
proliferation marker, and VEGFA, responsible for angiogenesis, were downregulated in
mice fed with a cloves-rich diet. CD44, CD24, and ALDH1 are markers for cancer stem
cells (CSC) in breast cancer. All three CSC markers were downregulated due to a cloves
diet [80]. Li et al. studied the effects of aqueous extracts of cloves in pancreatic and colon
cancer models. The extract induced autophagy in cancer cells. The role of the AMPK
pathway in the autophagy process is well known. An aqueous extract of cloves led to
an increase in AMPK and ULK, thus proposing modulation of AMPK/ULK-mediated
autophagy to be the probable mechanism. Colon tumor growth in mice was inhibited
by oral administration of a cloves extract. The inhibition was higher than the standard
cyclophosphamide therapy [81]. Nirmala et al. developed an oil-based nanoscale emulsion
of cloves buds and tested its anti-cancer efficacy against thyroid cancer cells (HTh-7). The
nanoscale emulsion showed anti-proliferative effects against thyroid cancer cells, with
apoptosis seen as the mode of cell death [82]. This study provides a novel method for the
delivery of cloves. Thus, it can be said that the phytochemicals in cloves along with the
whole cloves bud and its extract helps combat cancer.

2.2.2. Turmeric (Curcuma longa)

Turmeric is another famous spice used in various cuisines worldwide. Historically,
turmeric has been used by South Asian populations as an antiseptic in healing wounds
and as an anti-inflammatory agent. The most active phytocompound in turmeric is the
beta-diketone curcumin, which has been studied in-depth for its anti-cancer effects in
numerous cancers. Turmeric is been tested in clinical trials for almost all types of cancers.
Curcumin, the main chemical present in turmeric, has been found by Sahu et al.
to inhibit pancreatic cancer cell growth, with apoptosis being the mode of cell death.
Curcumin also arrests the growth of pancreatic cancer cells (BxPC-3) in the G2/M phase.
Phosphorylation of H2A.X and Chk1, the markers of DNA damage, were upregulated,
whereas DNA polymerase-ß, a DNA repair enzyme, was downregulated due to curcumin
treatment. In addition, ATM phosphorylation was increased due to curcumin treatment
along with a decrease in cyclin B1, confirming the G2/M arrest of cells. It can be concluded
that ATM/Chk1 plays an important role in mediating the G2/M arrest of cells caused by
curcumin, leading to the anti-tumor effects against pancreatic cancer [83]. Curcumin also
increases the sensitivity of non-small lung cancer cells to cisplatin, the standard therapy.
This effect was regulated via the endoplasmic reticulum stress pathway [84]. Curcumin
suppressed the Akt/PI3K/mTOR signaling axis and upregulated miR-199a to inhibit
oral squamous cell carcinoma [85]. Curcumin suppressed papillary thyroid cancer by
modulating the long non-coding RNA LINC00691 through the Akt signaling axis [86].
Cancers 2022, 14, 5482 8 of 40

Curcumin also works on several other cancers such as glioblastoma by acting through
MMP, NF-κB, STAT3, and PI3K/Ak/mTOR downregulation [87]; breast cancer by p53
regulation [88], and lung cancer metastasis inhibition by regulating the adiponectin/NF-
κB/MMPs signaling pathway [89].
CLEFMA (4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid]),
is a curcuminoid that exhibits anti-cancer properties [90]. CLEFMA has been proposed
to elicit its anti-cancer effects by perturbating redox homeostasis in cancer cells [91]. It
also mediates cell death via the intrinsic apoptosis pathway, leading to the activation
of procaspase-3 and procaspase-9 [92]. CLEFMA also induces apoptosis by increasing
BAX and BID [93]. It down-regulates pro-apoptotic proteins by acting on the NF-κB
pathway [90,94,95]. Moreover, it also suppresses expression of the pro-inflammatory
COX2 [90]. CLEFMA also decreased the expression of cyclin D and caused cell-cycle
arrest in the S phase of H441 cells. CD31, a marker of angiogenesis, and ICAM1, which
is responsible for cell migration and adhesion, were also downregulated by CLEFMA
treatment [90]. Several other spices with anti-cancer properties are black cumin (Nigella
sativa), rosemary (Salvia rosmarinus), saffron (Crocus sativus), oregano (Origanum vulgare),
and basil (Ocimum basilicum) [96]. All these spices have been studied for numerous cancer
models with positive results.

2.3. Cruciferous Vegetables

Cruciferous vegetables belong to the Brassicaceae (formerly Cruciferae) family, which
include Broccoli (Brassica oleracea var. italica), Cabbage (Brassica oleracea var. capitata),
Cauliflower (Brassica oleracea var. botrytis), Kale (Brassica oleracea var. sabellica), Mustard
(Brassica juncea), Watercress (Nasturtium officinale), Horseradish (Armoracia rusticana), etc.
Cruciferous vegetables have been studied extensively for their antineoplastic potential.
These vegetables have a few common phytochemicals, such as isothiocyanates, diindolyl-
methane, and sulforaphane, which exert anti-cancer effects. Molecular mechanisms under-
lying the anti-carcinogenic effect of these phytocompounds are discussed below.

2.3.1. Isothiocyanates (ITC)

ITCs suppress the carcinogen activation and increase the detoxification of the same.
Glucosinolates store ITCs in cruciferous vegetables. Even the glucosinolates have been
found to exert anti-cancer effects. Overall, ITCs exert their anti-cancer effect by inducing
oxidative stress, apoptosis, and cell-cycle arrest, inhibiting the tumor’s metastasis and
inhibiting angiogenesis [97]. Three main isothiocyanates that are extensively studied are
benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), and sulforaphane, as
discussed in this review. In addition to cruciferous vegetables, BITC is also found in papaya
seeds (Carica papaya).

Benzyl Isothiocyanate (BITC)

BITC has several beneficial physiological effects along with its anti-cancer potential
against different cancers such as breast cancer [98], non-small lung cancer [99], prostate
cancer [100], leukemia [101], colon cancer [102], hepatocellular cancer [103], and pancre-
atic cancer [104]. BITC also sensitizes the tumors to standard chemotherapies, thereby
diminishing the problem of drug resistance [105].
BITC treatment caused DNA damage in cells, which resulted in G2/M cell-cycle
arrest in pancreatic cancer cells. The mode of cell death against pancreatic cancer cells
was apoptosis [106]. Sahu et al. also confirmed that apoptosis by BITC was selective to
cancer cells but did not affect the viability of normal human pancreatic ductal epithelial
(HPDE) cells. They found that the apoptosis induced in pancreatic cancer cells was through
the inhibition of STAT3 signaling. They also showed the tumor-suppressing efficacy
of BITC in BxPC3 tumor xenografts in mice [104]. In another study, inhibition of the
PI3K/AKT/FOXO pathway was found to be another mechanism by which BITC exerted
its effect against pancreatic cancer [107]. Boreddy et al. found the inhibition of HIF-
Cancers 2022, 14, 5482 9 of 40

1α/VEGF/Rho-GTPases by STAT3 to be the reason for suppression of angiogenesis and

invasion of pancreatic tumors [108]. Thus, BITC is a strong anti-cancer agent effective
against pancreatic cancer acting via inhibition of PI3K/AKT/FOXO-, STAT-3-, and STAT-3-
mediated HIF-1α/VEGF/Rho-GTPases signaling axes. Lai et al. found the effectiveness of
BITC against colon cancer, where they found that BITC was able to inhibit the migration
and invasion of human colon cancer cells. This effect was due to the downregulation of
urokinase-type plasminogen activator (uPA) linked to protein kinase C (PKC), the MAPK
signaling pathway, and the MMP-2/9 pathway [102]. The anti-tumor effect of BITC was
confirmed in breast cancer, which showed potentiation of p53 signaling. The activation of
p53 was extrapolated to the activation of p53-LKB1 and p73-LKB1 axes. The mammosphere-
forming ability of breast cancer cells was also diminished by BITC treatment [109]. Overall,
it can be concluded that BITC exerts strong anti-cancer potential through the inhibition of
several oncogenic pathways and has therapeutic selectivity towards cancer cells, averting
the cytotoxic effects on normal cells.

Phenethyl Isothiocyanate (PEITC)

Multiple researchers have established the efficacy of PEITC, both in vitro and in vivo
experimentally in various cancers such as prostate, breast, cervical, lung, colorectal, and
metastatic breast cancer, as well as leukemia and glioblastoma. Gupta et al. observed that
oral administration of PEITC suppresses the metastasis of breast tumor cells to the brain.
This effect was observed within days of PEITC administration in an in vivo study exhibiting
its high potency [110]. This research group established HER2 as the potential target of
PEITC in breast cancer. PEITC also enhanced the sensitivity of breast tumors towards
the standard therapy, such as doxorubicin, exhibiting synergistic effects [111]. PEITC
was also shown to induce immune modulation in tumor-bearing mice xenografts. The
suppression of breast tumor growth was associated with the reduction in myeloid-derived
tumor suppressor cells (MDSCs) and T regulatory lymphocytes [112]. Boyanapalli et al.
showed that PEITC treatment resulted in the arrest of prostate cancer cells in the G2/M
phase and the induction of apoptosis. This effect of PEITC was due to the reactivation
of the tumor suppressor RASSF1A [113]. Wu et al. observed a significant reduction in
the tumor incidence in the transgenic TRAMP model of prostate cancer in mice fed with
PEITC supplemented diet. The effect was attributed to the attenuation of cell-cycle/Cdc42
signaling in PEITC-fed mice and an inverse regulatory relationship between the RNA
expression of Adgrb1 and Ebf4 genes and CpG methylation [114]. Thus, it can be said
that PEITC attenuates prostate cancer growth by the activation of RASSF1A, cell-cycle
arrest, and reduced inflammation along with an impact on the global CpG epigenome
and transcriptome. PEITC was also effective against leukemia. Liu et al. found that
PEITC induced ROS generation in chronic lymphocytic leukemia (CLL) cells deficient
in p53. Similar results were also observed in vivo, where PEITC significantly increased
the survival of p53 knock-out mice as compared to the control group [115]. PEITC could
likely be effective against CLL, with patients having p53 mutations. It is known that
several metabolic alterations occur in the immune cells due to cigarette smoke [116–120].
Yuan et al. observed that PEITC reduced the metabolic activation of 4-(methylnitrosamino)-
1-(3-pyridyl)-1-butanone (NNK), a tobacco carcinogen, by 7.7% in smokers [121]. Taken
together, PEITC is a promising phytochemical against several cancers.

Sulforaphane (SFN)
Sulforaphane, an isothiocyanate, is a well-known phytochemical present in broccoli
and other cruciferous vegetables. It has exhibited its anti-cancer potential against several
cancers such as prostate, colon, breast, lung, and oral. SFN exerts its anti-cancer effects by
inducing apoptosis, cell-cycle arrest, modulation of oncogenic signaling pathways, and the
inhibition of angiogenesis. It acts by Nrf2 activation and HDAC inhibition [122].
Cancers 2022, 14, 5482 10 of 40

2.3.2. Diindolylmethane (DIM)

DIM is naturally presented as a glucosinolate conjugate in cruciferous vegetables
and is released upon hydrolysis when the plant is damaged either by cutting or chewing.
Kandala et al. showed the anti-cancer efficacy of DIM against ovarian cancer; wherein
the anti-proliferative effect against ovarian cancer cells was observed due to induction
of apoptosis and cell-cycle arrest in the G2/M phase [123]. They observed that DIM
increased the phosphorylation of H2A.X and activated checkpoint kinase 2 (Chk2) [123]
and downregulated the phosphorylated EGFR [124], MEK, and ERK. DIM also suppressed
p-STAT3 [125], VEGF, and HIF-1α [125]. Decreases in VEGF and HIF-1α demonstrated that
DIM significantly reduced cell-invasion and angiogenesis. The results were corroborated
by the tumor inhibitory effects of orally administered DIM on the SKOV3 ovarian tumor
xenografts in athymic nude mice [125]. DIM induced macroautophagy in ovarian cancer
cells and activated AMPK, leading to apoptosis [126]. Anoikis is a mode of cell death that
occurs after the cell detaches from the extracellular matrix (ECM). Cancer cells are resistant
to anoikis, thus leading to enhanced cell proliferation and invasion [127]. Kandala et al.
found that DIM reduced anoikis resistance through the downregulation of Gli1. The results
were confirmed in vivo using Gli1 knockout cells in mice [128]. DIM has also been effective
against breast cancer cells. Ganesan et al., out of the different derivatives of DIM, showed
that DIM-1 and DIM-4 were the most potent variants. These compounds were able to
inhibit cell migration and the activity of MMP-2 and MMP-9, indicating that DIM can
prevent cancer metastasis. With an increase in the expression of cleaved PARP, cleaved
caspase-3, and Bax and a decrease in the expression of Bcl-2, apoptosis was proposed to
be the mode of cell death. The DIMs blocked the EGF receptor and thereby inhibited the
Ras-mediated Akt/PI3K/mTOR signaling axis [129]. Munakarmi et al. found that DIM
inhibited hepatocellular carcinoma (HCC) cell growth by inducing the caspase-dependent
apoptotic pathway. DIM suppressed the epithelial–mesenchymal transition (EMT) by
targeting the ER-stress and unfolded protein response (UPR) [130]. Several studies have
also shown DIM to be effective against prostate cancer. Wang et al. found that DIM
inhibits the LPS-mediated induction of IL1ß mRNA and protein in undifferentiated THP-1
monocytes. However, this was not the case in differentiated THP-1 macrophages. Also,
knockdown studies showed that this effect was regulated by the aryl hydrocarbon (AHR)
pathway. DIM inhibited CD84 mRNA but not the protein. Thus, it can be said that DIM
treatment leads to crosstalk between AHR and the inflammation-mediated pathway in
monocytes, resulting in modulation of the tumor microenvironment. However, this effect
was not observed in macrophages. Also, the crosstalk was independent of the CD84-
mediated pathways [131]. DIM was observed to exert its anticancer effects via inhibition of
the PI3K/Akt/mTOR signaling pathway and the aryl hydrocarbon receptor pathway [132].

2.4. Cucurbitaceous Foods

Some vegetables and fruits belong to the Cucurbitaceae family. They are also called
the gourd family, and their members are called the cucurbits. They include cucumber,
melon, watermelon, pumpkin, gourd, squash, etc.
Cucurbits contain a triterpenoid steroid, cucurbitacin B (CuB), which has been shown
to exhibit anti-tumor effects against several cancers. Gupta et al. showed the anti-
proliferative effects of CuB against breast cancer cells at low concentrations, ranging from
18 to 50 nM, and acting via the downregulation of HER2 and integrin signaling. Several
integrins (ITG) such as ITGA6, ITGB1, ITGB3, and ITGB4 have different roles. ITGA6 and
ITGB4, which are overexpressed in breast cancer, were downregulated, whereas ITGB1
and ITGB3, which are responsible for causing integrin-mediated cell-death, were induced
by CuB treatment. The anti-tumor efficacy was confirmed in the in vivo model, where
Gupta et al. showed a significant inhibition of MDA-MB-231 and 4T-1 breast tumors in-
jected orthotopically in BALB/c mice. Since 4T1 cells are the stage-IV representative of
breast tumor, these findings bolster the significance of CuB being effective against breast
Cancers 2022, 14, 5482 11 of 40

cancer [133]. This research group also showed that cucurbitacin B helped suppress the
metastasis of breast cancer cells to the brain [134].
Cucurbitacin B has also been effective in attenuating colorectal cancer, lung cancer, pan-
creatic cancer, breast cancer, neuroblastoma, and acute myeloid leukemia. It acts through
the inhibition of STAT3 in all these cancers [133,135–139]. Several other mechanisms associ-
ated with anti-cancer effects of cucurbitacin B were the modulation of the EGFR pathway
in colorectal cancer [139], the MAPK pathway in neuroblastoma [136], and inhibition of the
CIP2A/PP2A/C-KIT signaling axis in myeloid leukemia [135].
Taken together, it can be inferred that cucurbitaceous foods have physiological effects
against numerous cancers via the inhibition of oncogenic pathways, principally being the
JAK/STAT axis.

2.5. Root Vegetables

Root vegetables are an edible portion of plants grown under the ground. Botanically
they might be classified as root or non-root; however, collectively, they are referred to as root
vegetables. Root vegetables with anti-cancer potential include ginger, garlic, beetroot, onion,
carrots, turnips, sweet potato, and rutabagas. This review encompasses the molecular
mechanisms underlying the anti-cancer effects of the phytochemicals in different root
vegetables such as ginger, garlic, beetroot, and onion.

2.5.1. Ginger (Zingiber officinalis)

Ginger is used as a taste enhancer in various types of foods and beverages and has
shown anticancer activity in various cancer models. Ginger has demonstrated its efficacy
in prostate cancer, wherein the whole extract of ginger was found to be more efficacious
than the extract containing the phytoconstituents of ginger. This observation indicated
the importance of the compound’s natural form, hinting that other natural components in
ginger or any natural product may play essential roles in their overall activity [140]. Several
phenolic compounds such as 6-gingerol, 6-shagol, zingerone, and 6-paradol have shown
oncolytic effects in various experimental models [140–151]. Ginger extract inhibits breast
tumor growth through the blockade of the G2/M phase. Researchers found that ginger
caused cell death in breast cancer cells by different modes such as typical apoptosis, caspase-
independent apoptosis, autophagy-dependent apoptosis, and autophagy [143,145,152,153].
Ray et al. observed that 6-shogaol, a phenol present in ginger, induced autophagic cell
death in breast cancer cells along with the modulation of the Notch signaling pathway [143].
Lee et al. found that gingerol, another phenolic compound in ginger, inhibited the metasta-
sis of MDA-MB-231 human breast cancer cells [154]. These findings were corroborated by
Martin et al. with similar observation in vivo [155]. Another study showed a significant
reduction in breast tumor growth in the orthotopic model of mice due to treatment with
zerumbone, a cyclic sesquiterpene in ginger [152]. Seshadri et al. found that zingiberene, a
constituent of ginger, inhibited the 7,12-dimethylbenz(a)anthracene-induced breast cancer
growth in Sprague–Dawley rats [151]. Zerumbone and 6-shogaol treatment arrested the
growth of prostate cancer cells (DU-145) in the G1 phase. This effect was attributed to the
inhibition of STAT-3 and NF-κB signaling [156]. Similar inhibition of prostate cancer (PC3)
tumor growth was observed in vivo by oral feeding of ginger extract [157]. Zerumbone
treatment led to G2/M arrest in hepatocellular carcinoma cells. The underlying mechanism
for this effect was the inhibition of PI3K/Akt/mTOR and the STAT3 signaling axis. The
cells underwent cell-cycle arrest due to the shunting of glucose-6-phosphate in the pentose
phosphate pathway [158].
Ginger and its phytoconstituents have also been effective against other cancers such as
ovarian [158], colon [146], non-small lung [159], lung [159], gastric adenocarcinoma [160],
melanoma [161], and cervical [162] by modulating NF-κB, p21, ERK1/2, p38, p53, Wnt/ß-
catenin, and AMPK. Gingerols were also found to be effective in preventing emesis caused
by chemotherapies [147]. Thus, the phytoconstituents in ginger not only help treat cancer
but also prevent side effects due to chemo-drugs.
Cancers 2022, 14, 5482 12 of 40

2.5.2. Garlic (Allium sativum) and Onion (Allium sepa)

Onion and garlic are Allium vegetables belonging to the Amaryllidaceae family. They
have been studied extensively for the treatment of cancer. Sulfur-containing compounds
such as allicin, allylpropyl disulfide, diallyl sulfide (DAS), diallyl disulfide (DADS), and
diallyl trisulfide (DATS) are responsible for the anti-cancer effects of garlic. Saud et al.
demonstrated the efficacy of garlic against colitis-induced colon cancer through the mod-
ulation of the NF-κB pathway [163]. DADS suppresse breast cancer, liver cancer, and
leukemia by inhibiting histone deacetylases. The results were confirmed via in vivo animal
tumor models [164]. Studies have also observed that the organosulfur compounds in garlic
induced phase-2 metabolizing enzymes to prevent cancer [165]. Hu et al. showed that
DAS, DADS, and DATS, when administered to mice orally, induced the expression of α
(mGSTA1-2, mGSTA3-3, mGSTA4-4), µ (mGSTM1-1), and π (mGSTP1-1) classes of GST
enzymes in the lung, liver, and forestomach. However, mGSTP1-1 was most closely related
to the inhibition of forestomach tumorigenesis induced by chemical carcinogens [166–168].
Thus, it can be said that organosulfur compounds in garlic act by modulating the phase-2
metabolizing enzymes, predominantly glutathione S-transferases (GST). The anticancer
mechanisms of DADS and DATS involve ROS generation, downregulation of p-Akt and
p-IGFR, upregulation of p-JNK/p-ERK along with G2/M cell-cycle arrest, induction of
apoptosis, inhibition of histone deacetylases, and induction of phase-2 metabolic enzymes.
The efficacy of the bioactive compounds in onion has been observed against prostate,
esophageal, colorectal, stomach, pharynx, larynx, renal, breast, ovary, and endometrial can-
cers [169]. Like garlic, onions also contain organosulfur compounds (OSCs), which exhibit
anti-cancer properties. OSCs in onion control breast cancer by targeting heat shock protein
HSP70, binding immunoglobulin protein (BiP), and stress inducible HSP70 [170]. Most of
the tumor inhibition mechanisms of these OSCs remain similar to those of garlic compounds.
Taken together, the allium vegetables onion and garlic contain organosulfur com-
pounds that are responsible for the antineoplastic effects in different cancer models.

2.5.3. Beetroot (Beta vulgaris Subsp. vulgaris)

Betanin, a glyosidic food dye, is the principal component of beetroot responsible for
its anti-cancer effect. Betanin induced apoptosis in cancer cells by activating the cleav-
age of caspase-3 followed by loss of the transmembrane potential of mitochondria [171].
Sreekanth et al. showed in vitro that betanin inhibited the proliferation of chronic myeloid
leukemia human K562 cells, leading to apoptosis mediated by the release of cytochrome c
from the mitochondria into the cytosol [172]. Betalain and betanine also have the potential
to inhibit the growth of hepatocellular cancer (HepG2) cells [173]. Beetroot’s anti-cancer
efficacy has been observed in the in vivo breast cancer models, wherein researchers showed
a significant decrease in papillomas after treatment with 0.0025% betanin, a constituent of
beetroot. The study also showed some promise against lung cancer in the in vivo model [10].
These findings provide a foundation to suggest the anti-cancer efficacy of beetroot.

2.6. Tropical Fruits

Tropical fruits are those grown in the hot and humid regions near the tropics of
Cancer and Capricorn, covering the tropical regions of Asia, Africa, Central America, South
America, the Caribbean, and Oceania. Of the several tropical fruits, Guava and Dragon
fruit have shown strong anti-cancer potential. Their efficacy against several cancers and
the mechanism of action are elaborated below.

2.6.1. Guava (Psidium guajava)

The protective effects of guava extract have been shown against several cancers such
as colorectal cancer, lung cancer, myeloid leukemia, myeloma, cervical cancer, squamous
cell carcinoma, breast cancer, and gastric cancer [174–177]. Terpenoids in guava principally
exhibit anti-cancer effects. A pharmacology network study by Jiang et al. showed that
guava leaves were associated with several oncolytic mechanisms. In this study, Akt/PI3K,
Cancers 2022, 14, 5482 13 of 40

STAT3, and TP53 were the major players modulated by guava. Gene Ontology (GO) and
Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses found 153 targets
that were associated with small and non-small lung cancers affected by guava leaves [178].
Guava seeds contain a polysaccharide, guava seed polysaccharide fraction 3 (GSF3), which
has been shown to inhibit breast cancer cell (MCF7) growth. Lin et al. proposed an
increase in the Bax/Bcl-2 ratio and an increase in Fas mRNA expression as the probable
mechanism [179]. Ryu et al. found that GHF, i.e., the hexane fraction of guava, exhibited
anti-cancer potential against prostate cancer by modulating Akt/mTOR/S6K and MAPK
pathways. The ERK/JNK/p38 signaling axis was also modulated in this study. In addition
to GHF, the study also identified several other compounds, notably ß-eudesmol, α-copaene,
α-patchoulene, ß-caryophyllene oxide (CPO), octadecane, and α-terpineol, for their anti-
cancer efficacy [180]. Liu et al. found that guava extract inhibited the proliferation of
several TNBC cells and induced apoptosis in them [181]. Rizzo et al. showed the efficacy of
guava extracts in vivo against solid Ehrlich tumors at 50 mg/kg with no toxicity. Moreover,
the guava treatment proved to be more efficacious than doxorubicin, the standard therapy
of care [175]. The findings from the in vivo study corroborated the anti-cancer potential of
guava. These findings also provide a promising foundation for deciphering the anti-cancer
potential of guava in humans as well.

2.6.2. Dragon Fruit (Selenicereus undatus)

Dragon fruit has shown anti-proliferative effects against prostate and colon cancer
cells. Interestingly melanoma cells seemed relatively resistant to dragon fruit [182]. Dragon
fruit exerts physiological effects due to the presence of antioxidant components such as
betalains, steroids, and triterpenoids. Of these, betalains inhibit COX enzymes and lipid
peroxidation. Betalain has been shown to inhibit the proliferation of breast (MCF-7), colon
(HCT-116), stomach (AGS), glioblastoma (SF268), and lung (NCl-H460) cancer cells [183].
Betalain is also a component of beetroot. Although these findings look promising, more
research is needed to corroborate the anti-cancer claims of dragon fruit and to decipher the
detailed molecular mechanism.

2.7. Grass Family Members:

Lemongrass and wheatgrass are the food components belonging to the grass family,
which exhibit anti-cancer properties.

2.7.1. Lemongrass (Cymbopogon citratus)

Lemongrass is an essential component of different cuisines such as Thai, Vietnamese,
Malaysian, Indian, and Southeast Asian foods, as well as in beverages. Lemongrass oil
(LEO) consists of several terpenes and terpenoids such as citral, geraniol, α-bisabolol, ger-
anyl acetate, and iso-intermedeol, which are responsible for its anticancer effects. LEO and
its phytochemicals have been found to be effective against colon, liver, lung, cervical, oral,
prostate, and brain (neuroblastoma) cancers. Overall, it was observed that LEO terpenes in-
duce apoptosis by activating procaspase-3 and G2/M phase cell cycle arrest [184,185]. The
double bond, conjugated with an aldehyde in the core of citral, serves as a potent casapsae-3
activator [185]. Citral also acts on several oncogenic pathways and leads to suppression of
Src (Y416) and STAT3, as well as phosphorylation and inhibition of AMPK [186]. It also
inhibits fatty acid synthase (FASN), leading to inhibition of the lipogenesis of prostate
cancer cells [187]. Citral binds to microtubule affinity regulating kinase 4 (MARK4), an
AMP-activated protein kinase, thus inhibiting its kinase activity [188]. Citral also modulates
ERK1/2 and MAPK signaling cascades along with an increase in the phosphorylation of
tumor suppressor p53 [189,190]. Geraniol, a terpene in lemongrass, possesses antiangio-
genic effects, as confirmed by the suppression of VEGFR-2, leading to the reduction of
Ki-67 and CD3-microvessels in vivo. It also increases ROS production, which helps in the
killing of cancer cells [191]. Altogether, it can be said that lemongrass oil and its terpenes
Cancers 2022, 14, 5482 14 of 40

and terpenoids possess anti-cancer potential. However, human studies are lacking, and
they will help in the translational aspects of the anticancer claims of lemongrass.

2.7.2. Wheatgrass (Thinopyrum intermedium)

Wheatgrass is mainly consumed as a juice, and its powdered form is used in different
cuisines. Although not much research has been done on wheatgrass for its anti-cancer
potential, it has been used historically in different traditional forms of medicines, mainly the
Ayurveda (Indian traditional medicine system). Studies have shown that the wheatgrass
extract may help reduce metastasis by reducing the protein expression of VEGF, MMP-9,
and COX-2 along with an increase in TIMP-2 in epithelial carcinoma (HEp2) cells. The
anti-cancer effect was attributed to the inhibition of the Akt/PI3K pathway [192]. Sim et al.
observed that the wheatgrass extract attenuates hypoxia induced factor (HIF1-α) and the
mucins MUC5A, MUC5B, and MUC8 in A549 lung adenocarcinoma cells [193]. Wheatgrass
juice has also been observed to be effective in reducing the vascular damage caused by
chemotherapy in colon cancer and in increasing anti-inflammatory cytokine IL-10. These
effects exhibit the protective actions of wheatgrass [194,195]. Overall, it seems that wheat-
grass exerts antioxidant and anti-inflammatory effects. More robust in vitro and in vivo
studies are needed to understand the underlying molecular mechanism of wheatgrass.

2.8. Caffeinated Plants (Tea (Camellia sinensis) and Coffee (Coffea arabica))
Tea and coffee are caffeinated plant products used as beverages worldwide. Caffeine,
the principal component of tea and coffee, has promising anti-cancer effects. Although
a few earlier studies indicated that coffee might help in cancer progression, research
with better study designs later showed that coffee could potentially be useful against
various cancers such as cancer of the head, neck, mouth, oral cavity, pharynx, throat [196],
thyroid [197], liver [198], prostate [199], and endometrium [200]. Coffee has been shown to
induce autophagy in vivo along with inhibiting the enzymatic activity of mammalian target
rapamycin complex 1 (mTORC1) [201]. Kahweol, a diterpene in coffee, induces apoptosis
in liver cancer cells acting through the Src/mTOR/STAT3 signaling pathway [202]. PT93, a
phenolic derivative of caffeic acid, is present in coffee. It has been observed to be effective
against glioblastoma (GBM). It acts by the inhibition of MMP-2 and MMP-9 in both in vitro
and in vivo models. FLVM and FLVZ, the other two derivatives of caffeic acid, target IL17A,
HIF-1α, and vascular endothelial growth factor (VEGF) by inhibiting angiogenesis [203].
Collectively, it was observed that caffeine arrests cancer cells in the G0/G1 phase through
inhibition of Cdk4 and Cdk6. Caffeine and caffeic acid derivatives also act by inhibition of
Akt, STAT3, p-ERK, p-FAK, and ROCK pathways [204] in liver cancer cells.
Epigallocatechin-3-gallate (EGCG), a catechin in green tea, is the main phytocom-
pound that has shown tumor preventive properties against breast, kidney, colon, brain,
leukemia, and prostate cancers [205,206]. EGCG inhibits tumor-associated macrophage
(TAM) infiltration and M2 polarization [207]. In liver cancer cells, it activated AMPK
and inactivated NF-κB [208,209]. EGCG inhibited c-Met signaling and upregulated p21
waf1, KIP1/p27, INK4a/p16, and INK4c/p18 expression in prostate cancer cells [210,211].
G2/M cell-cycle arrest, ROS generation, and downregulation of p-Akt and Wnt/ß-catenin
pathway were a few common mechanisms by which EGCG exhibited its anticancer effects
in different cancers.

2.9. Other Plant-Based Foods

As seen in Figure 2, blueberries (Vaccinium myrtillus) contain pterostilbene, which
alleviates breast cancer growth and its metastasis via suppression of the NF-κB/microRNA
448 circuit [212]. It also contains anthocyanins, which help against breast cancer [213].
Quinoa (Chenopodium quinoa) inhibits colon cancer by stimulating gastrointestinal diges-
tion [214]. Caffeic acid in quinoa increases the G0/G1 population in HT29 (colon cancer)
cells with the induction of apoptosis [215]. Avocado (Persea americana) has also been shown
to induce the anti-cancer effects by inducing apoptosis, wherein Western blot analysis
 Cancers 2022, 14, 5482 15 of 40

revealed an increase in cleaved caspase-3 and cleaved PARP levels. The concentration-
dependent killing of cancer cells was also observed [216]. Pomegranate juice (Punica
granatum) contains ellagic acid. The microbially generated metabolite (produced in human
OR PEER REVIEW
colonic microflora) urolithin is useful against colon, breast, and prostate cancers [217].
Citrus fruits have also been found to be useful against esophageal cancer [218] and breast
cancer [219].

Figure 2. Various bioactive food components cause cell-cycle arrest at G0/G1, G2/M, and S phases in cancer cells. (Figure created with Bioren
Figure 2. Various bioactive food components cause cell-cycle arrest at G0/G1, G2/M, and S phases
in cancer cells. (Figure created with Biorender.com).

Table 1 summarizes the anti-cancer mechanisms of different plant-based food con-

stituents along with the cell-lines that have been studied.
Cancers 2022, 14, 5482 16 of 40

Table 1. Mechanisms of different plant-based food bioactive agents used to treat cancer.

No. Food Bioactive Component Cancer/Organ Model Cell-Line Mechanism of Action References
1 Black pepper Piperine Breast cancer ↓pAKT, STAT3, p65, IκBα [31]
Ovarian cancer A2780 ↓JNK, p38 MAPK, STAT3 [13,14]
Gastric cancer TMK-1 ↓IL-6 [14]
↓CDK2-cyclin-E, CDK-4/6-cyclin D
Glioblastoma Jnk/p38 [16]
G1/S cell cycle arrest
↑p53
Lung cancer A549 G2/M cell cycle arrest and induction of intrinsic [17]
apoptosis
Induction of both intrinsic and extrinsic apoptotic
Leukemia HL60 and K-562 [29,41]
pathway
Colorectal cancer HCT116, SW480 ↓Wnt/β-catenin signaling [43]
MDA-MB-231 and
2 Black pepper Piperidine Breast cancer G0/G1 cell cycle arrest [44]
MCF-7 cells
Piperidine ↑Bax
Prostate cancer PC3 [24,45]
(17a) ↓Bcl-2 and XIAP
Piperidine
G0/G1 cell cycle arrest
(2-amino-4-(1- Colon cancer HT29 and DLD-1 [46,47]
↓FOXA2, vimentin
piperidine)
Induction of redox homeostasis
Apoptosis induction
Piperidine (CLEFMA) Lung cancer H441 cells [90,92,94]
S-phase cell cycle arrest
↓COX2, cyclin D, NFκB, CD31
↓c-met via ROS-dependent
mechanism
3 Long pepper Piperlongumine Renal cancer PNX0010 [48]
↓STAT3, NFκB, PI3K/Akt, and
ERK/MAPK
Cancers 2022, 14, 5482 17 of 40

Table 1. Cont.

No. Food Bioactive Component Cancer/Organ Model Cell-Line Mechanism of Action References
Piperlongumine Glioblastoma U87, U251 ↑HTRPV2 [49]
Cervical, pancreatic, and HeLa, PANC1, and
Piperlongumine ↓GSTP1 [50]
colorectal SW620
Induction of ROS and apoptosis
4 Chili pepper Capsaicin Pancreatic cancer AsPC-1 and BxPC-3 [53]
↓Bcl-2, survivin, β-catenin, JNK
↑Inhibition of mitochondrial complex-1 and
Capsaicin Pancreatic cancer AsPC-1 and BxPC-3 [54]
complex-3 followed by ROS generation
Capsaicin Bladder cancer ↓SIRT-1 deacetylase [61]
G0/G1 phase arrest
5 Clove Whole extract Colon cancer HT29 ↓E2F1, thymidylate synthase [79]
↑p21, WAF1/Cip1, γ-H2AX
↑ALDH1, caspase-3, and Bax
Whole extract Breast cancer MCF-7 [80]
↓CD44, CD24, and ALDH1
Pancreatic and colon ASPC-1 and human
Aqueous extract ↑AMPK and ULK [81]
cancer colon HT-29
Hth-7, B-CPAP, BHT-101,
Nanoemulsion Thyroid cancer Apoptosis induction [82]
and KTC-1 cell line
G2/M phase arrest
↑pH2A.X, CHK1, p-ATM,
6 Turmeric Curcumin Pancreatic cancer BxPC-3 ↓Cyclin B1 [83,84]
DNA damage effect is regulated via ER stress
pathway
Oral squamous Akt/PI3K/mTOR
Curcumin HSC-3 cells [86]
carcinoma ↑miR-199a
Curcumin Glioblastoma ↓MMP, NF-κB, STAT3, Akt [87]
Cruciferous ↑DNA damage
7 Benzyl isothiocyanate Pancreatic cancer Capan-2 [106]
vegetables G2/M phase arrest and apoptosis induction
BxPC3, MiaPaCa2, and
Benzyl isothiocyanate Pancreatic cancer ↓STAT-3, PI3K/AKT/FOXO [104,107]
Panc-1
Cancers 2022, 14, 5482 18 of 40

Table 1. Cont.

No. Food Bioactive Component Cancer/Organ Model Cell-Line Mechanism of Action References
↓Urokinase-type plasminogen activator (uPA)
Benzyl isothiocyanate Colon cancer HT29 protein kinase C (PKC), MAPK signaling pathway, [102]
and MMP-2/9 pathway
Phenethyl isothiocyanate MDA-MB-231-BR
Breast cancer ↓HER2 [110]
(PEITC) (BR-brain seeking)
MDA-MB-231 (in vivo
PEITC Breast cancer xenografts in artificial ↓MDSC cells [112]
immune environment)
Reactivation of tumor suppressor gene RASSF1A
and apoptosis induction
PEITC Prostate cancer LNCap cells [113,114]
Cell cycle arrest and impact on global CpG
epigenome
Chronic lymphocytic Primary leukemia cells
PEITC ROS generation via glutathione depletion [115]
leukemia deficient in p53.
↑p-H2A.X, Chk2
SKOV-3, TOV-21G, and
Diindolylmethane (DIM) Ovarian cancer ↓p-EGFR, MEK, ERK, p-STAT3, VEGF, and HIF-1α [123,124,126]
OVCAR-3
Induction of macroautophagy with AMPK activation
A2780 and OVCAR-429
DIM Ovarian cancer ↓Gli-1 [128]
cells
↓MMP-2, MMP-9, and Akt/PI3K/mTOR signaling
DIM Breast cancer MDA-MB-231 [129]
axis, EGFR
Hepatocellular
DIM Hep3B and HuhCell Suppression of EMT via ER stress induction [130]
carcinoma
↑Nrf2 activation
Prostate, colon, breast, ↓HDAC
Sulphoraphane [122]
lung, and oral Apoptosis induction, cell cycle arrest and inhibition
of angiogenesis.
↓HER2 and ITGA and ITGA4
8 Cucurbitaceous food Cucurbitacin B (CuB) Breast cancer [133]
↑ITGB1 and ITGB3
Cancers 2022, 14, 5482 19 of 40

Table 1. Cont.

No. Food Bioactive Component Cancer/Organ Model Cell-Line Mechanism of Action References
Colorectal cancer, lung
cancer, pancreatic cancer,
CuB breast cancer, Inhibition of STAT3 signaling [133,135]
neuroblastoma, and
acute myeloid leukemia
HT-29 and HCT-116 cell
CuB Colorectal cancer Inhibition of EGFR and JAK/STAT pathway [139]
lines
CuB Neuroblastoma SHSY5Y cells Inhibition of MAPK pathway [136]
Kasumi-1, acute
promyelocytic leukemia
(HL60), acute
myelomonocytic
leukemia (U937), chronic
CuB Myeloid leukemia CIP2A/PP2A/C-KIT signaling axis [135]
myelogenous leukemia
(K562), Burkitt’s
lymphoma (Raji) and T
cell acute lymphoblastic
leukemia (Molt-4)
MCF-7 and Autophagic cell death and modulation of Notch
9 Ginger 6-Shogaol Breast cancer [143]
MDA-MB-231 signaling
MCF-7 and
Gingerol, zerumbone, MDA-MB-231
Breast cancer Metastatic inhibition and cell cycle arrest [152,154,155]
zingiberene Human brain seeking
(MDA-MB-231BrM)
Zerumbone and Cell cycle arrest in G1 phase
Prostate cancer DU-145 [156]
6-shogaol ↓STAT-3 and NF-κB
HepG2, SNU-182,
Hepatocellular Hep3B, SNU-449, G2/M arrest
Zerumbone [158]
carcinoma Sk-Hep-1, and Huh-7 ↓PI3K/Akt/mTOR and STAT3 signaling axis
cells
10 Garlic Diallyl disulfide (DADS) Colon cancer SW480 cells ↓NF-κB [163]
Cancers 2022, 14, 5482 20 of 40

Table 1. Cont.

No. Food Bioactive Component Cancer/Organ Model Cell-Line Mechanism of Action References
Diallyl sulfide (DAS),
Lung, liver, and ↑GST enzymes (α (mGSTA1-2, mGSTA3-3,
DADS, and diallyl [166–168]
forestomach mGSTA4-4), µ (mGSTM1-1), and π (mGSTP1-1))
trisulfide (DATS)
Organosulfur ↑Heat shock proteins (HSP70) and binding
11 Onion Breast cancer [170]
compounds immunoglobulin protein (BiP).
Chronic myeloid Induction of apoptosis by cytochrome c release from
12 Beetroot Betanin K562 cells [172]
leukemia mitochondria
Betalain and betanine Hepatocellular cancer HepG2 cells Free radical scavenging activity [173]
Guava seed
13 Guava polysaccharide fraction Breast cancer MCF-7 cells Apoptosis induction by increasing Bax/Bcl-2 ratio [179]
3 (GSF3)
Guava leaf hexane
fraction (GHF),
ß-eudesmol, α-copaene,
α-patchoulene, Prostate cancer PC-3 and LNCaP cells ↓Akt/mTOR/S6K and MAPK signaling [180]
ß-caryophyllene oxide
(CPO), octadecane,
α-terpineol
Total extracts and
smaller molecular MDA-MB-231 and
Breast cancer Apoptotic and necrotic cell death induction [181]
weight (<30 kDa) MDA-MB-468 cells
extracts from guava fruit
Breast cancer, colon
MCF-7, HCT-116, AGS,
cancer, stomach,
14 Dragon fruit Betalain SF268, and NCI-H460 Inhibition of lipid peroxidation and COX enzymes [183]
glioblastoma, and lung
cells
cancer
A549, NCI-H1975,
↑Caspase-3
15 Lemongrass Lemongrass oil terpenes Lung cancer NCI-H1650, and [184,185]
G2/M cell cycle arrest
NCI-H1299
Small-cell lung cancer
Citral LU135 SCLC cell line Inhibition of Src/STAT3 activity [186]
(SCLC)
Cancers 2022, 14, 5482 21 of 40

Table 1. Cont.

No. Food Bioactive Component Cancer/Organ Model Cell-Line Mechanism of Action References
Suppression of lipogenesis through inhibition of
p-AMPK and downregulation of sterol regulatory
PC-3 and PC-3M element-binding protein (SREBP1),
Citral Prostate cancer [187]
(metastatic) 3-hydroxy-3-methylglutaryl-coenzyme A reductase
(HMGR), fatty acid synthase (FASN), and acetyl coA
carboxylase (ACC)
Citral Colon cancer HT29 and HCT-116 ↑p53 and apoptosis induction via ROS generation [190]
Endometrial ↑Bax, caspase3, caspase-8, cytochrome C, and Fas
Geraniol Ishikawa cells [191]
adenocarcinoma genes
Methanol extract of ↓VEGF, MMP-9, and COX-2 along with inhibition of
16 Wheatgrass Epithelial carcinoma HEp2 [192]
wheatgrass (MEWG) Akt/PI3K signaling.
Lung adenocarcinoma A549 cells ↓HIF-1α, MUC5A, MUC5B, and MUC8 [193]
Hepatocellular Hep3B, SNU182, and
17 Coffee Kahweol Inhibition of Src/mTOR/STAT3 signaling axis [202]
Carcinoma SNU423
PT93 U87 MG and DBTRG PT93 inhibits MMP-2 and MMP-9 expression
Glioblastoma [203]
FLVM and FLVZ MG FLVM and FLVZ target IL17A, HIF-1α, and VEGF
Epigallocatechin-3-
Hepatocellular HLE, HepG2, HuH-7,
18 Green tea gallate Inactivation of AMPK and NF-κB [208,209]
carcinoma and PLC/PRF/5
(EGCG)
EGCG Prostate cancer DU145 cells ↓Phosphorylation of c-Met, Akt, and Erk [210]
MCF-7 and
19 Blueberries Pterostilbene Breast cancer ↓NFkB/microRNA 448 circuit [212]
MDA-MB-231
MCF-7 and
Anthocyanin Breast cancer - [213]
MDA-MB-231
↑Gastrointestinal digestion, apoptosis, and G0/G1
20 Quinoa Caffeic acid Colon cancer HT29 [214,215]
cell cycle arrest
Hepatocellular, oral,
Chloroform extract of ↑Cleaved caspase-3 and cleaved PARP leading to
21 Avocado prostate, and breast [216]
avocado apoptosis
cancer
Cancers 2022, 14, 5482 22 of 40

Table 1. Cont.

No. Food Bioactive Component Cancer/Organ Model Cell-Line Mechanism of Action References
Ellagic acid, urolithin A
22 Pomegranate juice Breast cancer MCF-7 ↓17 Beta estradiol [217]
and urolithin B
Esophageal and breast
23 Citrus fruits - - - [218,219]
cancers
24 Tomatoes Tomatidine Gastric cancer - Regulation of ISG genes [68]
Modulation of AKT/EZH2/androgen receptor
Lycopene Prostate cancer - [69]
signaling pathway
Whole powder Prostate cancer - - [70]
Hepatocellular
Lycopene - ↓ cyclin D1, HIF-1α, and PCNA [71]
carcinoma
Cancers 2022, 14, 5482 23 of 40

3. Probiotics in Cancer
Probiotics have been shown to reduce cancer cell proliferation and induce apoptosis
in vitro. Lactobacillus paracasei and Lactobacillus rhamnosus are Gram-positive bacteria that
are used as probiotics. Orlando et al. showed the efficacy of these probiotics in mouse
and human colon cancer cells, wherein an increase in apoptosis was observed [220]. Short
chain fatty acids (SCFAs) are the metabolites of probiotics. It has been indicated that
beneficial effects of probiotics are mediated via SCFAs [221]. SCFAs keep the gastric envi-
ronment healthy by maintaining the appropriate acidity. They also prevent the formation of
secondary bile acids and induce apoptosis in cancer cells [222]. Butyrate, a metabolite pro-
duced exhibits apoptotic effects in colorectal cancer cells. In order to enhance the effects of
butyrate, probiotics are administered. SCFAs such as conjugated linoleic acid (CLA) induce
the expression of apoptotic genes including caspase-3 and caspase-9 in colon cancer [223].
Additionally, it was found that SCFA-producing bacteria and other beneficial pro-
biotics reduce the production of toxins and carcinogenic metabolites [224]. Compared
to non-cancer colon tissues, colorectal cancer tissues have a less diverse microbial pop-
ulation [225]. Treatment with probiotics leads to a highly diverse microbial population,
which might help reduce tumorigenesis or the further spread of cancer cells. Probiotics
also reduce microbes from the Fusibacter genus, which are purported to be responsible for
tumor initiation [226]. In general, probiotics play a crucial role in cancer prevention. The
primary mechanisms of prevention include (1) downregulation of oncogenes, (2) cell cycle
arrest, (3) inhibition of mutagens and carcinogens, (4) tumor suppressor gene activation,
(5) induction of apoptotic and autophagic cell death, and (6) immune modulation for in-
creased T cell infiltration [227]. Probiotics downregulate oncogenes such as MAPK, NF-κB,
cyclin E, cyclin D, and β-catenin [228–230]. Downregulation of MAPK and NF-κB leads to
apoptotic cell death [229]. For example, Lactobacillus plantarum (LPCLA) induced apoptosis
in breast cancer cells by downregulating the NF-κB pathway, while other bacteria such
as Lactobacillus crispatus and L. rhamnosus modulated the pro-oncogenic Wnt/β-catenin
pathway in various cancer cell lines [231,232]. Another bacterial species, Propionibacterium,
is known to induce apoptosis in colon cancer cells. The bacteria secrete propionate and
acetate as the major cytotoxic components, which induce a three-phase apoptosis, mitochon-
drial alteration, caspase activation, followed by nuclear degradation. The two components
caused mitochondrial membrane disruption followed by ROS generation and caspase
activation [233]. Probiotics have also been observed to induce cell cycle arrest. For example,
a bacteriocin called colicin produced by E. coli caused formation of pores on the plasma
membrane of breast cancer cells while excluding normal human fibroblasts from this effect.
Pore formation led to G1 phase cell cycle arrest [234]. Various studies have reported re-
activation of tumor suppressor genes following probiotic treatment. For example, SCFAs
produced by probiotics are known to cause epigenetic regulation and upregulation of
tumor suppressor genes via metabiotic regulation of host specific physiological function.
Metabiotics extracted from L. rhamnosus upregulated the expression of p53, a tumor sup-
pressor gene in colon cancer [235]. Some probiotics also inhibit the metastatic spread of
cancer cells. The secreted factors from L. casei and L. rhamnosus GG (LGG) downregulated
matrix metalloproteinase-9 (MMP-9) and increased the level of tight junction protein ZO-1
in colon cancer [236,237].
An emerging role of probiotics in anti-cancer therapy is their immune modulatory
effects. A study on the clinical responses to nivolumab and pembrolizumab concluded
that fecal SCFA concentrations may be associated with anti-PDL1 efficacy. The findings
of this study suggested that patients with high concentrations of fecal SCFAs, such as
propionic acid, butyric acid, valeric acid, and acetic acid, had longer survival rates than
their counterparts with no or less fecal SCFAs [238].
In a study by Shi et al., a combination of TGF-β receptor blockers and the Escherichia coli
strain Nissle 1917 (EcN) led to a reduced immunosuppressive environment while increasing
the infiltration of T cells and dendritic cell activation [239]. Another example of the
Cancers 2022, 14, 5482 24 of 40

microbiome modulating the tumor microenvironment (TME) is the presence of Bacteroides

in melanoma. The activity of CTLA4 blockade treatment was enhanced in the presence of
Bacteroides thetaiotaomicron or Bacteroides fragilis. In this study, mice that received antibiotic
therapy did not responded to CTLA-4 blockade, but this was reversed after administrating
B. fragilis through oral gavage [240]. In another study, renal cell carcinoma (RCC) patients
who received probiotic supplements containing Clostridium butyricum showed a higher
response to immune checkpoint blockade. The probiotic contained the C. butyricum strain
CBM588, which was being widely used as an over-the-counter probiotic for anti-microbial-
associated diarrhea [241]. In this study, patients received nivolumab and ipilimumab
alone or with dual therapy along with probiotic CBM588. In both groups, progression-free
survival was significantly higher than in the control arm. Also, as previously discussed,
gut microbiota diversity was greater in patients who responded to the ICB therapy [242].
On the contrary, a study on immunotherapy in melanoma led by researchers from the
National Cancer Institute (NCI) and the University of Texas M.D. Anderson Cancer Center
found that probiotics did not improve the response to immunotherapy. The high fiber diet
intake alone proved beneficial for potentiating the immune response without using any
probiotic supplement. This is possibly due to the increase in healthy gut microbes following
a high fiber diet [243]. This study leads to a question whether commercial probiotics for
cancer immunotherapy provide an advantage. Further studies in larger cohorts will help
in understanding whether the potentiating effect is cancer type specific.
It can be concluded that anti-cancer research with respect to probiotics is still in its
infancy. Moreover, probiotic research is mainly focused on chemopreventive effects rather
than therapeutic effects. Thus, more detailed mechanistic studies and clinical findings will
help us substantiate the anti-cancer claims of probiotics.
Different mechanisms of several probiotics along with the cell-lines that have been re-
searched are mentioned in Table 2. Figure 3 summarizes the general scheme of mechanisms
by which probiotics exert their anti-cancer effect.

Table 2. Mechanisms of different probiotics used to treat cancer.

No. Probiotic Type of Cancer Cell-Line Mechanism References

Lactobacillus paracasei Colon and gastric DLD-1 (colon) and
1. Induction of apoptosis [220]
Lactobacillus rhamnosus cancer HGC-27 (gastric)
Lactobacillus plantarum
2. Breast cancer MDA-MB-231 ↓NF-κB pathway [230]
(LPCLA)
Lactobacillus crispatus Various cancer HeLa, MDA-MB-231,
3. ↓Wnt/β-catenin pathway [232]
and L. rhamnosus types and HT-29
Induction of apoptosis by
4. Propionibacterium Colon cancer HT-29 and Caco-2 secreting propionate and [233]
acetate
G1 phase cell cycle arrest
and pore formation through
5. Escherichia coli Breast cancer MCF-7, MDA-MB-231 [234]
production of a chemical
called colicin
6. L. rhamnosus Colon cancer Animal study ↑Tumor suppressor p53 [235]
Lacticaseibacillus casei Inhibit metastatic spread by
7. Colon cancer HCT-116 [236,237]
and L. rhamnosus downregulating MMP-9
Escherichia coli strain Liver and breast ↑Infiltration of T cells and
8. 4T1 and H22 cell lines [239]
Nissle 1917 (EcN) cancer dendritic cells
Sarcoma, MCA205 (sarcoma),
↑Response to CTLA
9. Bacteroides fragilis melanoma, and MC38 (colon), and Ret [240]
-4 blockade
colon carcinoma melanoma model
Cancers 2022,14,
Cancers2022, 14,5482
x FOR PEER REVIEW 2525ofof42
40

Figure 3. General scheme of molecular mechanisms by which probiotics exert anticancer effects.
Figure 3. General scheme of molecular mechanisms by which probiotics exert anticancer effects.
(Figure created with Biorender.com).
(Figure created with Biorender.com).
Table
4. 2. Mechanisms
Combination of different probiotics
Strategies—The used to Opportunity
Therapeutic treat cancer.

No. Probiotic In order

Type to exploit the food
of Cancer bioactive agents to the Mechanism
Cell-Line best of their potential, combination
Reference
Lactobacillus paracasei strategies
Colon andare needed.
gastric The possible
DLD-1 combinations
(colon) and can be (1) the combination of two or more
1. combination ofInduction of apoptosis [220]
Lactobacillus rhamnosusfood bioactive
cancercompounds, (2) the
HGC-27 (gastric) food bioactive compounds with other
Lactobacillus plantarum physiologically active phytochemical/s, (3) the combination of food bioactive compounds
2. alongBreast cancer
with chemotherapeutic MDA-MB-231 ↓NF-κB pathway
agents, and (4) the combination [230]
of food bioactive compounds
(LPCLA)
with immunotherapy.
Lactobacillus crispatus Various cancer HeLa, MDA-MB-231,
3. ↓Wnt/β-catenin pathway [232]
and L. rhamnosus 4.1. Combination types of Two or More andFood
HT-29Bioactive Compounds
Piperine and curcumin emulsosome Induction of apoptosis by secret-
4. Propionibacterium Colon cancer HT-29 and Caco-2was observed to be effective in treating colorectal [233]
cancer. The combination was more potent thaning thepropionate
bioactive and agentacetate
alone [244]. Li et al.
observed that when leukemic G1 phase
cells were cotreated cellpiperine
with cycle arrestandand
curcumin, cells
MCF-7, MDA-MB-
5. Escherichia coli were Breast
arrestedcancer pore formation
in the S phase. Moreover, the migration through
capability produc-
of these [234]
cells decreased
231
significantly due to the cotreatment. The mode tionofof a chemical
cell death due called colicin
to this combination was
6. L. rhamnosus foundColon
to be both
cancer apoptosisAnimal
and autophagy
study [29]. Khor ↑Tumor
et al. suppressor
observed a p53
significant reduction
[235]
Lacticaseibacillus casei in PC-3 prostate tumor volume with the combination
Inhibit metastatic spread by as compared
of PEITC and curcumin,
7. Colon cancer HCT-116 [236,237]
and L. rhamnosus to PEITC or curcumin alone. This in vivo study exhibited a strong MMP-9
downregulating synergistic effect, where
PEITC increased the efficacy of curcumin against prostate tumor [245].
Cancers 2022, 14, 5482 26 of 40

Triphala is a well-known medicinal formulation consisting of a mixture of Indian

gooseberry (Emblica officinalis), a fruit consumed extensively in the South Asian region,
along with Haritaki (Terminalia chebula) and Vibhitaki (Terminalia bellirica), which are well-
known medicinal natural herbs [246]. This polyherbal medicine, native to India, originates
in Ayurveda, the Indian medicine system practiced for the last 3000 years. Triphala exhibits
anti-inflammatory and antioxidant properties. It has been used to treat heart diseases,
diabetes, premature ageing, and arthritis. Triphala’s anti-cancer effects have also been
studied extensively along with these effects. Shi et al. studied the effects of Triphala against
pancreatic cancer. This was the first-of-its-kind study deciphering the underlying molecular
mechanism of the oncolytic effects of Triphala. Triphala was able to inhibit the proliferation
of capan-2 pancreatic cancer cells. It induced apoptosis and enhanced ROS generation in
capan-2 cells. In vivo, Triphala significantly inhibited capan-2 pancreatic tumor xenografts
as compared to the control group. These effects were attributed to the activation of p53 and
ERK. Thus, it can be said that Triphala exerts its pancreatic tumor suppressive effects by
activating p53 and ERK [247].

4.2. Combination of Food Bioactive Compounds with Other Physiologically Active Phytochemical/s
Betacyanines (beetroot) when combined with vitexin-2-O-xyloside synergistically in-
hibited T24 urinary bladder cancer cells by inducing apoptosis. The synergistic combination
leading to apoptosis was associated with the upregulation of the pro-apoptotic Bax, and
downregulation of survivin, an inhibitor of apoptosis. The combination also downregu-
lated ß-catenin expression, suggesting modulation of the ß-catenin signaling axis as the
main mechanism [248].

4.3. Combination of Food Bioactive Compound along with Chemotherapeutic Agents

When coated with pectin, curcumin in combination with 5-fluorouracil was found to
be useful against colorectal cancer [249]. In a study by Karthika et al., standard therapy
5-fluorouracil was combined with curcumin, and a synergistic effect was observed against
the colon cancer cells (HCT116). The combination had the lowest IC50 when given in a ratio
of 1:4, namely, one part 5-FU and four parts curcumin. This combination was coated with
pectin, a citrus fruit constituent. Pectin is a polymer and is highly pH sensitive. Thus, it
helped in the targeted delivery of the drug even when given orally. The study also found
that titanium dioxide, part of many food items such as candies, was the root cause of
cancer-induction in the colon [249]. It is important to know that certain food components
can also cause cancer.
Piperlongumine and bortezomib have synergistic effects against renal cancer cells, with
the downregulation of proto-oncoproteins [48]. In a study by Jeong et al., it was observed
that piperine or TMZ alone could not inhibit the migration capability of GBM cells, as
assessed by the wound healing assay. However, a combination of both led to the inhibition
of migration. The combination also activated the JNK/p38 MAPK signaling axis [16].
Mitomycin C (MMC) is an anticancer antibiotic used to treat cervical cancer. However, due
to multi-drug resistance, it was found that the tumors become resistant to this treatment.
Han et al. studied the combined effects of piperine and MMC on cervical cancer cells and
observed that the combination inhibited the proliferation of these cells. Moreover, piperine
was able to decrease the resistance caused by MMC. The combination also suppressed
p-STAT3 and NF-κB signaling. There is reported crosstalk between NF-κB and STAT3; thus,
the mechanism of action of piperine and MMC combination could be through the reduced
NF-κB/STAT3 signaling cross-talk. The combination treatment suppressed p65 expression
in the nucleus and p-IκB expression in the cytoplasm, maintained a high Bax:Bcl-2 ratio
and PARP and caspase-3, -8, and -9 activation, indicating apoptosis to be the mode of cell
death [28,250]. A black pepper and doxorubicin combination increased cancer cell killing
and decreased the genotoxicity of doxorubicin against ovarian cancer [251]. Piperine, when
combined with MMC, inhibited cervical cancer growth [28].
Cancers 2022, 14, 5482 27 of 40

Enzalutamide (ENZ) is an anti-cancer agent for the treatment of prostate cancer;

however, cancer cells eventually become resistant to it. Tsao et al. evaluated the effects
of the combination of 3,30 -diindolylmethane (DIM), a plant indole found in cruciferous
vegetables, and ENZ against the prostate cancer cell-line 22Rv1. It was observed that DIM
was able to produce anti-proliferative effects, even in ENZ-resistant cells. The combination
led to the regulation of Wnt signaling, confirmed by the downregulation of ß-catenin,
concomitant with the upregulation of GSK3ß and APC. The combination also decreased
EMT along with the expression of androgen receptors [252].
Draz et al. observed that combining an autophagy inhibitor with DIM led to better
tumor inhibition. The combination of DIM with the autophagy inhibitor chloroquine
(CQ) significantly decreased prostate tumor growth in mice. Also, CQ treatment led to
increased sensitization of prostate cancer cells to DIM treatment. Thus, DIM and CQ acted
synergistically to inhibit prostate cancer [253].
Phenethyl isothiocyanate (PEITC), combined with doxorubicin, exhibited anti-tumor
effects against brain cancer, downregulating HER2 and STAT3 [111]. Cang et al. appreciated
the synergistic effect of phenethyl isothiocyanate (PEITC) and paclitaxel against breast
cancer cells. PEITC improved paclitaxel’s efficacy, and this combination enhanced apoptosis
in breast cancer cells along with the hyperacetylation of iα-tubulin [254]. Mukherjee et al.
found that the combination of PEITC and doxorubicin sensitized cervical cancer cells to
doxorubicin. The combination acted through the modulation of protein kinase C and
telomerase along with activation of caspase-3 and -8 [255].

5. Novel Strategies for Enhanced Delivery of Natural Food Bioactive Agents for
Cancer Chemoprevention
Researchers have been trying to develop novel drug delivery systems to improve the
site-specific targeting of the bioactive compounds along with their enhanced efficacy. The
use of nanotechnology and thus nanoformulations has been extensively explored [256–259].
Below are a few examples of novel drug delivery methods to enhance the efficacy
of phytocompounds.
Abadi et al. prepared a nanoemulsion of cloves essential oil and tested its efficacy
against HT29 colon cancer and HFF skin cancer cells. The nanoemulsion significantly
reduced the proliferation of both cell lines [260]. Nirmala et al. found that an oil-based
nanoscale emulsion of cloves buds was effective against thyroid cancer cells (HTh-7) and
induced apoptosis in these cells [82].
Piplartine, also known as piperlongumine, is an alkaloid and the main phytochem-
ical in black pepper. It has poor solubility, leading to the lack of proper formulations.
Fofaria et al. formulated a nanoemulsion of piplartine and found that formulated pi-
plartine had a greater oral bioavailability (1.5-fold) with anti-proliferative action against
melanoma cells (A375 and B16). This nanoformulation exhibited higher solubility and
stability with a low polydispersity index. Oral administration of piplartine nanoemul-
sion significantly inhibited melanoma tumor growth in mice [261]. Thus, this study is
an example of how physiologically active food components can be exploited for their
anti-cancer use. Piperlongumine’s (PL) hydrogel formulation was applied on mouse brain,
resulting in the inhibition of U251 and U87 GBM tumors, exhibiting the enhancing effects
of a hydrogel [49].
Qhattal et al. prepared a formulation of benzyl isothiocyanate (BITC) in a nano-
emulsion form with the aim of enhancing its solubility and dissolution. The nano-emulsion
significantly increased the accumulation of BITC in the tumor cells and enhanced perme-
ability. Thus, a modification in the formulation could help enhance the drug action on the
desired site, and the anti-cancer potential of BITC could be exploited [262].

6. Discussion
Certain fruits and vegetables have bioactive compounds principally responsible for
their anti-cancer effects through apoptotic pathways. The action of these phytochemicals is
Cancers 2022, 14, 5482 28 of 40

extrapolated to the modulation of several cell signaling cascades [263]. Immune modulation
is also one of the mechanisms by which several chemotherapeutic agents act [264]; however,
it has not been studied extensively in the case of natural products. An overall trend in
research shows that natural products have been studied mostly for their chemopreventive
or chemoprotective effects; however, immunomodulatory effects remain to be discovered.
It can also be seen that most of these anti-cancer food constituents arrest the progression of
cell-cycle at different phases as illustrated in Figure 2.
Food components and natural products amalgamate several complex chemical com-
pounds. Thus, extrapolating the physiological effect to a particular phytochemical could be
erroneous. Expecting an effect using a single phytochemical would not always be the best
idea, as the physiological effect exerted could be the concerted effect of the combination of
several phytochemicals. Thus, an overall anti-cancer effect observed in several epidemio-
logical studies may not corroborate molecular studies using a single phytochemical.
Several phytochemicals pose challenges due to poor solubility, poor bioavailability,
or bad taste or odor, posing a big hurdle not only for patient compatibility but also for
the appropriate delivery of the drug to its target sites. Although several researchers are
working on enhancing the delivery system, an appreciable amount of work still needs to
be done to enhance the drug delivery, bioavailability, site specific targeting, and patient
compatibility. A study by Fofaria et al. is one example where the otherwise unexplored
piplartine from black-pepper was discovered for its anti-tumor efficacy by formulating a
nanoemulsion [261]. The prodrug approach is also a great option to enhance the specificity
of the phytocompound and to avoid off-target effects.
While several studies show the anti-cancer promise of various phytochemicals in vitro,
the translational ability of these compounds in humans will remain a question until these
claims are bolstered with in vivo studies followed by clinical trials. Several published
studies infer that the anti-cancer potential of phytochemicals is solely based on their
cytotoxic effect against cancer cells, claiming anti-cancer efficacy would be overarching.
This review omits the food components whose anti-cancer claim has been made solely
based on cytotoxicity assays. A meta-analysis would help to assess the anti-cancer efficacy
of these phytochemicals, which could be holistically explained more in another systematic
review. However, it would be challenging in the case of a narrative review like this, as the
primary focus here is to decipher the molecular mechanisms by which these actions are
elicited. With the current literature available, although we see many promising anti-cancer
effects, the studies with null or negative results cannot be overlooked.
There are several molecular players that act as double-edged swords. JNK and MAPK
are two such players. They change their roles depending on the cell-type and cell-death
mechanism [265,266]. Thus, in this review, it can be seen that in some studies, the mecha-
nism responsible for the anti-cancer effect was due to the activation of the JNK/p38 MAPK
axis, while in other studies, it was through their inhibition.
It can be seen that the mode of cell death by most food bioactives in this review is
apoptosis, with a few exceptions of autophagy and anoikis. Although this hints that natural
food bioactives act through apoptosis, we cannot overlook the possibility of other less stud-
ied pathways of cell death. Other cell death mechanisms such as necroptosis, pyroptosis,
and ferroptosis are currently being studied. There is a high chance that these pathways
may play a significant role in the efficacy of anticancer effects of several phytochemicals
and may have been missed by researchers.
It can be seen that these functional foods have been effective in a wide range of
concentrations. Thus, it can be challenging with the available information to decide on
a particular dose. However, as far as the doses are concerned, several clinical trials have
been conducted on a “trial and error basis”. The bioavailability of phytochemicals is still a
concern; therefore, novel delivery methods are in the development to tackle this problem.
Nonetheless, significant work needs to be done in this field.
Cancers 2022, 14, 5482 29 of 40

7. Conclusions and Future Perspectives

Food bioactive agents exhibit promising anti-cancer effects and safe toxicity profiles,
which can be attributed to the fact that they are food components. Most of the food
constituents and functional foods act by targeting the hallmarks of cancer, as shown in
Figure 4. A much deeper research design and more animal and human studies are needed
to validate the anti-cancer claims of these agents. Natural herbs find their uniqueness in the
fact that their effects are orchestrated due to the complex natural combination of bioactive
chemicals they possess. In addition to studying the individual phytochemicals, deciphering
their combination with other food bioactive agents or chemotherapeutics agents will help
achieve synergistic effects. Enhanced drug delivery with specific targeting to the desired
Cancers 2022, 14, x FOR PEER REVIEW 30 of 42
sites needs to be studied more to utilize this mother nature’s gift to the best of its potential
in the treatment of cancer.

Figure 4. Hallmarks of cancer (original hallmarks, enabling factors, and emerging hallmarks) along
Figure 4. Hallmarks of cancer (original hallmarks, enabling factors, and emerging hallmarks) along
with their corresponding therapeutic targets and various food constituents acting through it. (Figure
with their
created corresponding
with therapeutic targets and various food constituents acting through it. (Figure
Biorender.com).
created with Biorender.com).
Author Contributions: Conceptualization and design, M.Y.A., S.G. and S.K.S.; Data analysis,
Author
M.Y.A.;Contributions: Conceptualization
Writing–original and
draft preparation, design,
M.Y.A., M.Y.A.,
S.G. S.G.editing,
and S.S.; and S.K.S.; Data analysis,
suggestions, M.Y.A.;
and super-
Writing–original
vision, S.K.S. Alldraft preparation,
authors have readM.Y.A., S.G. and
and agreed S.S.;
to the editing, version
published suggestions,
of theand supervision, S.K.S.
manuscript.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
Conflicts of Interest: The authors declare no conflict of interest.
Note: The authors would like to apologize if inadvertently the work of other contributors in the field
is not The
Note: authors would like to apologize if inadvertently the work of other contributors in the field
cited.
is not cited.
Appendix A
Appendix A
List of fruits and vegetables covered in this review. Peppers: black-pepper, long-pep-
per, List of fruits andnightshade
and chili-pepper; vegetablesvegetables:
covered ineggplant
this review. Peppers:
and tomato; black-pepper,
spices: long-
cloves and cur-
pepper,
cumin; and chili-pepper;
cruciferous nightshade
vegetables: vegetables:
broccoli, cabbage, eggplant andkale,
cauliflower, tomato; spices:watercress,
mustard, cloves and
and horseradish; cucurbitaceous food: cucumber, melon, watermelon, pumpkin, gourd,
and squash; root vegetables: ginger, onion, garlic, and beetroot; tropical fruits: guava and
dragon fruit; grass family members: wheatgrass, and lemongrass; caffeinated beverages:
tea and coffee; others: blueberry, quinoa, avocado, pomegranate, and citrus fruits.
Cancers 2022, 14, 5482 30 of 40

curcumin; cruciferous vegetables: broccoli, cabbage, cauliflower, kale, mustard, watercress,

and horseradish; cucurbitaceous food: cucumber, melon, watermelon, pumpkin, gourd,
and squash; root vegetables: ginger, onion, garlic, and beetroot; tropical fruits: guava and
dragon fruit; grass family members: wheatgrass, and lemongrass; caffeinated beverages:
tea and coffee; others: blueberry, quinoa, avocado, pomegranate, and citrus fruits.

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