http://www.jcpjournal.

org
pISSN 2288-3649 · eISSN 2288-3657
Review https://doi.org/10.15430/JCP.2021.26.1.1

Beetroot as a Potential Functional Food for Cancer

Chemoprevention, a Narrative Review
Mei Lan Tan1,2, Shahrul Bariyah Sahul Hamid2
1
School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, 2Advanced Medical and Dental Institute, Universiti
Sains Malaysia, Kepala Batas, Pulau Pinang, Malaysia

Patients with cancer are prone to several debilitating side effects including fatigue, insomnia, depression and cognitive disturbanc-
es. Beetroot (Beta vulgaris L.) as a health promoting functional food may be potentially beneficial in cancer. As a source of poly-
phenols, flavonoids, dietary nitrates and other useful nutrients, beetroot supplementation may provide a holistic means to prevent
cancer and manage undesired effects associated with chemotherapy. The main aim of this narrative review is to discuss beetroot’s
nutrient composition, current studies on its potential utility in chemoprevention and cancer-related fatigue or treatment-related side
effects such as cardiotoxicity. This review aims to provide the current status of knowledge and to identify the related research gaps
in this area. The flavonoids and polyphenolic components present in abundance in beetroot support its significant antioxidant and
anti-inflammatory capacities. Most in vitro and in vivo studies have shown promising results; however, the molecular mechanisms
underlying chemopreventive and chemoprotective effects of beetroot have not been completely elucidated. Although recent clinical
trials have shown that beetroot supplementation improves human performance, translational studies on beetroot and its functional
benefits in managing fatigue or other symptoms in patients with cancer are still lacking.

Key Words Beetroot, Betacyanin, Betaxanthin, Betanin, Cancer

INTRODUCTION of ailments including cardiovascular-related conditions, ane-

mia, sexual weakness and bladder stones [2]. Some recent
Patients with cancer are prone to several debilitating effects clinical studies have also indicated the usefulness of beetroot
due to chemotherapy or the disease itself. The behavioural in managing blood pressure and cardiovascular health [3-6].
disturbances experienced by patients with cancer include Beetroot has also gained popularity as a supplement to boost
fatigue, insomnia, depression, and cognitive disturbances. energy and improve performance in athletes [7-10].
These symptoms are very common and may persist for Interestingly, in the Traditional Persian Medicine practic-
months or years even after completion of treatment and may es, beetroot is one of the foods used in the prevention and
affect patient’s quality of life. Functional foods have long been managing of metastatic progression of cancer [11]. It is also
linked to improve human performance and health, and hence widely used in other medicinal systems including the Arab,
are considered beneficial as part of the cancer patients’ diet. traditional Chinese and Ayurvedic medicine. Beetroot, juiced
Beetroot (Beta vulgaris L.) is one of high-nutrient vege- or blended, is a popular functional food among breast, pros-
tables used for salads and juices, and a valuable source of tate and colorectal cancer patients as reported in Trinidad. A
natural pigments. It belongs to the botanical order Amaran- study at two clinical sites on the island revealed that beetroot
thaceae –Chenopodiaceae , which is cultivated commercially. is being consumed by patients for the purpose of treatment,
Beetroot, also known as table or garden beet, is usually health improvement and amelioration of side effects asso-
grown for its roots. It has a characteristic earthy mushy aroma ciated with chemotherapy treatment [12]. Similarly, beetroot
and flavour, mainly due to the presence of geosmin, a volatile is also the most frequently used alternative dietetic measure
bicyclic alcoholic compound [1]. Beetroot is known for its an- among patients with cancer in Germany [13] and among a
tioxidant activities and widely used as a remedy for a variety majority of gastrointestinal cancer patients in Serbia [14].

Received February 3, 2021, Revised February 27, 2021, Accepted March 5, 2021
Correspondence to Mei Lan Tan, E-mail: [email protected], https://orcid.org/0000-0001-6565-699X

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-
commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright © 2021 Korean Society of Cancer Prevention

J Cancer Prev 26(1):1-17, March 30, 2021

Tan and Hamid

Red beetroot is highly popular and widely used for cancer beet, beetroot, sugar beet, beta vulgaris, cancer, antioxidant,
patients in some parts of the world. Although there is pau- anti-inflammatory, cardioprotective, anti-tumor, chemopre-
city of data indicating its direct role in cancer treatment and vention, fatigue, performance and clinical trials using Boolean
chemoprevention its antioxidant, anti-inflammatory and other operator “AND” in various combinations. Articles were first
supplementary effects are potentially beneficial for patients screened by year (2000 to 2021), followed by title, language
with cancer at certain stages of disease including during and abstract. Only relevant articles were selected, and addi-
chemotherapy and post-chemotherapy. This narrative review tional articles were sourced by examining the bibliographic
aims highlight to provide the valuable phytochemical compo- list. Flowchart illustrating the brief search strategy is shown in
nents present in red beetroot, the current knowledge on its Figure 1.
health benefits as a possible chemopreventive functional food
and to identify related research gaps in this area of research. Phytochemical and nutritional composition of
beetroot
DATA ANALYSIS
Phytochemicals present in beetroot are found to be beneficial
To summarize the current literature on beetroot and cancer, for the human health. Betalains, pigments derived from beta-
three databases such as Pubmed, Sciencedirect and Sprin- lamic acid, are an important group of bioactive phytochemi-
gerlink were screened. The search terms used included cals in beetroot. Structurally, betalains are compounds with

Flowchart illustrating search strategy

Pubmed: https://pubmed.ncbi.nlm.nih.gov/

Database Springer link: https://link.springer.com/

Sciencedirect: https://www.sciencedirect.com/

Beet sugar AND beta vulgaris

Beet vulgaris AND beet root
Beet vulgaris AND cancer
Beet vulgaris AND anti-oxidants
Beet vulgaris AND anti-inflammatory
Beet vulgaris AND cardioprotective
Beet vulgaris AND anti-tumor
Beet vulgaris AND chemoprevention
Beet vulgaris AND fatigue
Beet vulgaris AND performance
Beet vulgaris AND clinical trials
Beet vulgaris AND clinical trials AND cancer
Search terms Beet vulgaris AND clinical trials AND cancer AND breast cancer
Beet root AND cancer
Beet root AND anti-oxidants
Beet root AND anti-inflammatory
Beet root AND cardioprotective
Beet root AND anti-tumor
Beet root AND chemoprevention
Beet root AND fatigue
Beet root AND performance
Beet root AND clinical trials
Beet root AND clinical trials AND cancer
Beet root AND clinical trials AND clinical trial AND cancer
Beet root AND clinical trials AND clinical trial AND cancer AND functional

Year 2000 2020

Title
Screening criteria
Abstract
Language (English)

Review papers
Commentary
Excluded
Book chapters
Conference abstracts

Figure 1. Flowchart illustrating the

Relevant articles were selected, and additional articles were sourced by
Selection search strategy for studies related
examining the bibliographic list of the selected articles
to beetroot and cancer.

2 J Cancer Prev 26(1):1-17, March 30, 2021

 Beetroot and Cancer

positive nitrogen in a polyene system and this cyclic amine Other classes of phytochemicals found in beetroot include
reactive group has been considered an important contributor phenolics and flavonoids. Some betalains are also phenolic
to their reducing properties [15]. According to a recent study, compounds, namely, isobetanin, prebetanin and neobet-
red beetroot has the richest source of betalains among all anin, vulgaxanthin I, vulgaxanthin II and indicaxanthin [24].
tested plants such as prickly pear (Opuntia ficus-indica ) and Other phenolic compounds isolated from beetroot include
white beetroot varieties [16]. Betalains are synthesised from 5,5,6,6-tetrahydroxy-3,3-biindolyl, N-trans-feruloyltyramine,
tyrosine into the yellow-orange betaxanthins and red–violet N-trans-feruloylhomovanillylamine, and phenolic acids such
betacyanins [17]. Betalamic acid (Fig. 2A) is the common as 4-hydroxybenzoic acid, chlorogenic acid, caffeic acid,
chromophore for all betalain compounds. The pigment clas- catechin hydrate and epicatechin [25-27]. On the other hand,
sification as either betaxanthin (Fig. 2B) or betacyanin is flavonoids are, in general, secondary metabolites with a poly-
dependent on the way in which betalamic acid is added as phenolic structure. They are typical biologically active com-
a residue (Fig. 2C). Betaxanthins (Fig. 2B), are betalamic pounds with health-promoting properties and are important
acid conjugated with an amine or amino acid. Meanwhile, the components used for various applications. The flavonoids
betacyanins (Fig. 2C) are the end products of spontaneous present in beetroot include betagarin, betavulgarin, cochlio-
Schiff base condensation between the conjugated betalamic philin A and dihydroisorhamnetin [28]. Other flavonoid com-
acid moiety and the closed structure of cyclo-DOPA (cyc- pounds isolated are 3,5-dihydroxy-6,7-methylenedioxyflava-
lo-3,4-dihydroxy-phenylalanine) [17]. This reaction changes none, 2,5-dihydroxy-6,7-methylenedioxyisoflavone, quercetin,
the absorption from 480 nm (betaxanthins, yellow) to 540 rutin and kaempferol [20,24,28-31]. The major contributor to
nm (betacyanins, violet). The colour is due to the presence the earthy flavor in red beet is geosmin (trans -1,10-dimethyl-
of double bonds resonating in the structures. Red beetroot trans -9-decanol) [32,33]. Another unique feature of beetroot
contains a large amount of betacyanins but lower levels of is its high concentration of volatile compounds such as pyr-
betanidin and betaxanthins [18]. More than 80% of total red idine and 4-methylpyridine. Additional components present
beetroot pigments are made of betacyanins, mainly betanin include furfural, isopentanol, ethanol, dimethyl sulfide and
(betanidin 5-O -β-glucoside) (Fig. 2D) and its isomer, isobet- isovaleraldehyde [32]. A summary of the phytochemical and
anin (Fig. 2E). The concentration of betanin in red beet was nutritional components is shown in Table 1.
reported to be 300 to 600 mg/kg [19]. Other betacyanins re- The basic nutritional composition of beetroot includes sug-
ported include prebetanin, neobetanin, amaranthin, lampran- ars, dietary fibre, fatty acids, minerals and vitamins (Table
thin I and lampranthin II [20-23]. 1) [27,34]. Among sugars present, sucrose is the main com-

A B C R3 O
R1 R2
O N
+

O OH
+
R4 N
O

HO O HO O
N
H N
H HO O
O OH N
O OH H
O OH

D HO
OH E HO
OH

OH OH
HO HO
O O

O O

HO OH HO OH
Figure 2. Chemical structures of:
+ +
N N
O O (A) Betalamic acid; (B) Betaxanthin,
where R1 is an amine or amino acid
and R2 is normally hydrogen; (C)
Betacyanins (when R3 and R4 are
HO O HO O hydrogen, the structure corresponds
N
H
N
H to betanidin); (D) Betanin; (E)
O OH O OH Isobetanin.

http://www.jcpjournal.org 3
Tan and Hamid

Table 1. Phytochemical and nutritional composition of beetroot

No Class Compound (synonym) References
1 Betalains Betaxanthin [15,16]
Betacyanin Betanin (betanidin 5-O-beta-glucoside) [17,27]
Isobetanin (isobetanidin 5-O-beta-glucoside)
Prebetanin (betanidin 5-O-(6'-sulfate)-beta-glucoside)
Neobetanin (neobetanidin 5-O-beta-glucoside)
Amaranthin (betanidin 5-O-sophorobiuronic acid) [20-23]
Lampranthin I
Lampranthin II
2 Phenolics Betalains Vulgaxanthin I [20,67]
Vulgaxanthin II
Indicaxanthin
Betanin (betanidin 5-O-beta-glucoside)
Isobetanin (isobetanidin 5-O-beta-glucoside)
Prebetanin (betanidin 5-O-(6'-sulfate)-beta-glucoside)
Neobetanin (neobetanidin 5-O-beta-glucoside)
Non-betalains 5,5,6,6-tetrahydroxy-3,3-biindolyl [25-27,34]
5,6-dihydroxyindolecarboxylic acid
N-trans-feruloyltyramine
N-trans-feruloylhomovanillylamine
4-hydroxybenzoic acid
Chlorogenic acid
Caffeic acid
Catechin hydrate
Epicatechin
3 Flavonoids Betagarin (5,2-dimethoxy-6,7-methylenedioxyflavanone) [20,24,26,28-31,34]
Betavulgarin (2′-hydroxy-5-methoxy-6,7-
methylenedioxyisoflavone)
Cochliophilin A (5-hydroxy-6,7-methylenedioxyflavone)
Dihydroisorhamnetin (3,4',5,7-tetrahydroxy-3'-
methoxyflavanone)
3,5-dihydroxy-6,7-methylenedioxyisoflavanone
2,5-dihydroxy-6,7-methylenedioxyisoflavone
Quercetin (3,5,7,3',4'-pentahydroxyflavone)
Rutin (3,3',4',5,7-pentahydroxyflavone-3-rutinoside)
Kaempferol (3,4',5,7-tetrahydroxyflavone)
4 Volatiles 4-methylpyridine [32,33]
Pyridine
Dimethylsulfide
Isovaleraldehyde
Ethanol
Isopentanol
Furfural (2-Furaldehyde)
Geosmin (trans l, lO-dimethyl-trans-9-decalol)
5 Nutritional Mineral Calcium [34,35,39,42]
Magnesium
Potassium
Sodium
Vitamin Vitamin A
Vitamin C
Carbohydrate Sucrose
Fat Fatty acids
Amino acid Essential amino acids (EAA)
Non-essential amino acids (NEAA) – Glutamic acid
Gamma-aminobutyric acid (GABA)
Others Dietary nitrate (NO3-)
Dietary fiber

4 J Cancer Prev 26(1):1-17, March 30, 2021

 Beetroot and Cancer

ponent. Fatty acids are present in combination of saturated, consumption may increases the protection against free radi-
monounsaturated and polyunsaturated acids which occur in cals. Several earlier studies have also indicated that beetroot
minimal amounts. Minerals such as sodium, potassium, cal- is an essential source of natural antioxidants [25,49-53]. Ap-
cium and magnesium are present in relatively high concen- parently, the antioxidant effects of beetroot is not limited to its
trations while aluminium, barium, boron, copper, iron, manga- tubers, but also evident in its leaves [54].
nese and zinc are found at lower levels. Beetroot are also rich The antioxidant and anti-inflammatory capacity of beetroot
in both vitamins A and C [27]. Moreover, beetroot contains a has been evaluated in both in vitro and in vivo experiments.
substantial amount of both non-essential and essential amino Beetroot ethanol extract (lyophilized) has shown substantial
acids. Examples are methionine, threonine, lysine, leucine, antioxidant, electron-donating ability and radical scavenging
isoleucine, tryptophan, phenylalanine, valine, tyrosine, cys- activities and was found to inhibit the nitric oxide production in
teine, alanine, histidine, arginine, serine, proline, glycine and lipopolysaccharide-treated mouse macrophage RAW 264.7
aspartic acid [27]. Interestingly, a large amount of glutamine cells [55]. Antioxidant activity, evaluated using the cell-free
is also present in beets [35]. Glutamine is a non-essential system and three standard spectrophotometric tests, have
amino acid and is a precursor in nucleotide, glucose and pro- shown that red beetroot extracts displayed the strongest an-
tein synthesis [36]. Its metabolism produces large quantities tioxidant potential as compared with other vegetable extracts
of glutamate, a component required for glutathione synthesis. [16]. However, in the same study, there were no significant
Glutathione is important for the maintenance of the cellular cytotoxic nor any protective effects against oxidative DNA
redox state [37,38]. In addition, γ-aminobutyric acid (GABA) damage in HT29 (human colon adenocarcinoma) cells chal-
and β-alanine were also isolated from the red beetroot lenged with reactive oxygen species (ROS) when 10% (v/v)
[35,39]. Interestingly, GABA is known to be potentially useful water extracts of red beetroot was tested [16]. Similarly, the
as a component of functional food. As an important inhibitory water extracts were not found to induce the activity of phase
neurotransmitter in the nervous systems, GABA has antioxi- II detoxification enzymes significantly. This is in contrary to
dant, anti-anxiety, anti-hypertensive properties [40,41]. earlier published studies. Esatbeyoglu and co-workers report-
Dietary nitrate found in green leafy and root vegetables ed that betanin significantly reduced H2O2-induced DNA dam-
such as beetroot is an important source of nitric oxide (NO) age in HT29 cells [56]. Betanin at a low concentration (15
formed via the nitrate-nitrite-NO pathway [42]. Ingested in- µM) functioned as a free radical scavenger and as an inducer
organic NO3- is metabolized in vivo to bioactive nitrite (NO2-) of endogenous cellular enzymatic antioxidant defence mech-
and NO2- exerts its effects by conversion to functional nitro- anisms [56]. However, the exact amount of betanin contained
gen oxides, including NO [43]. NO is an important biologically in the 10% (v/v) water extract used in the earlier study was
active and signalling molecule involved in a multiple physi- unclear and hence, difficult to compare with results of studies
ologic process, especially regulation of blood pressure and that used betanin alone.
blood flow. It is a potent dilator, reduces systemic blood pres- In another study, the antioxidant capacity of betanin was
sure and inhibits atherogenesis by reducing inflammatory cell also found to be prominent as it significantly diminished the
recruitment and platelet aggregation [44]. NO-mediated sig- intracellular ROS level elevated by phorbol myristate ace-
nalling is crucial for protecting the heart against cellular injury tate (PMA) stimulation (~3 fold) and significantly enhanced
or death. It also regulates mitochondrial respiration by inhibit- caspase-3 activity in stimulated neutrophils [57]. Betanin
ing cytochrome c oxidase [45]. Dietary nitrate is an important also decreased the content of DNA in the Comet tails in the
component of the “Dietary Approaches to Stop Hypertension PMA-stimulated neutrophils [57]. Similar observation was
(DASH)” diet to lower blood pressure and the Mediterranean found in another work using Caco-2 intestinal cells. Betanin
diet to lower cardiovascular and cancer risk [46]. Nitrate and was found to reduce DNA damage caused by H2O2 and sig-
nitrite are known to reduce blood pressure, protect tissues nificantly enhanced caspase-3 activity in both neutrophils and
against ischemic injury, reduce oxidative stress, improves mi- Caco-2 cells [58]. Based on these findings, betanin is likely to
tochondrial function and enhances exercise performance. be responsible for the effect of beetroot products on oxidative
DNA damage and apoptosis in neutrophils. Since cytokines
Properties of beetroot that are potentially and other inflammatory mediators produced by the white
chemopreventive blood cells are direct contributors to cancer initiation, promo-
tion and metastasis, functional food which mitigates chronic
Antioxidant and anti-inflammatory activities inflammation is thought to be an important cancer prevention
Red beetroot has been ranked among the ten most potent strategy.
antioxidant vegetables [47]. Betacyanins are known to be a Beetroot juice containing 79.3 mg/100 mL of betaxanthines
class of compounds with radical scavenging and antioxidant and 159.6 mg/100 mL of betacyanins was found to be pro-
activities [18,48]. On the other hand, betanin, consisting of tective against N-nitrosodiethylamine (NDEA)-induced oxida-
a phenolic and a cyclic amine group, is shown to be a very tive stress and liver injury in male rats. NDEA is a food-born
good electron donor, acting as antioxidants [18]. Hence, its carcinogen and is present in smoked or salted meat [59].

http://www.jcpjournal.org 5
Tan and Hamid

The metabolic activation of NDEA by the hepatic microsomal root were demonstrated in both in vitro as well as in vivo
cytochrome P450 system produces ethyl diazonium ion as a (animal) studies. Betanin is also a major betacyanin com-
reactive intermediate which elicits DNA alkylation and subse- ponent isolated from Opuntia ficus-indica . Several in vitro
quently promotes carcinogenesis. In this study, rats treated studies have indicated that betanin possesses cytotoxic and
with beetroot juice prior to NDEA administration exhibited a growth inhibitory activities against different cancer cell lines.
significant reduction of DNA damage in blood leukocytes. For example, the proliferation of human chronic myeloid
Beetroot juice also restored the activity of some of the antiox- leukemia cell line (K562 cells) treated with betanin was re-
idant enzymes in the liver and prevented xenobiotic-induced duced in a concentration- and time dependent manner with
oxidative stress [59]. In addition, beetroot juice was found to an IC50 value of 40 μM. Betanin-treated K562 cells appeared
reduce the levels of liver injury biomrkers including ALT, SDH, to undergo intrinsic apoptosis mediated by the mitochondrial
GGT and bilirubin and reduced DNA damage triggered by release of cytochrome c into the cytosol [66]. Betanin exerted
NDEA treatment [60]. The protective effect of beetroot juice its pro-apoptotic activities through activation of procaspase-3
against oxidative damages and the metabolic alterations in- cleavage and caspase-3 activity followed by the loss of mi-
duced by beetroot feeding may likely safeguard against liver tochondrial transmembrane potential [58]. This indicates that
damage [60]. Furthermore, the ethanol extract of beetroot betanin elicits the release of ROS and triggers apoptotic cell
was found to exert similar protective effects on hepatotoxicity death, further supporting its cancer preventive activity.
by altering various indicators of liver damage induced by lipo- In addition, both betanin and betaine extracted from beet-
polysaccharide or alcohol in experimental rats [55]. roots have demonstrated anti-proliferative effects against
The anti-inflammatory effects of betalains and beetroot ex- hepatocellular cells [67]. On the other hand, betacyanins
tract appear to be mediated by interfering with the NF-κB sig- tested in combination with vitexin-2-O -xyloside, produced a
nalling cascade [2]. The transcription factor NF-κB promotes synergistic effect in inhibiting the proliferation of human uri-
immunity directly by activating gene targets that up-regulates nary bladder cancer cells (T24) but not on normal human skin
the inflammatory molecules such as chemokines and cyto- keratocytes. When used concurrently, both compounds in-
kines that stimulate the phagocytic cells [61]. In an animal creased the pro-apoptotic BAX protein levels and down regu-
model study to investigate the protective effect of beetroot lated expression of BIRC5 (survivin) and CTNNB1 (β-catenin)
extract on gentamicin-induced nephrotoxicity, up-regulation of which are prosurvival components [68]. In yet another study,
nuclear expression of NF-κB (p65), production of TNF-α and doxorubicin and red beetroot extract exerted synergistic cyto-
interleukin-16 (IL-6), myeloperoxidase activity, and the nitric toxicity against human pancreatic, prostate and breast cancer
oxide level were significantly down regulated upon beetroot cell lines [69]. Since there is similarity in the configuration and
supplementation [2]. Beetroot extract treatment also signifi- chemical structure of both betanin and doxorubicin, a possi-
cantly reduced the expression of cleaved caspase-3 and Bax ble mechanisms may include DNA intercalation [69].
protein and up-regulated the anti-apoptotic Bcl-2 protein in Furthermore, Nowacki and co-workers [70] found that
the kidney cells. It ameliorated the extent of histologic renal betanin-enriched beetroot extract induced apoptosis in
injury and reduced inflammatory infiltration in the tubules [2]. breast cancer cells. Betanin/isobetanin-enriched concen-
Betalains were also reported to supress COX-2 expres- trate produced from red beetroots inhibited proliferation of
sion, a pro-inflammatory enzyme responsible for prosta- cancer cells and induced their death but has limited effects
glandin biosynthesis [62-64]. The COX-2 inhibitory effects of towards normal cells. The concentrate appeared to inhibit
betanin were found to be comparable to or greater than com- aggregated cancer cell proliferation (3D cell culture) through
pounds such as lycopene, chlorophyll, bixin, b-carotene and inhibition of the cell cycle progression, by decreasing the G1
cyanidin-3-O -glucoside. Its activities were also comparable cell number, promoting the increase of S phase and down
to anti-inflammatory drugs such as celecoxib and ibuprofen regulating cyclin A2 and cyclin B1 levels in the breast cancer
[64]. Betanin-rich beetroot supplements, in sufficient doses, cells [70]. Further, expression of FAS, TRAILR4, Bad and
were capable of exhibiting anti-inflammatory effects in a way p53 (apoptotic-related proteins) was significantly induced and
similar to synthetic drugs [65]. The anti-inflammatory effects the mitochondrial membrane potential was clearly MCF-7
of betanin were also demonstrated in the neutrophils from cells treated with betanin-enriched red beetroot. Suggesting
patients with bowel disease neutrophils. Betanin treatment that both intrinsic and extrinsic pathways were involved [70].
for 24 hours in neutrophils isolated from blood of patients with Although lysosomal vacuole formation was observed in the
Crohn’s disease and ulcerative colitis showed an increased extract-treated MCF-7 cells, there was insufficient evidence
DNA damage in these cells, hence demonstrating a reduced of autophagy. In a recent study, betavulgarin, isolated from
neutrophil activity in inflammatory conditions [58]. beetroot was found to suppress the growth, migration, colony
formation, and mammosphere formation in breast cancer
Anti-proliferative and other chemopreventive cell lines. This compound also reduced the proportion of
properties the CD44+/CD24- subpopulation and the expression of the
The anti-proliferative and chemopreventive activities of beet- self-renewal-related genes such as c-Myc , Nanog and Oct4 .

6 J Cancer Prev 26(1):1-17, March 30, 2021

 Beetroot and Cancer

Interestingly, betavulgarin inhibited the Stat3/Sox2 signaling juice for 1 month, the patient experienced an increase in cell
and induced breast cancer stem cell death [71]. counts and up-regulation of the uric acid level. Interestingly,
Oral consumption of red beetroot food color, in the form of her condition was reversed when beetroot-carrot juice was
commercial dye E162, inhibited N-nitrosomethylbenzylamine reintroduced. This observation provides single but limited
(NMBA)-induced tumor formation in the rat esophagus. The evidence for the effectiveness of the beetroot-carrot juice in
number of NMBA-induced esophageal papillomas were sig- eliminating malignant leukemic cells [77].
nificantly reduced by almost half in animals receiving the food Polyphenol-rich foods are generally known to have an-
color as compared with controls [72]. In addition, the levels ti-neoplastic effects. A clinical trial demonstrated significant
of inflammation and angiogenesis in the beetroot-treated short-term reduction of the prostate-specific antigen (PSA)
animals were also reduced with a concurrent increase in the level following supplementation with polyphenol-rich diet
apoptotic rate. The mechanisms of chemoprevention with red among elderly men [78]. Reduction in the serum PSA level is
beetroot appeared to involve reduction of cell proliferation, an endpoint biomarker for hormone-refractory human pros-
angiogenesis, inflammation and stimulation of apoptosis. tate cancer intervention. Since beetroot contains significant
Since red beetroot color contains betanins, these effects may polyphenolic flavonoid antioxidants, its ability to inhibit mani-
be mediated through inhibition of oxygen radical-induced sig- festation of biomarkers of cancer is expected. However, there
nal transduction [72]. is certainly limited information on the direct effects of beetroot
In another study, oral administration of betanin in Institute and its chemical composition on tumour markers i.e., cancer
of Cancer Research (ICR) mice inhibited PMA-induced pro- antigen (CA) 125, 15-3, 19-9 and carcinoembryonic antigen
motion of mouse skin tumors and glycerol-induced promotion (CEA). Prospective clinical studies using beetroot may pro-
of lung tumors as compared with control [73]. Betanin, in the vide better insight into its underlying mechanisms when given
form of beetroot extract, also significantly decreased tumor along with standard therapies. A summary of cancer preven-
multiplicity and burden in two mouse lung tumor models [74]. tion effects of beetroot is shown in Table 2.
Subsequent immunohistochemical characterization revealed
that betanin reduced angiogenesis and induced apoptosis in Cardioprotective activities
treated mice as well as in human cancer cells in vitro [74]. Dietary supplementation of beetroot juice has been shown
Apart from fresh beetroot juice, beetroot juice fermented to mitigate anthracycline-induced cardiotoxicity [79]. Doxo-
with Lactobacillus paracasei 0920 and Lactobacillus brevis rubicin and epirubicin are anthracyclines and are usually
0944 significantly reduced the number of carcinogen-induced part of breast cancer treatment protocol. Anthracyclines are
aberrant crypt foci in N-nitroso-N-methylurea-treated rats. important chemotherapeutic agents but unfortunately, chronic
Hence, supplementation of diet with lacto-fermented beetroot administration of anthracyclines induces cardiomyopathy and
juice was postulated to provide protection against precancer- congestive heart failure [80]. For example, doxorubicin, a
ous aberrant crypt formation [75]. In a separate animal study, quinone-containing anthracycline antibiotic, is widely used to
beetroot minimized radiation-induced DNA damage of sple- treat solid tumors such as breast and ovarian cancer. How-
nocytes. Beetroot extract given orally three times to C57BL/6 ever, its clinical use is hampered by its adverse reaction such
mice and, at day 10 after γ-ray irradiation, boosted differenti- as cardiomyopathy and congestive heart failure. Although
ation of hematopoietic stem cells (HSCs) into burst-forming epirubicin or idarubicin, as second-generation analogs, may
units-erythroid [76]. Furthermore, beetroot-treated mice also show improvements in their therapeutic index, there is still
displayed increased levels of red blood cells, hematocrit and risk of cardiomyopathy [80]. One of the commonly known
hemoglobin. Beetroot supplementation stimulated differentia- mechanisms of doxorubicin-induced cardiotoxicity is genera-
tion of HSCs and preserved integrity of bone marrow [76]. tion of ROS, which induces the apoptosis of the cardiomyo-
Clinical experiences on beetroot extracts or juice in cancer cytes [80]. Thus, doxorubicin elicits the formation of hydrogen
are currently lacking to support the findings of both in vitro peroxide and superoxide anions (O2−) through redox cycling
and animal studies. Only an isolated case report on an elder- of their aglycones which explains its anti-tumor activities [81].
ly patient diagnosed with chronic lymphocytic leukemia and Inflammation provoked due to ROS generation and ox-
her clinical experiences with beetroot juice was published. idative stress is a major adverse effect, especially on the
The patient who refused chlorambucil after a recurrence of heart [82,83]. Hence, improving the antioxidant defences of
disease, was started with beetroot-carrot juice [77]. In the cardiomyocytes is an important strategy to protect against
clinical follow-up duration, administration of beetroot-carrot doxorubicin-induced oxidative death [84]. In an animal study
juice alone induced a reduction in lymphocyte and peripheral to determine the protective effect of beetroot juice against
blood leukocytes count by 14.7% and 43.13%, respectively doxorubicin-induced cardiotoxicity, the combination of beet-
with a concurrent decrease in the uric acid level. Adminis- root juice with doxorubicin significantly reduced doxorubicin
tration of beetroot-carrot juice for 15 days resulted in an im- toxicity in rat cardiomyocytes by reducing generation of ROS
proved appetite, a sense of general well-being and increased [84]. Therefore, beetroot juice supplement is postulated to be
vigor. However, upon discontinuation of the beetroot-carrot cardioprotective in patients treated with anthracycline chemo-

http://www.jcpjournal.org 7
8
Table 2. A summary of cancer prevention effects of beetroot in in vitro or in vivo models
No Test items and dose Experimental model Dose and treatment duration Cancer preventive effects References
Tan and Hamid

In vitro antioxidant and anti-inflammatory activities

1 Beetroot ethanol extract • Cell-free system using DPPH 25-100 µg/mL • Good antioxidant, electron-donating ability [55]
(lyophilized) • NO inhibitory efficacy in mouse and radical scavenging activity
macrophage RAW 264.7 cell line • Increases inhibition rate of NO production
in LPS-treated cells
2 Water extracts of beetroot • Cell-free system using standard chemical • Strongest antioxidant potential as [16]
tests compared with other plants
• Cellular antioxidant activity assay in • 10% (v/v) extracts (24 h) • No significant cytotoxic nor any protective
HT29 (human colon adenocarcinoma) effect against oxidative DNA damage in

J Cancer Prev 26(1):1-17, March 30, 2021

cells ROS challenged cells
• Activity of phase II detoxification • 10% (v/v) (6-24 h) • No significant ability to induce activity of
enzymes: glutathione S-transferases phase II detoxification enzymes
(GST) and quinone oxidoreductase
(NQO1)
3 Betanin (red beet extract • Comet assay in HT-29 cells • 15 µM betanin (14 h) • Prevents DNA damage [56]
diluted with dextrin; CAS- • Nrf2 dual luciferase reporter gene assay • 1-15 µM betanin (24 h) • Induces Nrf2 at 15 µM betanin
Nr.: 7659-95-2) in Huh7 cells
• Antioxidant enzyme heme oxygenase-1 • 25 µM betanin (24 h) • Increases in HO-1 protein concentration
(HO-1) expression in Huh7 cells
• Glutathione (GSH) concentration in Huh7 • 1-15 µM betanin (24 h) • Increases cellular GSH
cells
4 Betanin (ABCR GmbH • In vitro PMA-induced DNA damage in • 200 µM betanin (30 min) • Diminishes intracellular ROS level [57]
& Co. KG, Karlsruhe, isolated human neutrophils (PMNs) elevated by PMA stimulation (~3 fold)
Germany) • DNA damage (Comet assay) in isolated • 20-200 µM (24 h) • Decreases the percentage of DNA in the
human neutrophils comet tails of the stimulated neutrophils
• Fluorometric analysis of caspase-3 • 20-300 µM (24 h) • Enhances caspase-3 activity in stimulated
activity neutrophils
5 Betanin (ABCR GmbH & • In vitro H2O2-induced DNA damage in • 200 µM (24 h) • Betanin reduces DNA damage (~14%) [58]
Co. KG) isolated human neutrophils and Caco-2 caused by H2O2
intestinal cells • 200 µM (24 h; neutrophils) • Enhances caspase-3 activity in neutrophils
• Caspase-3 activity • 20-200 µM (24 h; Caco-2 cells) and Caco-2 cells
• Triggers apoptotic cell death
In vivo antioxidant and anti-inflammatory activities
6 Beetroot juice • NDEA and CCl4-induced oxidative stress • 8 mL/kg/day for 28 days • Reduces DNA damage in blood leukocytes [59]
(79.3 mg/100 mL rat model • Restores the activity of some of the
betaxanthins and 159.6 antioxidant enzymes in the liver
mg/100 mL betacyanins) • Prevents xenobiotic-induced oxidative
stress
7 Beetroot juice (79.3 • Phase I and phase II enzymes, DNA • 8 mL/kg/day for 28 days • Reduces biomarker levels of liver injury [60]
mg/100 mL betaxanthins damage and NDEA-induced liver injury such as ALT, SDH, GGT and bilirubin
and 159.6 mg/100 mL model in rats • Reduces DNA damage triggered by NDEA
betacyanins treatment
 Table 2. Continued
No Test items and dose Experimental model Dose and treatment duration Cancer preventive effects References
8 Beetroot ethanol extract • Alcohol induced liver damage model • 200 or 400 mg/kg for 4 weeks • Decreases serum AST, ALT and γ-GTP [55]
(lyophilized) in rats concentrations
•D  ecreases fat accumulation and
inflammatory cell infiltration
• Improves morphological characteristics
of damaged liver lesion
•E  xert protective effects in hepatotoxicity
9 Beetroot ethanol extract • Gentamicin-induced nephrotoxicity • 250 and 500 mg/kg weight for • Inhibits gentamicin-induced up- [2]
(evaporated dry) in rats 20 days before gentamicin regulation of inflammatory markers and
• Oxidative/nitrosative stress, treatment and there after nitric oxide level
inflammatory and apoptotic markers concurrently with gentamicin • Reduces the expression of apoptotic
for 8 days markers in the kidney cells.
• Reduces inflammatory infiltration in the
kidney tubules
In vitro antiproliferative and other chemopreventive activities
10 Betanin and betaine • MTT assay in HepG2 cells •0
 -200 µg/mL • Inhibits cell proliferation in a dose [67]
isolated from beetroot dependent manner
extracts • 800 µg/mL • Inhibits HepG2 cells by 25%
11 Betacyanins purified from • Sulforhodamine B (SRB), apoptosis • 50 µg/mL at 24, 48 and 72 h • Betacyanins and vitexin-2-O-xyloside [68]
beetroot marker assay in urinary bladder cancer synergistically inhibit proliferation of
cells (T24) and normal human skin tumor cells and not normal cells
keratinocytes (NCTC 2544) • Induces apoptosis markers in tumor
cells
12 Beetroot extract (diluted • Trypan blue cell viability assay in human •0
 .29-290 µg/mL at 72 h • Synergistic antiproliferative effects when [69]
with dextrin) pancreatic (PaCa), breast (MCF-7) and used in combination with doxorubicin
prostate cancer (PC-3) cell lines • IC50 values reduced to almost 40%
13 Betanin/isobetanin • Cell proliferation, apoptosis and • 48 h • Decreases cancer cell proliferation and [70]
enriched powder from autophagy assay in mouse melanoma • IC50 about 25 µM for B16F10 viability.
beetroot cell line (B16F10), human breast cancer and MCF-7 cells and 35 µM • Increases the expression of apoptosis-
lines (MCF-7, MDA-MB-231), human for MDA-MB-231 cells related proteins and autophagosome
colorectal cells (HT-29) and normal vesicles
human fibroblasts (MRC-5)
14 Betavulgarin isolated from • Breast cancer cells (MDA-MB-231 • MDA-MB-231 (≥ 100 µM) and • Suppresses proliferation, migration, [71]
beetroot and MCF-7) MCF-7 cells at ≥ 50 µM for colony formation, and mammosphere
24 h formation
• Reduces the size of the CD44+/CD24−
subpopulation
• Reduces the expression of the self-
renewal-related genes, c-Myc , Nanog
and Oct4
• Inhibits the Stat3/Sox2 signaling
pathway and induces breast cancer

http://www.jcpjournal.org
stem cells death

9
Beetroot and Cancer
10
Table 2. Continued
No Test items and dose Experimental model Dose and treatment duration Cancer preventive effects References
In vivo antiproliferative and other chemopreventive activities
Tan and Hamid

15 E162-water (78 µg/mL • N-nitrosomethylbenzylamine (NMBA)- • 35 weeks • Reduces NMBA-induced esophageal [72]
E162 dye powder in induced tumors in the rat esophagus papillomas by 45%
water) (F344 rats) • Reduces rates of cell proliferation in
cancerous lesions
• Reduces level of angiogenesis and
inflammation
• Increases rate of apoptosis
16 Beetroot extract (betanin) • Mouse skin and lung carcinogenesis • 0.0025% (w/v) betanin in • Inhibits TPA-induced promotion of mice [73]
(TCI America, Portland, model drinking water for 20 weeks skin tumors
OR, USA) • Reduces 60% of lung tumors

J Cancer Prev 26(1):1-17, March 30, 2021

17 Betanin extract (betanin) • VC and B(a)P-induced lung tumors in • 25 and 100 µg/mL betanin in • Decreases tumor multiplicity and tumor [74]
(TCI America) mice drinking water for 20 weeks load
• Induces caspase-3 expression
• Inhibits angiogenesis
18 Beetroot extract (extracted • γ-ray irradiation in C57BL/6 mice • 400 mg/mouse orally three • Stimulates cell proliferation [76]
with 70% ethanol) times • Minimizes DNA damage of splenocytes
• Repopulates S-phase cells
• Boosts differentiation of HSCs into
burst-forming units
• Enhances level of hematocrit and
hemoglobin and RBC
Chemoprevention clinical studies
19 Beetroot-carrot juice • Case report of a patient diagnosed with • 330 mL of fresh raw beetroot- • Decreases leukocyte and lymphocyte [77]
B-cell chronic lymphocytic leukemia carrot juice orally (beetroot count from
(B-CLL) 200 g + carrots 250 g) 2 h • Reduces level of uric acid in blood
before breakfast 6 times/week • Increases appetite,
for 1.5 month • Improves fatigue
• 330 mL of fresh beetroot- • Decreases leukocyte, lymphocyte and
carrot juice 6 times per week, reticulocyte counts
in combination with the • Improves renal function
chlorambucil protocol 8 mg/ • Improved blood urea, serum creatinine
day for 37 days and uric acid levels
• Decreases LDH level
20 Beetroot (concentrated • Untreated squamous cell cancer of • 10 g Beetroot powder mixed • Duration of study from December ClinicalTrials.
organic beetroot crystals) the head and neck (Randomized phase with 4-8 oz 2014-May 2018 gov Identifier:
II Trial) • 12 weeks • Unpublished NCT02058849
21 Dietary supplement: • Malignant breast tissue neoplasm • 5-day dietary nitrate • Duration of study from May 2019-June ClinicalTrials.
beetroot juice intervention programme, 2020 gov Identifier:
taking 3 doses of • Unpublished NCT03944226
7 cl (centiliter) (0.4 g nitrate
per dose) concentrated
beetroot juice
NO, nitric oxide; LPS, lipopolysaccharide; ROS, reactive oxygen species; NDEA, N-nitrosodiethylamine; ALT, alanine aminotransferase; SDH, sorbitol dehydrogenase; GGT, gamma
glutamyl transferase; AST, aspartate aminotransferase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; VC, vinyl carbamate; B(a)P, benzo(a)pyrene; RBC, red blood
cell.
 Beetroot and Cancer

therapeutic drugs. The clinical application of beetroot juice as cognitive–behavioral interventions.

an adjunct therapy to combat against cardiotoxicity caused Functional foods have been increasingly accepted as part
by anthracycline drugs is promising and would have a benefi- of a healthy lifestyle and foods. A nitrate-dietary supplemen-
cial public health impact [79]. tation with beetroot juice is postulated as a nutritional strategy
in patients undergoing chemotherapy and post-chemothera-
Ameliorating cancer-related fatigue py due its antioxidant and chemopreventive activities. Symp-
Fatigue is a common adverse condition which affects the toms of fatigue may be ameliorated with beetroot supplemen-
quality of life of patients with cancer [85]. It is one of the tation due its high content of dietary nitrates and subsequent
most frequently reported complaints among cancer patients production of NO. NO is a ubiquitous signalling molecule with
[86,87]. As high as 60% to 93% of patients undergoing ra- important physiological functions in human tissues [105].
diotherapy and 80% to 96% of patients on chemotherapy NO plays a crucial role in skeletal muscle metabolic and
experienced fatigue [87,88]. Fatigue is reported as one of the vascular control. Beetroot juice contains high levels of in-
most distressing symptoms associated with cancer and its organic nitrate (NO3−), which serves as a precursor of NO.
treatment [89]. It is an independent predictor of poor quality Beetroot supplementation provides dietary inorganic nitrate
of life and patient satisfaction [90]. In addition, the degree of (NO3−) which positively affect muscle metabolic and hae-
anemia was also found to be predictive of the degree of fa- modynamic function [106,107]. Oral NO3− intake, either as
tigue among patients with cancer [91]. beetroot juice or pure sodium NO3−, are found to enhance en-
Off-treatment fatigue, weakness, and less vitality were durance exercise performance and capacity in young healthy
more prevalent among women who had breast cancer as volunteers [107-112]. In humans, acute (2 to 3 hours) and
compared with women who had benign breast problems [92]. chronic (3 to 6 days) dietary nitrate consumption has been
In an epidemiology study, breast cancer survivors were found shown to improve exercise tolerance and reduce blood pres-
to be complaining of lethargy more frequently than the refer- sure [112,113]. In addition, beetroot supplementation ame-
ence group. A significant number of the breast cancer survi- liorates the muscle metabolic perturbations that occur during
vors experienced sleep disturbances, pain and depression exercise, improves muscle oxygenation and elevates human
which were associated with severe fatigue [93]. In one me- mitochondrial efficiency [113-115]. In healthy elderly subjects,
ta-analysis, one in four breast cancer survivors suffered from serum nitrate concentrations were found to be inversely as-
severe fatigue. Some of the risk factors included chemother- sociated with general fatigue scores based on a self-rating
apy, higher disease stages and combination cancer therapy scale (Multidimensional Fatigue Inventory) [116,117]. Similar-
[94]. In one longitudinal study, persistent fatigue continued to ly, in another study, the level of the job strain appeared to be
be a challenge for breast carcinoma survivors [95]. directly proportional to the fatigue among women but inverse-
The pathogenesis of cancer-related fatigue is currently not ly associated with NO levels. NO has the capability to buffer
well understood. However, its development may be caused the association between fatigue and job strain [118]. Hence,
by a variety of mechanisms [96]. Cancer-related fatigue could based on these observations, beetroot juice supplementation
be related to the effects of cancer or its treatment on sleep and its ability to increase exercise performance and tolerance
or circadian rhythms, muscle energy metabolism and central in healthy subjects may ameliorate cancer-related fatigue.
nervous system [97]. Findings from animal and human re- Currently, there are yet any studies to provide direct evidence
search suggest that several cancer-related symptoms, nota- supporting beetroot’s effects on combating fatigue among pa-
bly fatigue and stress, may involved the actions of proinflam- tients with cancer.
matory cytokines [98]. In addition, there were studies which
showed links between fatigue and inflammatory markers. CONCLUSION AND FUTURE
Fatigued cancer survivors are characterized by an increased PERSPECTIVES
level of TNF-α, monocyte production of IL-6, elevated plasma
IL-1 receptor antagonist and soluble IL-6 receptor (sIL-6R/ Beetroot is a vegetable rich in micro-nutrients and bioactive
CD126) levels, etc., indicative of immune activation [99,100]. constituents with health beneficial properties and has been
Furthermore, the pathogenesis of fatigue is also thought to be gaining attention as a health promoting functional food. The
related to hormonal changes such as deprivation of androgen multiple bioactive constituents include the water-soluble
or premature menopause in women [101-103]. The usual ap- betalains consisting of betacyanins and betaxanthins, poly-
proaches to treatment of cancer-related fatigue include either phenols, flavonoids and saponins. Beetroot extracts and
pharmacologic management or non-pharmacologic interven- betacyanins have been extensively studied both in vitro and
tion such as patient education. Interestingly, in a systematic in vivo. A variety of studies have demonstrated that beetroot
review of 77 randomized controlled trials involving non-phar- extracts and betanin pigments were effective in preventing
macologic treatments of cancer-related fatigue, results were experimentally induced carcinogenesis. On the other hand,
promising for non-pharmacologic intervention [104]. These the flavonoids and polyphenolic components present in abun-
include psychoeducation, hypnosis, exercise, relaxation and dance in beetroot support its significant anti-inflammatory

http://www.jcpjournal.org 11
Tan and Hamid

and antioxidant capacities. Although most in vitro and in vivo Functional properties of beetroot
studies have shown promising results, the molecular mecha-
nisms of betanin chemoprevention have not been completely
elucidated and clinical studies on beetroot and cancer are still
lacking. In addition, the different extract preparation methods
and the lack of pharmacokinetic studies with betanin alone Antioxidant
Chemopreventive
make it difficult to determine if the therapeutic concentration
or dosage used in these studies are indeed achievable in hu-
man plasma concentration.
In fact, despite containing the richest amount of anti-ox-
idant compounds, the red beet extract showed neither
stronger cytotoxic effect towards HT29 human colon cancer
Anti-inflammatory Improves fatigue
cells, nor the ability to up-regulate the enzymes involved in
detoxification as compared with other vegetable or herbal
extracts [16]. Although beetroot supplementation has been Cardioprotective
studied in humans, most clinical studies were performed on Figure 3. Functional properties of beetroot.
a limited sample size and focussed on exercise performance
and endurance in healthy cohorts. Two relevant clinical trials
involving beetroot and cancer are listed in the ClinicalTrials. [32]. In addition, their possible interactions with anticancer
gov (US National Library of Medicine) database, which have drugs should also be considered, since a recent case report
yet to be published. So far, there has been no clinical study described a woman who developed methotrexate intoxication
which specifically examines the association between beetroot after drinking beetroot juice as a herbal remedy [121].
supplementation and chemo-prevention or cancer-related In summary, beetroot is a valuable vegetable to be con-
symptoms such as fatigue, quality of life and well-being or sumed for health maintenance and has great potential to
prognosis of disease. Evidence supporting the use of beet- be used for chemoprevention and in patients with cancer to
root in managing fatigue and/or managing the harsh side manage fatigue and other side effects of chemotherapy (Fig.
effects of chemotherapy is inevitable for its clinical applica- 3). However, long term safety assessment of dietary beetroot
tion. Both epidemiological and randomized clinical studies on supplementation and relevant translational studies are nec-
beetroot supplementation and patient with cancer are certain- essary for the clinical setting.
ly warranted.
Although beetroot, especially nitrates and the betalains, are ACKNOWLEDGMENTS
well absorbed and has good bioavailability in humans, there
are still insufficient data on its efficacy and long term safety The authors would like to acknowledge the Smartfund Chal-
of beetroot supplementation to propose the food as a long- lenge Grant (MOSTI) and FRGS Grant (KPT).
term strategy in managing diseases like cancer. In pregnan-
cy, nitrate-rich dietary supplementation may be problematic CONFLICTS OF INTEREST
as it may cause a wide range of unexpected maternal and
fatal adverse reactions such as thyroid problems, alteration No potential conflicts of interest were disclosed.
in embryonic cells, methemoglobinemia and other disorders
[119]. Hence, intake of excessive beetroot during pregnancy ORCID
may pose a health hazard. Although beetroot intake pro-
vokes no immediate negative health consequences, long Mei Lan Tan, https://orcid.org/0000-0001-6565-699X
term supplementation of beetroot juice should be cautioned Shahrul Bariyah Sahul Hamid,
in patients with metabolic syndromes or diabetes due to its https://orcid.org/0000-0002-2843-026X
high sucrose content. In addition, due to beetroot’s rich ox-
alate content, this vegetable can be harmful if taken in large REFERENCES
quantities, particularly for individuals at risk of calcium oxalate
stone formation in the kidneys [42]. The excretion of red or 1. Acree TE, Lee CY, Butts RM, Barnard J. Geosmin, the earthy
pink urine after intake of beetroot occurs in 10% to 14% of component of table beet odor. J Agric Food Chem 1976;24:430-
the population. This symptom appeared to be more common 1.
in malabsorption and iron deficiency cases [120]. Further- 2. El Gamal AA, AlSaid MS, Raish M, Al-Sohaibani M, Al-
more, the composition of volatile compounds such as pyri- Massarani SM, Ahmad A, et al. Beetroot (Beta vulgaris
dines and 4-methyl-pyridines in beetroot would also warrant L.) extract ameliorates gentamicin-induced nephrotoxicity
further studies with regards to their toxicological properties associated oxidative stress, inflammation, and apoptosis in

12 J Cancer Prev 26(1):1-17, March 30, 2021

 Beetroot and Cancer

rodent model. Mediators Inflamm 2014;2014:983952. 16. Koss-Mikołajczyk I, Kusznierewicz B, Wiczkowski W, Sawicki
3. Jones T, Dunn EL, Macdonald JH, Kubis HP, McMahon N, T, Bartoszek A. The comparison of betalain composition and
Sandoo A. The effects of beetroot juice on blood pressure, chosen biological activities for differently pigmented prickly pear
microvascular function and large-vessel endothelial function: (Opuntia ficus-indica ) and beetroot (Beta vulgaris ) varieties. Int
a randomized, double-blind, placebo-controlled pilot study in J Food Sci Nutr 2019;70:442-52.
healthy older adults. Nutrients 2019;11:1792. 17. Gandía-Herrero F, García-Carmona F, Escribano J. Fluorescent
4. Siervo M, Shannon O, Kandhari N, Prabhakar M, Fostier W, pigments: new perspectives in betalain research and
Köchl C, et al. Nitrate-rich beetroot juice reduces blood pressure applications. Food Res Int 2005;38:879-84.
in Tanzanian adults with elevated blood pressure: a double-blind 18. Kanner J, Harel S, Granit R. Betalains--a new class of dietary
randomized controlled feasibility trial. J Nutr 2020;150:2460-8. cationized antioxidants. J Agric Food Chem 2001;49:5178-85.
5. Stanaway L, Rutherfurd-Markwick K, Page R, Wong M, 19. Strack D, Vogt T, Schliemann W. Recent advances in betalain
Jirangrat W, Teh KH, et al. Acute supplementation with nitrate- research. Phytochemistry 2003;62:247-69.
rich beetroot juice causes a greater increase in plasma nitrite 20. Kujala T, Loponen J, Pihlaja K. Betalains and phenolics in
and reduction in blood pressure of older compared to younger red beetroot (Beta vulgaris ) peel extracts: extraction and
adults. Nutrients 2019;11:1683. characterisation. Z Naturforsch C J Biosci 2001;56:343-8.
6. Morris RC Jr, Pravenec M, Šilhavý J, DiCarlo SE, Kurtz 21. Alard D, Wray V, Grotjahn L, Reznik H, Strack D. Neobetanin:
TW. Small amounts of inorganic nitrate or beetroot provide isolation and identification from Beta vulgaris . Phytochemistry
substantial protection from salt-induced increases in blood 1985;24:2383-85.
pressure. Hypertension 2019;73:1042-8. 22. Bokern M, Heuer S, Wray V, Witte L, Macek T, Vanek T, et al.
7. Ormsbee MJ, Bach CW, Baur DA. Pre-exercise nutrition: the Ferulic acid conjugates and betacyanins from cell cultures of
role of macronutrients, modified starches and supplements Beta vulgaris. Phytochemistry 1991;30:3261-5.
on metabolism and endurance performance. Nutrients 23. Pourrat A, Lejeune B, Grand A, Pourrat H. Betalains assay
2014;6:1782-808. of fermented red beet root extract by high performance liquid
8. McQuillan JA, Casadio JR, Dulson DK, Laursen PB, Kilding AE. chromatography. J Food Sci 1988;53:294-5.
The effect of nitrate supplementation on cycling performance 24. Chhikara N, Kushwaha K, Sharma P, Gat Y, Panghal A.
in the heat in well-trained cyclists. Int J Sports Physiol Perform Bioactive compounds of beetroot and utilization in food
2018;13:50-6. processing industry: a critical review. Food Chem 2019;272:192-
9. Nyakayiru J, Jonvik KL, Trommelen J, Pinckaers PJ, Senden 200.
JM, van Loon LJ, et al. Beetroot juice supplementation improves 25. Georgiev VG, Weber J, Kneschke EM, Denev PN, Bley T,
high-intensity intermittent type exercise performance in trained Pavlov AI. Antioxidant activity and phenolic content of betalain
soccer players. Nutrients 2017;9:314. extracts from intact plants and hairy root cultures of the red
10. Montenegro CF, Kwong DA, Minow ZA, Davis BA, Lozada beetroot Beta vulgaris cv. Detroit dark red. Plant Foods Hum
CF, Casazza GA. Betalain-rich concentrate supplementation Nutr 2010;65:105-11.
improves exercise performance and recovery in competitive 26. Maraie NK, Abdul-Jalil TZ, Alhamdany AT, Janabi HA.
triathletes. Appl Physiol Nutr Metab 2017;42:166-72. Phytochemical study of the Iraqi Beta vulgaris leaves and its
11. Javadi B. Diet therapy for cancer prevention and treatment clinical applications for the treatment of different dermatological
based on Traditional Persian Medicine. Nutr Cancer diseases. World J Pharm Pharm Sci 2014;3:5-19.
2018;70:376-403. 27. Nemzer B, Pietrzkowski Z, Spórna A, Stalica P, Thresher
12. Clement YN, Mahase V, Jagroop A, Kissoon K, Maharaj A, W, Michałowski T, et al. Betalainic and nutritional profiles of
Mathura P, et al. Herbal remedies and functional foods used by pigment-enriched red beet root (Beta vulgaris L.) dried extracts.
cancer patients attending specialty oncology clinics in Trinidad. Food Chem 2011;127:42-53.
BMC Complement Altern Med 2016;16:399. 28. Kujala TS, Vienola MS, Klika KD, Loponen JM, Pihlaja K.
13. Obrist R, von Meiss M, Obrecht JP. [The use of paramedical Betalain and phenolic compositions of four beetroot (Beta
treatment methods by cancer patients. A inquiry on 101 vulgaris ) cultivars. Eur Food Res Technol 2002;214:505-10.
ambulatory patients]. Dtsch Med Wochenschr 1986;111:283-7. 29. Lim TK. Beta vulgaris. In: Lim TK, ed. Edible Medicinal and
German. Non-Medicinal Plants. Volume 10. Dordrecht, Springer, pp 26-
14. Nikolić I, Smiljenić D, Kukić B, Bogdanović B, Petrović T, 68, 2016.
Ivković-Kapicl T, et al. Application of alternative medicine in 30. Kujala T, Klika K, Ovcharenko V, Loponen J, Vienola M, Pihlaja
gastrointestinal cancer patients. Vojnosanit Pregl 2012;69:947- K. 5,5’,6,6’-Tetrahydroxy-3,3’-biindolyl from beetroot (Beta
50. vulgaris ) peel extract. Z Naturforsch C J Biosci 2001;56:714-8.
15. Tesoriere L, Allegra M, Butera D, Livrea MA. Absorption, 31. Kujala TS, Loponen JM, Klika KD, Pihlaja K. Phenolics and
excretion, and distribution of dietary antioxidant betalains in betacyanins in red beetroot (Beta vulgaris ) root: distribution and
LDLs: potential health effects of betalains in humans. Am J Clin effect of cold storage on the content of total phenolics and three
Nutr 2004;80:941-5. individual compounds. J Agric Food Chem 2000;48:5338-42.

http://www.jcpjournal.org 13
Tan and Hamid

32. Parliment TH, Kolor MG, Maing IY. Identification of the major antiradical activity of betalain from beetroot. J Biol Educ
volatile components of cooked beets. J Food Sci 1977;42:1592- 2000;35:49-51.
3. 49. Pavlov A, Kovatcheva P, Georgiev V, Koleva I, Ilieva M.
33. Pasch JH, von Elbe JH. Sensory evaluation of betanine and Biosynthesis and radical scavenging activity of betalains during
concentrated beet juice. J Food Sci 1978;43:1624-5. the cultivation of red beet (Beta vulgaris ) hairy root cultures. Z
34. Sobhy ES, Abdo E, Shaltout O, Abdalla A, Zeitoun A. Nutritional Naturforsch C J Biosci 2002;57:640-4.
evaluation of beetroots (Beta vulgaris L.) and its potential 50. Kayashima T, Katayama T. Oxalic acid is available as a
application in a functional beverage. Plants (Basel) 2020;9:1752. natural antioxidant in some systems. Biochim Biophys Acta
35. Westall RG. The use of ion-exchange resins for the isolation of 2002;1573:1-3.
glutamine and other nitrogenous substances from beetroot. J 51. Wettasinghe M, Bolling B, Plhak L, Xiao H, Parkin K. Phase II
Sci Food Agric 1950;1:191-3. enzyme-inducing and antioxidant activities of beetroot (Beta
36. Wang AL, Niu Q, Shi N, Wang J, Jia XF, Lian HF, et al. vulgaris L.) extracts from phenotypes of different pigmentation.
Glutamine ameliorates intestinal ischemia-reperfusion injury in J Agric Food Chem 2002;50:6704-9.
rats by activating the Nrf2/Are signaling pathway. Int J Clin Exp 52. Mohdaly AA, Sarhan MA, Smetanska I, Mahmoud A. Antioxidant
Pathol 2015;8:7896-904. properties of various solvent extracts of potato peel, sugar beet
37. Alves WF, Aguiar EE, Guimarães SB, da Silva Filho AR, pulp and sesame cake. J Sci Food Agric 2010;90:218-26.
Pinheiro PM, Soares Gdos S, et al. L-alanyl-glutamine 53. Rehman S, Shah S, Mehmood Butt A, Masood Shah S, Jabeen
preoperative infusion in patients with critical limb ischemia Z, Nadeem A. Biochemical profiling and elucidation of biological
subjected to distal revascularization reduces tissue damage and activities of Beta vulgaris L. leaves and roots extracts. Saudi J
protects from oxidative stress. Ann Vasc Surg 2010;24:461-7. Biol Sci 2021;28:592-602.
38. Newsholme P, Lima MM, Procopio J, Pithon-Curi TC, Doi SQ, 54. Hajihosseini S, Setorki M, Hooshmandi Z. The antioxidant
Bazotte RB, et al. Glutamine and glutamate as vital metabolites. activity of Beta vulgaris leaf extract in improving scopolamine-
Braz J Med Biol Res 2003;36:153-63. induced spatial memory disorders in rats. Avicenna J Phytomed
39. Westall RG. Isolation of gamma-Amino-butyric acid from 2017;7:417-25.
beetroot (beta vulgaris. Nature 1950;165:717. 55. Kim BH, Jung SH, Jung S. Beet root (Beta vulgaris ) protects
40. Cho YR, Chang JY, Chang HC. Production of gamma- lipopolysaccharide and alcohol-induced liver damage in rat.
aminobutyric acid (GABA) by Lactobacillus buchneri isolated Toxicol Res 2020;36:275-82.
from kimchi and its neuroprotective effect on neuronal cells. J 56. Esatbeyoglu T, Wagner AE, Motafakkerazad R, Nakajima
Microbiol Biotechnol 2007;17:104-9. Y, Matsugo S, Rimbach G. Free radical scavenging and
41. Inoue K, Shirai T, Ochiai H, Kasao M, Hayakawa K, Kimura antioxidant activity of betanin: electron spin resonance
M, et al. Blood-pressure-lowering effect of a novel fermented spectroscopy studies and studies in cultured cells. Food Chem
milk containing gamma-aminobutyric acid (GABA) in mild Toxicol 2014;73:119-26.
hypertensives. Eur J Clin Nutr 2003;57:490-5. 57. Zielińska-Przyjemska M, Olejnik A, Kostrzewa A, Łuczak M,
42. Santamaria P, Elia A, Serio F, Todaro E. A survey of nitrate Jagodziński PP, Baer-Dubowska W. The beetroot component
and oxalate content in fresh vegetables. J Sci Food Agric betanin modulates ROS production, DNA damage and
1999;79:1882-8. apoptosis in human polymorphonuclear neutrophils. Phytother
43. Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Res 2012;26:845-52.
Rehman F, et al. Inorganic nitrate supplementation lowers blood 58. Zielińska-Przyjemska M, Olejnik A, Dobrowolska-Zachwieja A,
pressure in humans: role for nitrite-derived NO. Hypertension Łuczak M, Baer-Dubowska W. DNA damage and apoptosis in
2010;56:274-81. blood neutrophils of inflammatory bowel disease patients and in
44. Moncada S, Higgs EA. Nitric oxide and the vascular Caco-2 cells in vitro exposed to betanin. Postepy Hig Med Dosw
endothelium. Handb Exp Pharmacol 2006;(176 Pt 1):213-54. (Online) 2016;70:265-71.
45. Ahluwalia A, Gladwin M, Coleman GD, Hord N, Howard G, 59. Kujawska M, Ignatowicz E, Murias M, Ewertowska M,
Kim-Shapiro DB, et al. Dietary nitrate and the epidemiology of Mikołajczyk K, Jodynis-Liebert J. Protective effect of red beetroot
cardiovascular disease: report from a National Heart, Lung, and against carbon tetrachloride- and N-nitrosodiethylamine-induced
Blood Institute workshop. J Am Heart Assoc 2016;5:e003402. oxidative stress in rats. J Agric Food Chem 2009;57:2570-5.
46. Mills CE, Khatri J, Maskell P, Odongerel C, Webb AJ. It is rocket 60. Krajka-Kuźniak V, Szaefer H, Ignatowicz E, Adamska
science - why dietary nitrate is hard to ‘beet’! Part II: further T, Baer-Dubowska W. Beetroot juice protects against
mechanisms and therapeutic potential of the nitrate-nitrite-NO N-nitrosodiethylamine-induced liver injury in rats. Food Chem
pathway. Br J Clin Pharmacol 2017;83:140-51. Toxicol 2012;50:2027-33.
47. Song W, Derito CM, Liu MK, He X, Dong M, Liu RH. Cellular 61. Baker RG, Hayden MS, Ghosh S. NF-κB, inflammation, and
antioxidant activity of common vegetables. J Agric Food Chem metabolic disease. Cell Metab 2011;13:11-22.
2010;58:6621-9. 62. Zielińska-Przyjemska M, Olejnik A, Dobrowolska-Zachwieja A,
48. Pedreño MA, Escribano J. Studying the oxidation and the Grajek W. In vitro effects of beetroot juice and chips on oxidative

14 J Cancer Prev 26(1):1-17, March 30, 2021

 Beetroot and Cancer

metabolism and apoptosis in neutrophils from obese individuals. rats. Exp Toxicol Pathol 2012;64:599-604.
Phytother Res 2009;23:49-55. 76. Cho J, Bing SJ, Kim A, Lee NH, Byeon SH, Kim GO, et al.
63. Vidal PJ, López-Nicolás JM, Gandía-Herrero F, García- Beetroot (Beta vulgaris ) rescues mice from γ-ray irradiation by
Carmona F. Inactivation of lipoxygenase and cyclooxygenase accelerating hematopoiesis and curtailing immunosuppression.
by natural betalains and semi-synthetic analogues. Food Chem Pharm Biol 2017;55:306-19.
2014;154:246-54. 77. Shakib MC, Gabrial SG, Gabrial GN. Beetroot-carrot juice
64. Reddy MK, Alexander-Lindo RL, Nair MG. Relative inhibition of intake either alone or in combination with antileukemic drug
lipid peroxidation, cyclooxygenase enzymes, and human tumor ‘chlorambucil’ as a potential treatment for chronic lymphocytic
cell proliferation by natural food colors. J Agric Food Chem leukemia. Open Access Maced J Med Sci 2015;3:331-6.
2005;53:9268-73. 78. Thomas R, Williams M, Sharma H, Chaudry A, Bellamy P. A
65. Clifford T, Howatson G, West DJ, Stevenson EJ. The potential double-blind, placebo-controlled randomised trial evaluating
benefits of red beetroot supplementation in health and disease. the effect of a polyphenol-rich whole food supplement on PSA
Nutrients 2015;7:2801-22. progression in men with prostate cancer--the U.K. NCRN
66. Sreekanth D, Arunasree MK, Roy KR, Chandramohan Reddy Pomi-T study. Prostate Cancer Prostatic Dis 2014;17:180-6.
T, Reddy GV, Reddanna P. Betanin a betacyanin pigment 79. Kuriakose RK, Kukreja RC, Xi L. Potential therapeutic strategies
purified from fruits of Opuntia ficus-indica induces apoptosis in for hypertension-exacerbated cardiotoxicity of anticancer drugs.
human chronic myeloid leukemia Cell line-K562. Phytomedicine Oxid Med Cell Longev 2016;2016:8139861.
2007;14:739-46. 80. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L.
67. Lee EJ, An D, Nguyen CT, Patil BS, Kim J, Yoo KS. Betalain and Anthracyclines: molecular advances and pharmacologic
betaine composition of greenhouse- or field-produced beetroot developments in antitumor activity and cardiotoxicity. Pharmacol
(Beta vulgaris L.) and inhibition of HepG2 cell proliferation. J Rev 2004;56:185-229.
Agric Food Chem 2014;62:1324-31. 81. Simůnek T, Stérba M, Popelová O, Adamcová M, Hrdina R,
68. Scarpa ES, Emanuelli M, Frati A, Pozzi V, Antonini E, Diamantini Gersl V. Anthracycline-induced cardiotoxicity: overview of
G, et al. etacyanins enhance vitexin-2-O-xyloside mediated studies examining the roles of oxidative stress and free cellular
inhibition of proliferation of T24 bladder cancer cells. Food Funct iron. Pharmacol Rep 2009;61:154-71.
2016;7:4772-80. 82. Guo W, Kong E, Meydani M. Dietary polyphenols, inflammation,
69. Kapadia GJ, Rao GS, Ramachandran C, Iida A, Suzuki N, and cancer. Nutr Cancer 2009;61:807-10.
Tokuda H. Synergistic cytotoxicity of red beetroot (Beta vulgaris 83. Ziech D, Franco R, Georgakilas AG, Georgakila S, Malamou-
L.) extract with doxorubicin in human pancreatic, breast Mitsi V, Schoneveld O, et al. The role of reactive oxygen species
and prostate cancer cell lines. J Complement Integr Med and oxidative stress in environmental carcinogenesis and
2013;10:113-22. biomarker development. Chem Biol Interact 2010;188:334-9.
70. Nowacki L, Vigneron P, Rotellini L, Cazzola H, Merlier F, Prost 84. Das S, Filippone SM, Williams DS, Das A, Kukreja RC. Beet
E, et al. Betanin-enriched red beetroot (Beta vulgaris L.) extract root juice protects against doxorubicin toxicity in cardiomyocytes
induces apoptosis and autophagic cell death in MCF-7 cells. while enhancing apoptosis in breast cancer cells. Mol Cell
Phytother Res 2015;29:1964-73. Biochem 2016;421:89-101.
71. Liu R, Choi HS, Zhen X, Kim SL, Kim JH, Ko YC, et al. 85. Gupta D, Lis CG, Grutsch JF. The relationship between cancer-
Betavulgarin isolated from sugar beet (Beta vulgaris ) related fatigue and patient satisfaction with quality of life in
suppresses breast cancer stem cells through Stat3 signaling. cancer. J Pain Symptom Manage 2007;34:40-7.
Molecules 2020;25:2999. 86. Ahlberg K, Ekman T, Gaston-Johansson F, Mock V. Assessment
72. Lechner JF, Wang LS, Rocha CM, Larue B, Henry C, and management of cancer-related fatigue in adults. Lancet
McIntyre CM, et al. Drinking water with red beetroot 2003;362:640-50.
food color antagonizes esophageal carcinogenesis in 87. Stasi R, Abriani L, Beccaglia P, Terzoli E, Amadori S. Cancer-
N-nitrosomethylbenzylamine-treated rats. J Med Food related fatigue: evolving concepts in evaluation and treatment.
2010;13:733-9. Cancer 2003;98:1786-801.
73. K a p a d i a G J , To k u d a H , K o n o s h i m a T, N i s h i n o H . 88. Curt GA. The impact of fatigue on patients with cancer: overview
Chemoprevention of lung and skin cancer by Beta vulgaris of FATIGUE 1 and 2. Oncologist 2000;5 Suppl 2:9-12.
(beet) root extract. Cancer Lett 1996;100:211-4. 89. Stone P, Richardson A, Ream E, Smith AG, Kerr DJ, Kearney N.
74. Zhang Q, Pan J, Wang Y, Lubet R, You M. Beetroot red Cancer-related fatigue: inevitable, unimportant and untreatable?
(betanin) inhibits vinyl carbamate- and benzo(a)pyrene- Results of a multi-centre patient survey. Cancer Fatigue Forum.
induced lung tumorigenesis through apoptosis. Mol Carcinog Ann Oncol 2000;11:971-5.
2013;52:686-91. 90. Lis CG, Rodeghier M, Grutsch JF, Gupta D. Distribution and
75. Klewicka E, Nowak A, Zduńczyk Z, Cukrowska B, Błasiak determinants of patient satisfaction in oncology with a focus on
J. Protective effect of lactofermented beetroot juice against health related quality of life. BMC Health Serv Res 2009;9:190.
aberrant crypt foci formation and genotoxicity of fecal water in 91. Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in

http://www.jcpjournal.org 15
Tan and Hamid

cancer patients compared with fatigue in the general United 106. Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B. Effects of
States population. Cancer 2002;94:528-38. dietary nitrate on oxygen cost during exercise. Acta Physiol
92. Andrykowski MA, Curran SL, Lightner R. Off-treatment fatigue (Oxf) 2007;191:59-66.
in breast cancer survivors: a controlled comparison. J Behav 107. Bailey SJ, Winyard P, Vanhatalo A, Blackwell JR, Dimenna FJ,
Med 1998;21:1-18. Wilkerson DP, et al. Dietary nitrate supplementation reduces
93. Bower JE, Ganz PA, Desmond KA, Rowland JH, Meyerowitz the O2 cost of low-intensity exercise and enhances tolerance
BE, Belin TR. Fatigue in breast cancer survivors: occurrence, to high-intensity exercise in humans. J Appl Physiol (1985)
correlates, and impact on quality of life. J Clin Oncol 2009;107:1144-55.
2000;18:743-53. 108. Lansley KE, Winyard PG, Bailey SJ, Vanhatalo A, Wilkerson
94. Abrahams HJG, Gielissen MFM, Schmits IC, Verhagen DP, Blackwell JR, et al. Acute dietary nitrate supplementation
CAHHVM, Rovers MM, Knoop H. Risk factors, prevalence, and improves cycling time trial performance. Med Sci Sports Exerc
course of severe fatigue after breast cancer treatment: a meta- 2011;43:1125-31.
analysis involving 12 327 breast cancer survivors. Ann Oncol 109. Lansley KE, Winyard PG, Fulford J, Vanhatalo A, Bailey SJ,
2016;27:965-74. Blackwell JR, et al. Dietary nitrate supplementation reduces the
95. Bower JE, Ganz PA, Desmond KA, Bernaards C, Rowland JH, O2 cost of walking and running: a placebo-controlled study. J
Meyerowitz BE, et al. Fatigue in long-term breast carcinoma Appl Physiol (1985) 2011;110:591-600.
survivors: a longitudinal investigation. Cancer 2006;106:751-8. 110. Bond H, Morton L, Braakhuis AJ. Dietary nitrate supplementation
96. Gutstein HB. The biologic basis of fatigue. Cancer 2001;92(6 improves rowing performance in well-trained rowers. Int J Sport
Suppl):1678-83. Nutr Exerc Metab 2012;22:251-6.
97. Parker KP, Bliwise DL, Ribeiro M, Jain SR, Vena CI, Kohles- 111. Cermak NM, Gibala MJ, van Loon LJ. Nitrate supplementation’s
Baker MK, et al. Sleep/Wake patterns of individuals with improvement of 10-km time-trial performance in trained cyclists.
advanced cancer measured by ambulatory polysomnography. J Int J Sport Nutr Exerc Metab 2012;22:64-71.
Clin Oncol 2008;26:2464-72. 112. Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna FJ, Pavey TG,
98. Cleeland CS, Bennett GJ, Dantzer R, Dougherty PM, Dunn Wilkerson DP, et al. Acute and chronic effects of dietary nitrate
AJ, Meyers CA, et al. Are the symptoms of cancer and cancer supplementation on blood pressure and the physiological
treatment due to a shared biologic mechanism? A cytokine- responses to moderate-intensity and incremental exercise. Am
immunologic model of cancer symptoms. Cancer 2003;97:2919- J Physiol Regul Integr Comp Physiol 2010;299:R1121-31.
25. 113. Kenjale AA, Ham KL, Stabler T, Robbins JL, Johnson JL,
99. Collado-Hidalgo A, Bower JE, Ganz PA, Cole SW, Irwin MR. Vanbruggen M, et al. Dietary nitrate supplementation enhances
Inflammatory biomarkers for persistent fatigue in breast cancer exercise performance in peripheral arterial disease. J Appl
survivors. Clin Cancer Res 2006;12:2759-66. Physiol (1985) 2011;110:1582-91.
100. Scott HR, McMillan DC, Forrest LM, Brown DJ, McArdle CS, 114. Vanhatalo A, Fulford J, Bailey SJ, Blackwell JR, Winyard
Milroy R. The systemic inflammatory response, weight loss, PG, Jones AM. Dietary nitrate reduces muscle metabolic
performance status and survival in patients with inoperable non- perturbation and improves exercise tolerance in hypoxia. J
small cell lung cancer. Br J Cancer 2002;87:264-7. Physiol 2011;589(Pt 22):5517-28.
101. Fan HG, Houédé-Tchen N, Yi QL, Chemerynsky I, Downie FP, 115. Larsen FJ, Schiffer TA, Borniquel S, Sahlin K, Ekblom
Sabate K, et al. Fatigue, menopausal symptoms, and cognitive B, Lundberg JO, et al. Dietary inorganic nitrate improves
function in women after adjuvant chemotherapy for breast mitochondrial efficiency in humans. Cell Metab 2011;13:149-59.
cancer: 1- and 2-year follow-up of a prospective controlled 116. Capuron L, Schroecksnadel S, Féart C, Aubert A, Higueret D,
study. J Clin Oncol 2005;23:8025-32. Barberger-Gateau P, et al. Chronic low-grade inflammation
102. Nelson AM, Gonzalez BD, Jim HS, Cessna JM, Sutton SK, in elderly persons is associated with altered tryptophan and
Small BJ, et al. Characteristics and predictors of fatigue among tyrosine metabolism: role in neuropsychiatric symptoms. Biol
men receiving androgen deprivation therapy for prostate cancer: Psychiatry 2011;70:175-82.
a controlled comparison. Support Care Cancer 2016;24:4159- 117. Smets EM, Garssen B, Bonke B, De Haes JC. The Multidi­
66. mensional Fatigue Inventory (MFI) psychometric qualities of an
103. Campos MPO, Hassan BJ, Riechelmann R, Del Giglio instrument to assess fatigue. J Psychosom Res 1995;39:315-
A. Cancer-related fatigue: a practical review. Ann Oncol 25.
2011;22:1273-9. 118. Takaki J. Circulating nitrite and nitrate are associated with job-
104. Lotfi-Jam K, Carey M, Jefford M, Schofield P, Charleson C, related fatigue in women, but not in men. Int J Environ Res
Aranda S. Nonpharmacologic strategies for managing common Public Health 2013;10:2813-24.
chemotherapy adverse effects: a systematic review. J Clin 119. Bahadoran Z, Mirmiran P, Azizi F, Ghasemi A. Nitrate-rich
Oncol 2008;26:5618-29. dietary supplementation during pregnancy: the pros and cons.
105. Stamler JS, Meissner G. Physiology of nitric oxide in skeletal Pregnancy Hypertens 2018;11:44-6.
muscle. Physiol Rev 2001;81:209-37. 120. Watts AR, Lennard MS, Mason SL, Tucker GT, Woods

16 J Cancer Prev 26(1):1-17, March 30, 2021

 Beetroot and Cancer

HF. Beeturia and the biological fate of beetroot pigments. intoxication in a patient with psoriasis who drank beetroot juice
Pharmacogenetics 1993;3:302-11. during methotrexate treatment. Clin Exp Dermatol 2016;41:893-
121. Gönül M, Keseroglu H, Hacınecipoğlu F. A case of methotrexate 5.

http://www.jcpjournal.org 17