Oncology Nutrition Connection ❙ Volume 25, Number 3, 2018 ❙ 17

ONCOLOGY NUTRITION linked to weight and muscle loss from side

effects like decreased dietary intake (4,5).

Does Beetroot or Beetroot Studied have reported that loss of muscle

and lean body mass can increase the risk and

Juice Improve Oncological severity of dose limiting toxicities (5,6). Lean

tissue loss can be most severe if the patient

Outcomes? is experiencing cancer cachexia, which is

characterized by metabolic aberrations,
decreased fat mass, loss of skeletal muscle
By Corey Hawes MS, RDN, CNSC, Dr. Luigi Brunetti PharmD, BCPS, CGP,
mass, and changes in pro-inflammatory
Dr. Jane Ziegler DCN, RD, LDN
cytokines (8). Cancer cachexia affects 50% to
85% of cancer patients at some point during
Abstract cancer care, and is estimated to cause up to
Dietary supplement usage continues to increase among cancer patients, 20% of cancer deaths (8).

with the goal of aiding in cancer remission and cure. Beetroot is of Etiology and pathophysiology of cancer
interest, because it contains betanin, a phytochemical believed to cachexia is driven by pro-inflammatory
have synergistic anti-tumor activity with concurrent chemotherapy. cytokines initiating acute phase protein
Betalains are the red and yellow nitrogen containing pigments found response, resulting in loss of skeletal muscle
even with adequate protein-energy intakes
in beets. Betalains are also of interest as they have been implicated in
(8). Nitrates are created during skeletal muscle
synergistically enhancing cytotoxic abilities of chemotherapy. The high metabolism, and are converted to nitric oxide
nitrogen content of beetroot also may benefit patients experiencing in the body (9). Nitric oxide (NO)-associated
increased protein metabolism and muscle wasting. Concurrent treatment processes in the body include blood flow and
energy metabolism (9). Nitrates lower oxygen
with beetroot demonstrated an increase in cytotoxic properties in
usage during exercise and increase efficiency
prostate and breast cancer human cells and has been shown to improve of cellular ATP-consuming processes and
protein metabolism and nitrogen balance in cancer patients. Future mitochondrial ATP synthesis, which improves
clinical trials are necessary to further assess the efficacy of concurrent muscle strength while increasing muscle
treatment with beetroot supplements and chemotherapy agents. growth potential (8). The use of beetroot juice,
because of its high nitrate content and anti-
inflammatory properties, has been the focus
Introduction flavonoids, and is one of the few vegetables
of research into adjunct treatments to
With the cancer epidemic growing, and, that contain a highly bioactive group of
minimize exacerbated muscle loss, lessen
a 2017 incidence of 1,735,350 new cases pigments known as betalains. Betalains are a
immunodeficiency, and provide nitrates to
expected to be diagnosed in 2018(1), many red nitrogen pigment found in foods that are
help build muscle tissue (8). Consequently, we
individuals affected by cancer search for any absent of anthocyanin (3). They are a highly
were interested in how beetroot may improve
and every treatment option that may provide bioavailable antioxidant known to prevent
oncological outcomes.
a survival benefit, including new medications, oxidative processes and anti-inflammatory
clinical trials, chemotherapy, radiation therapy, properties (3). Betalains have also been found
Results
or combination therapies. According to a 2008 to inhibit lipid peroxidation in very low
Many plant extracts and phytochemicals are
study by Velicer et al, in the Journal of Clinical concentrations (3). Cytotoxic properties of
reported to work synergistically with a variety of
Oncology, between 14% and 23% of people betalains are of interest, as these compounds
chemotherapy agents. One such combination is
with cancer begin using dietary supplements are thought to work synergistically to enhance
that of beetroot and doxorubicin. Kapadia et
after diagnosis(2). the cytotoxic activity of chemotherapy drugs
al reviewed the synergistic antiproliferative
(3). Cancer treatments have severe cytotoxic
activity of red beetroot and doxorubicin in
Red beetroot, also known as Beta vulgaris effects that cause apoptosis of cancer cells
prostate and breast human tumor cells (10).
rubra, has gained attention as a potentially and may affect normal cells as well. Numerous
Cytotoxic effects on two cancer cell lines
beneficial supplemental therapy for cancer side effects dependent on medication type,
(prostate PC-3, and breast MCF-7), were tested
patients (3). Although the interest in beetroot dosage, number of medications, and
using a variety of beetroot and doxorubicin
is primarily due to the dietary nitrates it provides, treatment types have been reported (3).
concentrations ranging between 0.29-290 ug/
other compounds in beetroot also contribute Cytotoxic medicines can affect the bone
ml and in combinations of 1:0, 1:1, 5:1, 1:5, and
to its beneficial effects (3). Beetroot is rich in marrow, which subsequently alters and
0:1 of beetroot to doxorubicin(10). Synergy
ascorbic acid, carotenoids, phenolic acids, and depresses the immune system, and have been
was assessed using the Chou-Talalay method,
18 ❙ Oncology Nutrition Connection ❙ Volume 25, Number 3, 2018
which assesses effects of drug combinations
(11). Chou-Talalay is based on the median-
effect equation, derived from the mass-action
law principle (11). The resulting combination
index (CI) theorem of Chou-Talalay offers a
quantitative definition for additive effect
(CI = 1), synergism (CI < 1), and antagonism
(CI > 1) in drug combinations (11).
The study noted an overall positive reduction
in cell growth in both cell lines. The best
synergism was noted at a ratio of 1:5 of
beetroot to doxorubicin, in both cell lines (10).
Another study tested the concurrent
treatment of doxorubicin with beetroot juice
and its effects on the breast cancer cell line,
MDA-MB-231(12). Since doxorubicin is known
to be cardiotoxic, this study also investigated
beetroot juice’s ability to reduce the
percentage of cardiomyocyte cell death (12).
Das et al. created cell treatment groups of
adult rat cardiomyocytes and the cancer cell
line MDA-MB-231. The cardiomyocytes and
MDA-MB-213 cells were exposed to different
concentrations (0.5, 5, 50, 250, 500 µg/ml) of
beetroot juice, with or without doxorubicin
(2µM, with a control of growth medium) (12).
Doxorubicin administered alone at a
concentration of 2µM significantly increased
(P<0.001) cardiotoxicity compared with
the control group (12). When comparing
doxorubicin alone to beetroot juice alone and
to beetroot juice + doxorubicin, there was a
significant decrease of cardiomyocyte death
(P<0.001) in all groups except for the 500µg/
ml beetroot juice + doxorubicin combination
(12). Twenty-four hours post-treatment
however, cardiotoxicity increased as the
concentration of beetroot juice increased,
compared to the control, but overall remained
lower than the doxorubicin only treated group
(12). These results were duplicated with
significant (P<0.001) values after 48 hours
as well (12). MDA-MB-231 cancer cell viability
was not significantly reduced at concentrations
of beetroot juice under 250µL (P>0.05),
however, cell viability was significantly
reduced in MDA-MB-231 cancer cells with
beetroot juice concentrations of 250 and
500 µg/ml (P<0.001)(12).
To further assess beetroot juice’s ability as
an effective concurrent treatment with
doxorubicin, Das et al looked at MDA-MB-231
cell apoptosis after 48 hours of treatment with
doxorubicin and beetroot juice (12). The same
concentrations from previous cycles were used
and showed a significant increase (P<0.001) in
cell apoptosis for all concentrations when
combined with doxorubicin, at a rate of nearly
double when compared to the doxorubicin
only treated group (12). Animal data suggest
beetroot extract may have protective effects
during cancer treatment as well. Gamal, et al.
assessed the efficacy of beetroot extract to
ameliorate gentamicin-induced nephrotoxicity
in rats (13). Serum urea, uric acid, serum total
protein, creatinine, and histopathology of
kidney failure were monitored to assess
nephrotoxicity during gentamicin (GM) therapy
(13). The rats were divided into 4 groups, 6
animals per group; group 1 served as a control
while groups 2, 3, and 4 received GM (13).
Group 2 was given 85mg/kg/day of GM for 8
days without beetroot to determine effect of
GM alone compared with control. Groups 3
and 4 were treated with 85mg/kg/day of GM
and beetroot extract at 250 and 500mg/kg,
respectively, for 20 days prior to GM treatment
and during the standard 8-day treatment (13).
Blood was collected 24 hours after the last GM
dose to assess creatinine, uric acid, and urea
serum concentrations (13). Kidney tissues were
used to assess malondialdehyde, non-protein
sulfhydryl, catalase, myeloperoxidase levels,
and serum total protein content of the kidneys
(13). It was noted that beetroot (Beta Vulgaris
L.) extract (BVE), combined with GM did reduce
blood urea (P <0.001), uric acid (P <0.001) and
creatine serum levels (P <0.001), as well as
increase protein concentration (P <0.01)
compared with GM alone (13). Blood
concentrations of uric acid, urea, and creatinine
all increased while protein decreased with GM
alone when compared to the placebo (13).
BVE also demonstrated an effect on
malondialdehyde, a highly reactive compound
resulting from lipid peroxidation that is
potentially mutagenic (12). Malondialdehyde
exponentially increased after treatment with
GM which indicates oxidative stress. Concurrent
treatment with BVE showed an expected dose-
dependent reduction in malondialdehyde,
because BVE is an antioxidant substance (12).
Results from the study noted 37.54% and
58.28% malondialdehyde reduction for
250 and 500mg/kg of BVE, respectively,
compared to the GM treated group (p <0.01)
(10). Non-protein sulfhydryl (NP-SH) are thiols
which can be found throughout the body.
NP-SHs are important as they have been linked
to antioxidant properties and gastroduodenal
integrity (12). More specifically, they have been
noted to protect against cell, tissue, and organ
damage that was chemically-induced (12).
NP-SH was significantly reduced by GM
(37.94%), however, there was a noted increase
in NP-SH when treated with BVE (12). This
suggests BVE can aid in replenishing NP-SH to
normal levels, indicating that BVE can decrease
protein catabolism and rebalance nitrogen (12).
For both catalase and total protein levels, GM
treated rats experienced significant decrease in
serum concentrations. When treated with BVE,
however, there was a significant increase
in both catalase and total protein levels,
demonstrating initiation of normal kidney
cell proliferation and ability to restore levels
indicative of kidney function (12). Anti-
inflammatory properties of BVE were
demonstrated through decreases in IL-6
and myeloperoxidsase activity (12).
Histopathological assessments on kidney
tissues demonstrated interstitial nephritis with
shedding of renal tubule cells with GM only
treatment. Subjects concurrently treated with
GM and BVE at 500mg/kg/d demonstrated
normal glomeruli and tubules, and decreased
nephritis (13). Nowacki, et al further looked at
betanin’s role in cell death of MCF-7 cells, a
human breast adenocarcinoma cell line,
typically treated with anti-estrogens (14).
Measuring apoptosis-related protein,
expression (Bad, TRAILR4, FAS, and p53) of
MCF-7 cells treated with betanin-enriched
extract (BEE) showed a significant increase in
apoptosis and decrease cancer cell proliferation
(14). Treatment with BEE decreased MCF-7 cell
viability. Cell cytotoxicity revealed that wild
type p53 cancer cell lines were highly sensitive
to BEE treatment, but mutated p53 cells were
less sensitive to treatment (14). This suggests
BEE can inhibit aggregated cancer cell
proliferation of p53 mutated cells, which are
known to be more resistant to apoptosis
induction (14). A decrease in G1 cell numbers
and an increase in cells in the S phase were also
noted (14). Furthermore, the viability of MCF-7
cells was strongly decreased when treated with
 Oncology Nutrition Connection ❙ Volume 25, Number 3, 2018 ❙ 19

BEE. The lack of significant changes noted

when BEE was applied to normal cells indicate
BEE treatment yields limited adverse side
effects (14).

Discussion
Betanin and Betalain, similar red pigments
found in red beetroot, have shown significant
ability alone, and in combination with
chemotherapy drugs, to induce cytotoxicity in
an array of cancer cell lines. The antioxidant
properties of these phytochemicals, and their
ability to work synergistically with cytotoxic
drugs, provides a promising avenue for further
research. Further, not only do beetroot,
beetroot juice, and beetroot supplements
provide increased nitrates, which may be
beneficial for cancer patients to maintain
adequate nitrate intake for appropriate lean
body mass maintenance through increased
ATP production, it also appears to provide
further protection for those undergoing
cytotoxic treatments (8,9,12-14). Due to
inadequate intake of protein/nitrates, cancer
patients are more susceptible to cancer
cachexia or loss of lean body mass (9). Beetroot
juice may provide assistance in maintaining
lean body mass during chemotherapy, which
can aid in improving outcomes (9). The cell
and animal studies presented demonstrate
betanins or beetroot/beetroot juice improve
cytotoxicity when compared to controls, and
may also enhance cancer cell cytotoxic
properties of chemotherapy agents. Beetroot
also may reduce renal specific adverse effects
of chemotherapy agents (14). Beetroot
decreased the risk of acute renal failure
associated with chemotherapy treatments in
rats, while increasing the kidney’s ability to
preserve protein, resulting in a decreased risk
of lean body mass loss (14).

Although these studies provide positive data

to support the concurrent use of dietary
beetroot or beetroot supplements/juices,
during chemotherapy, there are limitations in
the quantity and types of studies (10-14). The
studies on human cell lines and rat models
need to be validated in human trials. Other
limitations include the small selection of
chemotherapy agents tested compared to the
array of chemotherapy agents currently in use
in oncology treatment. Further studies are
required to determine if beetroot also works
20 ❙ Oncology Nutrition Connection ❙ Volume 25, Number 3, 2018
well with other types of cytotoxic agents,
hormone- and biotherapy-based approaches,
targeted drugs, and/or immunotherapies. As
with most nutraceuticals, the investigation
of beetroot juice and cancer treatment
concurrently is relatively new. Other
weaknesses in terms of application to
humans include the lack of regulation of
dietary supplements, which could lead to
confounding factors, such as the presence of
unknown ingredients in tested supplements.
Those affected by cancer, specifically, are
known to have a high rate of nutritional
supplement usage (2). Initiation of
supplement use is frequent, at about 25% of
all newly diagnosed cancer patients (2). Many
patients believe that by starting dietary
supplements, they will improve their overall
response to treatment, improve cancer
therapy outcomes, or reduce adverse side
effects from chemotherapy agents (2).
A clinical concern with dietary supplement
use in those with cancer is how these products
may affect their therapy regimen and
response to treatment, and potential
interactions between dietary supplements
and chemotherapeutic agents. Although
the pre-clinical results presented here
demonstrate improvement in cancer cell
cytotoxicity with concurrent beetroot extract
administration, concerns about adverse
side effects from supplement use during
chemotherapy must be further investigated
before beetroot can be routinely
recommended to cancer patients currently
in treatment.
Conclusion
New evidence suggests beetroot
supplementation may benefit cancer patients
undergoing chemotherapy treatment.
This evidence warrants human research
to determine efficacy of beetroot juice
supplementation for newly diagnosed cancer
patients. Human trials need to be completed
prior to making use of beetroot juice a regular
practice for cancer patients. Guidelines for
supplementation, including recommended
dosage, potential side effects, and toxicity
levels must be established as well. Finally,
studies to assess whether supplementation is
appropriate for all types of cancer treatment
are urgently needed.
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