Review

Role of antioxidants in cancer therapy

Vanessa Fuchs-Tarlovsky Ph.D., R.D.
*
Servicio de Oncologa, Hospital General de Mexico, Dr. Balmis #148 Col. Doctores, Mexico DF, 06750, Mexico
a r t i c l e i n f o
Article history:
Received 2 August 2011
Accepted 28 February 2012
Keywords:
Antioxidant
Cancer therapy
Oxidative stress
a b s t r a c t
Oxidative stress is a key component in linking environmental toxicity to the multistage carcino-
genic process. Reactive oxygen species (ROS) are generated in response to both endogenous and
exogenous stimuli. To counterbalance ROS-mediated injury, an endogenous antioxidants defense
system exists; however, when oxidation exceeds the control mechanisms, oxidative stress arises.
Chronic and cumulative oxidative stress induces deleterious modications to a variety of macro-
molecular components, such as DNA, lipids, and proteins. A primary mechanism of many
chemotherapy drugs against cancer cells is the formation of ROS, or free radicals. Radiotherapy is
based on the fact that ionizing radiation destroys tumor cells. Radiotherapy induces direct lesions
in the DNA or biological molecules, which eventually affect DNA. Free radicals produced by
oncology therapy are often a source of serious side effects as well. The objective of this review is to
provide information about the effects of antioxidants during oncology treatments and to discuss
the possible events and efcacy. Much debate has arisen about whether antioxidant supplemen-
tation alters the efcacy of cancer chemotherapy. There is still limited evidence in both quality and
sample size, suggesting that certain antioxidant supplements may reduce adverse reactions and
toxicities. Signicant reductions in toxicity may alleviate dose-limiting toxicities so that more
patients are able to complete prescribed chemotherapy regimens and thus, in turn, improve the
potential for success in terms of tumor response and survival.
2013 Elsevier Inc. All rights reserved.
Introduction
Oxidative stress is a key component in linking environmental
toxicity to the multistage carcinogenic process (Fig. 1). Reactive
oxygen species (ROS) are generated in response to both endog-
enous and exogenous stimuli [1]. Evidence from both in vivo and
in vitro studies has linked environmental agents like radiation,
xenobiotics, and chlorinated compounds, as signicant inducers
of cellular damage via ROS-mediated toxicity [2,3].
To counterbalance ROS-mediated injury, endogenous anti-
oxidant defense systems exist and function by chelating and
clearing intracellular ROS activity and accumulation and main-
taining redox equilibrium [4]. This is very important in the case
of intracellular imbalance (resulting from chronic oxidative
stress) where the occurring damage to cellular macromolecules
(DNA, lipids, and proteins) will result in irreversible modication
of cellular viability and function [2]. The endogenous enzymatic
antioxidant defenses (superoxide dismutase, glutathione
peroxidase, and catalase) can counterbalance oxidative micro-
environments by chelating superoxide and various peroxides.
Also, the non-enzymatic endogenous antioxidants (Vitamins
E and C, coenzyme Q, b-carotene, and glutathione) have the
ability to quench ROS activity [1].
Chronic and cumulative oxidative stress induces deleterious
modications to a variety of macromolecular components, such
as DNA, lipids, and proteins [1].
ROS can also mediate an indirect attack to DNA, primarily by
reacting with other cellular components (ie, phospholipids),
resulting in the generation of secondary reactive intermediates
and irreversibly couple to DNA bases, forming DNA adducts [5].
Formation of DNA adducts is central in the carcinogenic process
because, if such adducts escape cellular repair mechanisms and
persist, they may lead to miscording and ultimately to mutations
[6]. Oxidative lesions have been implicated in the etiology of
cancer, and the (8-oxo-dG) lesions serve as a critical biomarker of
oxidative DNA damage [711]. ROS can interact directly with
cellular membrane phospholipid moieties [12,13].
Phospholipids are present at high concentrations within
polyunsaturated fatty acid residues and have been identied as
prime targets for oxidation due to the presence of their
* Corresponding author. Tel.: 52 (55) 278920 00, ext 1062; fax: 52 (55) 5272
33 93.
E-mail address: vanessafuchs@hotmail.com
0899-9007/$ - see front matter 2013 Elsevier Inc. All rights reserved.
doi:10.1016/j.nut.2012.02.014
Contents lists available at ScienceDirect
Nutrition
j ournal homepage: www. nut ri t i onj rnl . com
Nutrition 29 (2013) 1521
methylene group [5]. Both malondialdehyde (MDA) and
4-hydroxynonenal constitute the major aldehyde products of
lipid peroxidation. MDA (the end product of peroxyl radical
conversion) is suggested to have both mutagenic and carcino-
genic effects. Lipid peroxidation indices formation of DNA-
protein cross-links is one of the many mechanisms from which
protein oxidative damage is generated [12]. Recent evidence
suggests that, in the presence of exogenous metals, proteins are
highly susceptible to damage by a variety of oxidants like
hydrogen peroxide by participating in Fenton-type chemical
reactions [12,14]. Metal-catalyzed damage to proteins has been
cited to involve a variety of radicals such as oxidative scissions,
carbonyl groups, and protein-centered alkyl, alkoxyl, and alkyl-
perosyl molecules [12]. Reactions involving such radicals lead to
disruptions in protein polypeptide backbone and this further
perpetuates oxidative protein damage.
The objective of this review is to provide information about
the effects of antioxidants during oncology treatments and to
discuss the possible events and efcacy.
Because evidence from clinical and bench studies indicate
that elevated intracellular ROS contribute to early events
involved in cancer initiation and progression, an opposite
approach to mediating an increase in cellular ROS levels is to use
antioxidants to deplete tumor cells from ROS-induced survival
signaling pathways. Such treatment may also have preventive
functions [15].
Clinical studies have linked gain of oncogenic mutations in
K-ras and subsequent ROS formation of pancreatic inammation
and macrophage-mediated generation of hydrogen peroxide and
superoxide to events leading to an increased risk for pancreatic
cancer [16,17]. Other examples are individuals with high cancer
risk due to the deciency of inherited tumor suppressor genes
such as p53 or PTEN. For these groups, a treatment with anti-
oxidants may be effective in delaying or even preventing tumor
development. Depending on the therapeutic strategy, the use of
antioxidants in combination therapy may have an adverse effect
on anticancer drugs that act on tumor cells by increasing ROS
levels to induce cell death. However, a combination therapy with
antioxidants and therapeutics that induce apoptosis indepen-
dent of oxidative stress may be effective [18].
Oncology therapy
Radiotherapy is based on the fact that ionizing radiation
destroys tumor cells. X rays and g rays are able to penetrate the
tissue depth, destroying tumor cells even from deep layers.
Radiotherapy induces direct lesions in the DNA or biological
molecules, which eventually affect DNA. These changes deregu-
late cell division, and daughter cells nally die [19].
A primary mechanism of many chemotherapy drugs against
cancer cells is the formation of ROS, or free radicals. Drugs that
form ROS include, but are not limited to, alkylating agents
(melphalan, cyclophosphamide), anthracyclines (doxorubicin,
epirubicin), podophyllin derivatives (etoposide), platinum coor-
dination complexes (cisplatin, carboplatin), and camptothecins
(topocan, irinotecan) [20]. Chemotherapy uses chemical
substances that act electively on cells in mitosis, and antimitotic
agents nally aim to destroy cancer cells.
Unfortunately, the free radicals produced with chemotherapy
are often a source of serious side effects as well. For example,
nephrotoxicity, ototoxicity, and peripheral neuropathy are often
produced by cisplatin and other platinum-based chemother-
apies. Anthracyclines such as doxorubicin often cause car-
diotoxicity [21].
The hematological toxicity of antimitotic drugs particularly
and drastically is manifested by leucopenia and thrombopenia.
The toxic aggression on the bone marrow results in the
destruction of cells in multiplication, in maturation, and on
reserve cells. Substances fromthe alkyl group act on the stemcell
population [22].
Clearly, interactions between chemotherapeutic compounds
and antioxidants are complex and other factors affect the
production of free radicals, such as dose, localization, and
metabolism of the drug. In addition, some antioxidants have the
potential to act also as oxidative molecules, depending on their
use and/or their relative concentration [21].
Strong evidence indicates that ROS play an important role in
the initiation as well as the promotion phase of carcinogenesis.
Studies support the role of ROS in cancer in part showing that
dietary antioxidants act as cancer preventive agents. Although
results are promising, the research on this topic is still contro-
versial [23].
Antioxidants
There are studies that show that low antioxidant status and
increased oxidative stress are seen in cancer patients, even
before oncology treatment starts. Sharma et al. [24] evaluated
patients with tongue carcinoma and found that the pretreatment
levels of plasma lipid peroxide and conjugated dines were
Fig. 1. Three-stage model of carcinogenesis and the level of carcinogenic effect. A multistage process such as cancer development is characterized by the cumulative action of
multiple events occurring in a single cell and can be described by three stages: (1) initiation, (2) promotion, and (3) progression. ROS can act in all these stages of carci-
nogenesis. (1) Initiation stage produces an altered cell followed by at least one round of DNA synthesis to x the damage (eg, 8-OH-G) produced during the initiation. (2) The
promotion stage is characterized by the clonal expansion of initiated cells by the induction of cell proliferation and/or inhibition of programmed cell death (apoptosis). (3)
Progression stage involves cellular and molecular changes that occur from the preneoplastic to the neoplastic state, is irreversible and s characterized by accumulation of
additional genetic damage, leading to the transition of the cell from benign to malignant, and is characterized by genetic instability and disruption of chromosome integrity.
(Adapted from Vineis et al. [14].)
V. Fuchs-Tarlovsky / Nutrition 29 (2013) 1521 16
signicantly elevated in patients with carcinoma, as compared
with controls (P 0.001). Signicantly lowered levels of reduced
glutathione, glutathione peroxidase, superoxide dismutase, and
vitamin C and E were observed in cancer patients, when
compared to control subjects. They concluded that increased
levels of oxidative stress markers and decreased levels of anti-
oxidants in carcinoma or the tongue suggest that oxidative stress
markers play a signicant role in pathophysiology of this cancer.
In a study by Badajatia et al. [21], results showed that serum
levels of vitamin C and E, whole blood levels of superoxide dis-
mutase and glutathione peroxidase, and serum antioxidant
activity were signicantly lower (P < 0.001), whereas serum
levels of MDA were signicantly higher (P < 0.001) in patients
than controls. Levels of all the biochemical parameters were
correlated with the degree and severity of the disease. Results by
Klarod et al. showed that when measuring serum levels of non-
enzymatic antioxidants in lung cancer patients, retinol and
lycopene levels were statically lower at early stages, whereas
vitamin E, b-carotene, selenium, and zinc were even lower at
advanced stages of the disease, and that serum selenium levels
happened to be different when patients were divided according
to their body mass index [25].
Vitamin E or a-tocopherol (Fig. 2) has been dened as
a radical-chain breaker, which, due to its hydrophobic nature,
operates in a lipid environment. The effects of a-tocopherol as an
antioxidant are thus restricted to its direct effects in membranes
and lipoprotein domains. Consequently, other denitions such as
secondary antioxidants as an inhibitor of enzymes that
produce radicals, or activation of genes coding for antioxidant
enzymes, are confusing [26].
Tocopherols react with free radicals, notably peroxide radi-
cals, and with singlet molecular oxygen (O
2
), which is the base
of its function as an antioxidant [26]. RRR-a-Tocopherol is the
major peroxyl radical scavenger in biological lipid phases such
as membranes or low-density lipoproteins. In membranes such
high reactivity is important because tocopherols react with
lipid peroxyl radicals to yield a relatively stable lipid hydro-
peroxide, and the tocopheroxyl radical interrupts the radical
chain reaction, thereby affording protection against lipid per-
oxidation [27,28].
Vitamin E is the major lipid soluble antioxidant protecting
lipids against peroxidative damage. Studies indicate that oxida-
tive cleavage of the phytyl side chain is a major metabolic
pathway in humans, operative at saturated vitamin E plasma
concentrations [28].
In a study by Chitra et al, 2008 [29] aimed to evaluate early
and late effects of radiation and a-tocopherol on the secretion of
saliva and on the selected saliva salivary parameters in oral
cavity patients, the conclusion was that supplementation with
a-tocopherol improved the salivary ow rate, thereby main-
taining the salivary parameters.
Vitamin C or L-ascorbic acid (Fig. 2) is water soluble and is
present in its deprotonated state under most physiological
conditions. It is considered to be the most important antioxidant
in extracellular uids [30] and has many cellular activities of an
antioxidant nature as well [32]. Vitamin C has been shown to
scavenge superoxide, hydrogen, peroxide, hydroxyl radical,
peoxyl radicals, and O
2
[12,33,34] efciently. Ascorbic acid can
also protect membranes against peroxidation by enhancing the
activity of tocopherol, the chief lipid-soluble vitamin (Fig. 3) [34].
Although the value of vitamin C as a potential cancer treat-
ment has been debated for decades [35], only one randomized
clinical trial was found that evaluated vitamin C treatment
concurrently with chemotherapy and reported on outcomes
[36]. In this study, a non-signicant advantage was shown in
objective response (complete response partial response),
which was higher in the vitamin C supplemented group (60%)
than in the placebo arm (33%). Additionally, although both
groups had signicant reductions in the sizes of the average
lump diameter before and after treatment, the mean change was
3.53 0.73 in the vitamin C group versus 1.93 0.77 in the
control group.
Two recent studies have included vitamin C as part of an
antioxidant mixture given concurrently with chemotherapy
(Table 1). Pathak et al. [38] evaluated vitamins C, E, and b-caro-
tene, whereas Weijl et al. [39] evaluated vitamins C, E, and
selenium. Weijl reported poor adherence to the supplemental
regimen: 46% of all patients did not drink the beverage (placebo
or antioxidant) throughout the entire study. Although the overall
response rates were similar between the two groups (48% anti-
oxidant group versus 44% control group), nine patients had
complete response in the antioxidant group versus six patients
in the placebo arm. A statistically signicant correlation
regarding improvement in toxicities was found between patients
with the highest serum levels of antioxidant supplements and
the lowest loss of high tone hearing after three cycles of
chemotherapy (P 0.019).
In the study by Pathak et al. [38], although none of the results
achieved statistical signicance, an advantage in overall
response rates (37% versus 33%) and median survival (11 mo
versus 9 mo) were seen for patients taking the antioxidant
supplements.
Fig. 2. Vitamin structure with antioxidant activity. The tocopherol series has the
phytyl side chain (R3), whereas in the tocotrienols the side chain has double bonds
at the 3
0
, 7
0
, and I I
0
positions. The radical function in the tocopheroxyl radical is at
position 6 of the chromane moiety. (Adapted from Sies et al. [31].)
V. Fuchs-Tarlovsky / Nutrition 29 (2013) 1521 17
Carotenoids are natural compounds with lipophilic prop-
erties; b-carotene is the most prominent (Fig. 2). Most carot-
enoids contain an extended system of conjugated double
bonds, which is responsible for their antioxidant activity;
b-carotene deactivates O
2
, depending largely on their physical
quenching [40].
Carotenoids have also been shown to be capable of inhibiting
free-radical reactions (Fig. 4). b-Carotene very efciently reduces
trichloromethylperoxyl radicals, inhibiting the oxidation of
model compounds by peroxyl radicals [41].
Two studies evaluated supplementation with vitamin A,
a weaker antioxidant. Israel et al. [42] observed that patients
supplemented with vitamin A showed grater than twofold
increase in the complete response rate (38% versus 15% for
controls, P < 0.02). Among chemotherapy responders in both
groups, the projected 43-mo survival rate, based on a life table
analysis using the Kaplan-Meier method and log rank test, was
93% in vitamin A supplemented responders versus 30% in non-
supplemented responders (P < 0.02). Classication of patients
by menopausal status indicated that serum retinol levels were
signicantly elevated only in postmenopausal patients supple-
mented with vitamin A (P < 0.001). For this subgroup, the
response rates duration of response and projected survivals
were signicantly elevated. Postmenopausal women taking
vitamin A (n 25) had a 78% chance of surviving for 43 mo,
compared with 19% for non-supplemented (n 30) post-
menopausal women (P < 0.02). In the study by Meyskens et al.
[43] patients in the control group experienced less grade 2
toxicities (4%) than the vitamin A group (23%) (P 0.002). This
was the only study to report a statistically signicant reduction
of toxicity in the control group versus the antioxidant group,
which was not unexpected for vitamin A supplementation.
Patients in the vitamin A group had longer durations of clinical
progression-free survival (median 46 mo) and overall survival
(51 mo) compared to those in the chemotherapy-alone group
(38 and 44 mo, respectively); however, the differences were not
statistically signicant.
There are other antioxidants currently proven in medical
practice, especially in cancer. One of them is quercetin, a plant-
derived aglycone form of avonoid glycosides, which has been
used as a nutritional supplement and may be benecial against
a variety of diseases, including cancer. The effect of quercetin on
the production of ROS and nitric oxide in lipopolysaccharides
(LPS)-stimulated human human acute monocytic leukemia cell
line (THP-1) acute monocytic leukemia cells was determined by
ow cytometry using CM-H2DCFDA dye. Authors demonstrated
that quercetin has a higher reduction potential compared with
curcumin, that it reduced LPS-induced ROS to near normal levels,
and that it reduced LPS-induced nitric oxide production [44].
Another study demonstrated that using avonoid quercetin
transiently inhibits the activity of taxol and nocodanzole through
interference with the cell cycle in cancer cells. Authors concluded
that long-termexposure of cancer cells to quercetin may prevent
cell proliferation and survival, and the interference of quercetin
with cell-cycle progression diminishes the efcacy of
microtubule-targeting drugs to arrest cells at G2/M [45].
Antioxidants are used and proven to be benecial to protect
healthy cells from anticancer therapy. Amifostine is a radio-
protectant drug that when dephosphorylated protects normal
but not malignant cells against oxygen-based radicals, alkylator
or organoplatinum anticancer drugs [22], and radiotherapy. It
acts as a free-radical scavenger and has been shown to reduce
pro-inammatory cytokine levels [46]. The protection of normal
cells results in part from improved vascularity, higher alkaline
phosphatase levels (required for dephosphorylation of amifos-
tine into its active metabolite WR-1065), and higher pH of
normal tissues [22]. One randomized trial has shown that ami-
fostine reduced the incidence of xerostomia, but not the severity
of oral mucositis after radiotherapy for head-and-neck cancers
[47]. A recent randomized trial suggested amifostine provided
Fig. 3. Biochemical pathways followed by tocopheroxyl radical. (The routes marked with a dotted line are the prooxidant potential route.) (Adapted from Mataix [37].)
V. Fuchs-Tarlovsky / Nutrition 29 (2013) 1521 18
signicant protection against mucositis in ovarian cancer
patients at stage IC, G3, II-III-IV treated with carboplatin and
paclitaxel; the incidence of mucositis in the group with a ami-
fostine dose of 910 mg/m
2
was signicantly lower (4.7%) versus
the placebo group (15.4%) [48].
The study by Spencer et al. [22] also suggested that amifostine
reduced the median grade of oral mucositis and the severity of
mucositis, but not the requirement of parenteral nutrition or
analgesic use after high-dose melphalan and haemopoietic
stem-cell transplantation (HSCT) for multiple myeloma. Finally,
amifostine reduced the frequency of severe esophagitis after
chemoradiotherapy for non-small-cell lung cancer [49]. Guide-
lines do not recommend amifostine for the prevention of oral
mucositis except for non-small-cell lung cancer patients under-
going concomitant chemoradiotherapy [50]. One of the main
issues with amifostine administration is the toxicity. Nausea,
vomiting, hypotension, sneezing, ushing, somnolence, metallic
taste, allergic reactions, and hypocalcemia have been reported
frequently. However, subcutaneous injection could be more
tolerable [51].
Another recent study aimed to investigate whether vitamins
C, E, and pequi fruit pulp oil (carotenoid-rich oil extracted from
pequi [Caryocar brasiliense Cam], a typical fruit of the Brazilian
Cerrado used in folk medicine to treat several diseases, including
in control of tumors) can provide individual protection and/or be
used afterward as an adjuvant in cancer therapy; results suggest
that the efciency and applicability of antioxidants in the
medical clinic can depend not only on the nature of the antiox-
idant, the type and stage of cancer being treated, and the pre-
vailing oxygen partial pressure in tissues, but also on the type of
antioxidant therapy chosen [23].
There are two recent interesting studies that demonstrate
that giving antioxidant therapy ameliorates cardiotoxicity
induced by doxorubicin. The rst one used tannic acid, an anti-
oxidant, in experimental animals receiving chemotherapy with
doxorubicin, which is used widely in the treatment of various
solid tumors including breast cancer, can ameliorate
doxorubicin-induced cardiotoxicity and potentiates its anti-
cancer activity in both in vitro (H9c2 and MDA-MB-231 cells) and
in vivo models of 7,12-dimethylbenz[a]anthracene (DMBA)-
induced mammary tumor animals [52].
The second one used Procyanidins fromgrape seeds as potent
free-radical scavengers that have been shown to protect against
anthracycline-induced cardiotoxicity. Authors pretreated rats
with procyanidins before the doxorubicin chemotherapy and
concluded that this treatment attenuated cytoplasm vacuoliza-
tion, increased left ventricular developed pressure, and
improved the electrocardiogram. The cardioprotective effect of
procyanidin corresponded to the decrease in lipid peroxidation
and the increase in cardiac antioxidant potency in the experi-
mental rat group. An in vitro cytotoxic study showed that pro-
cyanidins protected cardiomyocytes from doxorubicin-induced
cardiotoxicity via suppression of oxidative stress [53].
As shown in Table 1, one of our studies in 2011 [54] found that
supplementing cervical cancer patients with antioxidants
(vitamin C, E, b-carotene, and selenium) during treatment with
cisplatinum and radiotherapy maintained hemoglobin levels
above 12 g/dL, as well as increased quality of life compared with
the placebo group. This evidence is supported by a Canadian
study in 1999 [55], in which the authors demonstrated that the
conservation of hemoglobin levels is highly predictive of
outcome for patients with radiotherapy for carcinoma of the
cervix. Blood transfusions appeared to overcome the negative
prognostic effects of low presenting hemoglobin levels. T
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V. Fuchs-Tarlovsky / Nutrition 29 (2013) 1521 19
Conclusion
Much debate has arisen about whether antioxidant supple-
mentation alters the efcacy of cancer chemotherapy. There is
limited preliminary evidence by quality and sample size sug-
gesting that certainantioxidant supplements may reduce adverse
reactions including neurotoxicity, asthenia, stomatitis/mucositis,
and weight loss. Signicant reductions in toxicity may alleviate
dose-limiting toxicities sothat more patients are able to complete
prescribed chemotherapy regimens successfully, suggesting an
improved therapeutic index. Because of the potential of the
relationship between the reduction of dose-limiting toxicities
allowing for full chemotherapy cycles and the subsequent
potential for increased tumor response and/or survival, it is crit-
ical that future antioxidant/chemotherapy studies employ proper
sample sizes and methodologies so that the results are of clear
clinical relevance [20,56]. Many studies indicate that antioxidant
supplementation results in either increased survival times,
increasedtumor response, or both, as well as fewer toxicities than
controls; in some of the last systematic reviews in this specic
topic there is no evidence of antioxidant interference with
chemotherapy mechanisms, with a possibility that antioxidants
may even improve tumor response or patient survival [35].
Combining these results with the potential for improvement of
toxic side effects by antioxidants, additional strategies for further
research on antioxidants and chemotherapy are now warranted.
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