Chemotherapy and Dietary Phytochemical Agents

Abstract

Chemotherapy has been used for cancer treatment already for almost 70 years by targeting the proliferation potential and metastasising ability of tumour cells. Despite the progress made in the development of potent chemotherapy drugs, their toxicity to normal tissues and adverse side effects in multiple organ systems as well as drug resistance have remained the major obstacles for the successful clinical use. Cytotoxic agents decrease considerably the quality of life of cancer patients manifesting as acute complaints and impacting the life of survivors also for years after the treatment. Toxicity often limits the usefulness of anticancer agents being also the reason why many patients discontinue the treatment. The nutritional approach may be the means of helping to raise cancer therapy to a new level of success as supplementing or supporting the body with natural phytochemicals cannot only reduce adverse side effects but improve also the effectiveness of chemotherapeutics. Various plant-derived compounds improve the efficiency of cytotoxic agents, decrease their resistance, lower and alleviate toxic side effects, reduce the risk of tumour lysis syndrome, and detoxify the body of chemotherapeutics. The personalised approach using various phytochemicals provides thus a new dimension to the standard cancer therapy for improving its outcome in a complex and complementary way.

Full text

Hindawi Publishing Corporation
Chemotherapy Research and Practice
Volume 2012, Article ID 282570, 11 pages
doi:10.1155/2012/282570
Review Article
Chemotherapy and Dietary Phytochemical Agents
Katrin Sak
NGO Praeventio, N¨
aituse 22-3, 50407 Tartu, Estonia
Correspondence should be addressed to Katrin Sak, katrin.sak.001@mail.ee
Received 8 October 2012; Revised 23 November 2012; Accepted 29 November 2012
Academic Editor: G. J. Peters
Copyright © 2012 Katrin Sak. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Chemotherapy has been used for cancer treatment already for almost 70 years by targeting the proliferation potential and
metastasising ability of tumour cells. Despite the progress made in the development of potent chemotherapy drugs, their toxicity
to normal tissues and adverse side effects in multiple organ systems as well as drug resistance have remained the major obstacles
for the successful clinical use. Cytotoxic agents decrease considerably the quality of life of cancer patients manifesting as acute
complaints and impacting the life of survivors also for years after the treatment. Toxicity often limits the usefulness of anticancer
agents being also the reason why many patients discontinue the treatment. The nutritional approach may be the means of helping
to raise cancer therapy to a new level of success as supplementing or supporting the body with natural phytochemicals cannot only
reduce adverse side effects but improve also the effectiveness of chemotherapeutics. Various plant-derived compounds improve
the efficiency of cytotoxic agents, decrease their resistance, lower and alleviate toxic side effects, reduce the risk of tumour lysis
syndrome, and detoxify the body of chemotherapeutics. The personalised approach using various phytochemicals provides thus a
new dimension to the standard cancer therapy for improving its outcome in a complex and complementary way.
1. Introduction
Chemotherapy is one of the principal modes of the treatment
of cancer patients [1]. It was first used to treat advanced lym-
phoma in the late 1940s after it became known that the use
of mustard gas in the World War I caused leukopenia [2,
3]. Shortly after the World War II, it was also found that
folic acid stimulates the proliferation of acute lymphoblastic
leukaemia cells and antagonistic analogues to folic acid, first
aminopterin and then amethopterin (now known as metho-
trexate) induced the remission in children with acute lym-
phoblastic leukaemia [4]. Although the role of chemotherapy
in the treatment of common, epithelial malignancies was
limited to the treatment of symptomatic metastatic disease
for almost 30 years, nowadays cancer chemotherapy has three
main applications: it is curative for a small number of malig-
nancies including childhood leukaemia, Hodgkin’s and non-
Hodgkin’s lymphoma, and germ cell malignancies; it has a
palliative role for most metastatic epithelial malignancies;
and it has an adjuvant role in several types of resected
epithelial malignancies [3].
By definition, chemotherapy treatment should interfere
with the biochemical program that is involved or committed
to cellular replication and cause selective cell death. At that,
the host cell should be able to adapt and recover from
toxicity [2]. Many chemotherapeutic agents kill cancer cells
oxidatively via the production of reactive oxygen species and
the induction of either apoptosis or necrosis of tumorous
cells [2,5,6]; whereas others act on various components of
cellular metabolism influencing activities of different en-
zymes needful for cell division.
Cancer treatment is targeted at its proliferation potential
and its ability to metastasise; hence, the majority of chemo-
therapy drugs take advantage of the fact that cancer cells
divide rapidly [7]. Chemotherapy agents can be divided into
severalcategoriesbasedonthefactorssuchashowtheywork,
their chemical structure, and their relationship to another
drug. The most important categories of chemotherapeutics
include alkylating agents (e.g., cyclophosphamide, ifosfam-
ide, melphalan, busulfan), antimetabolites (e.g., 5-fluorou-
racil, capecitabine, methotrexate, gemcitabine), antitumour
antibiotics (e.g., daunorubicin, doxorubicin, epirubicin), to-
poisomerase inhibitors (e.g., topotecan, irinotecan, etopo-
side, teniposide), and mitotic inhibitors (e.g., paclitaxel,
docetaxel, vinblastine, vincristine) [8,9]. Most chemother-
apeutic drugs target the cell cycle machinery relying on the

2Chemotherapy Research and Practice
difference in the frequency of cell division to differentiate
between the cancer clones and normal cells. Within this
process slow-growing cancer clones will survive and evolve
into new fast growing strains. Chemotherapy is able to kill
offmost of the susceptible tumorous cells succeeding to send
cancer into remission for weeks or months after which it
reemerges as a more aggressive organism [10,11]. In fact, the
more chemotherapy is given, the higher is the aggressiveness
of relapse. In these cases, chemotherapy may indirectly select
the most resistant mutant cell for clonal expansion [2].
Cancer is a highly heterogeneous disease, especially
in its advanced forms [2], and such heterogeneity gives
it an advantage to survive under selection pressure of
drugs [12]. Moreover, the unique characteristics of tumour
microenvironment (hypoxia, low extracellular pH, high
interstitial fluid pressure), developed at least in part as a
result of the malformed tumour vasculature, act as barriers
to chemotherapy impairing the transport and delivery of
circulating therapeutic molecules in tumour tissue [13–
16]. Cancer hypoxia can thus reduce the effectiveness of
drugs [13,15,17]. Another major obstacle of conventional
chemotherapy proceeds from the drug resistance [1,12,18,
19]. Some tumours are intrinsically resistant to certain drugs,
whereas others can acquire resistance after treatment [1,18–
20]. Cancer cells can often develop resistance not only to the
agent, which they have been exposed to, but also to other
drugs and chemicals that they have not encountered. There
are a number of mechanisms mediating such multidrug
resistance [2,20,21]. Upregulation of drug efflux ATP-
binding cassette (ABC) transporters, such as P-glycoprotein
(P-gp), multidrug resistance protein 1 (MRP1), and breast
cancer resistance protein (BCRP), may be responsible for the
resistance to many chemotherapeutics affecting disposition
of these drugs in the tumour cells and modifying seriously
the clinical outcome [1,20,22,23]. Although the first
human ABC drug transporter P-gp was identified already for
more than 35 years ago, there are still no clinically applicable
inhibitors of ABC transporters available to date and this
failureislargelyduetotheunfavourabletoxicsideeffects
of tested chemical compounds. Novel chemosensitisers as
inhibitors of different MDR-linked ABC transporters are
actively explored turning increasing attention also to various
naturalproducts[23,24].
2. Factors Affecting the
Effectiveness of Chemotherapy
Effectiveness of chemotherapy depends on various factors,
including properties of cancer cells (if tumour is hypoxic
or mitochondrial function is severely compromised, or the
number of mitochondria within the cancer cell is low,
chemotherapy will be of limited value, only increasing the
clonal selection of the most resistant and possibly also the
most aggressive cancer phenotype [2]); tumour size (the
microscopic form of tumour is much more successfully
treated than macroscopic cancer [2]); number of chemother-
apy cycles [25]; administrating polychemotherapy versus
monotherapy (polychemotherapy may be more active than
single agent, whereas the order of administration of drugs as
well as their time schedule is also important: combining
drugs with different modes of action may lead to enhanced or
even synergistic antitumour effects without injuring the host
[25–28]); multitargeted approach (targeting both the cancer
cell and its microenvironment might increase the treatment
efficiency [29]); and the phase of the circadian cycle [30].
Circadian periodicity in cell proliferation provides an oppor-
tunity to improve the tolerability or efficiency (or both) of
anticancer treatment by targeting its timing at certain stages
of the circadian system of the host or the tumour [30–37].
It has been shown in animal studies that the toxicity and
efficacy of more than 30 anticancer agents vary by more than
50% depending on the circadian time when the agent is given
[2,31,32,35,36]. The peak time of drug delivery to achieve
optimal tolerability is characteristic for each chemothera-
peutic agent and the circadian time of administration of
cancer chemotherapeutic agents when they are best tolerated
also usually shows the highest efficacy against the tumour
[31,35,37]. Such chronotherapy may have a significant
impact on the treatment success and can ultimately lead to a
better tumour management [33,35,37]. The patient’s gender
could also have an essential role in the determination of
optimal chronotherapeutic schedule [2,36].
Cancer is a systemic and not a local disease [2]. Metastatic
spread of tumour cells may take place already at an early
stage of the malignancy; however, little is known about
the tumour-biological parameters of such disseminated cells
[38]. Metastatic foci might vary with genotype, phenotype,
and drug response [21], whereas expression profiles and
signalling pathways between primary tumour and metastatic
tissue can be different [27,38]. The considerable number of
adjuvant therapy failures may be explained by such molec-
ular differences between the surgically removed and histo-
pathologically examined primary tumour cells and the
remaining disseminated tumour cells [38]. Namely, the latest
would be the real targets for any systemic therapy to prevent
them forming a clinically relevant metastatic disease [21,38].
3. Typical Side Effects of Chemotherapy
Although the desired goal of chemotherapy is to eliminate
the tumour cells, diverse ranges of normal cell types are also
affected, leading to many adverse side effects in multiple
organ systems [5,39–43]. Such debilitating effects are a
major clinical problem [44], whereas the toxicity often limits
the usefulness of anticancer agents [44,45].
Knowing how the chemotherapy agent works is impor-
tant in predicting its side effects. For instance, treatment with
alkylating agents and topoisomerase II inhibitors increases
the risk of secondary cancer (acute leukaemia); anthracy-
clines (like doxorubicin) induce cardiotoxicity; and mitotic
inhibitors have the potential to cause peripheral nerve
damage [6].
The most common acute complaints of cancer patients
undergoing cytotoxic therapy are fatigue, nausea, vomiting,
malaise, diarrhoea, mucositis, pain, rashes, infections, head-
aches, and other problems [2,42,44,46,47]. Normal
haematopoietic cells, intestinal epithelial cells, and hair
matrix keratinocytes are often susceptible to the toxic effects

Chemotherapy Research and Practice 3
of anticancer agents [44]. Over 75% of cancer patients suffer
from therapy-associated fatigue; however, only about one-
third of treating physicians recognise this problem [42].
Fatigue is related to a reduced mitochondrial function of
tumorous cells and is often a significant reason why patients
discontinue the treatment [42,48]. Thus, cytotoxic agents
decrease considerably the quality of life of patients [43,
48,49]. Through the induction of nausea and vomiting,
difficulties in swallowing, dry mouth, alterations in taste and
smell, depression, poor energy, and aversion to food cyto-
toxic drugs affect also the nutritional status of patients [2,47]
showing that chemotherapy is a sufficient stressor in causing
malnutrition. It must be appreciated that malnutrition is the
reason why majority of the cancer patients die [2,50].
Most cytotoxic drugs have immune suppressive side
effects. Many chemotherapeutics kill dividing haematopoi-
etic cells manifesting as profound neutropenia and cytopenia
resulting in decreased immunity, increased susceptibility to
infections, and elevated risk of bleeding [2,3]. Coming from
the requirement of the bone marrow to repopulate white
cells and platelets in the blood, drugs are often administered
episodically followed by the drug-free intervals of 2-3 weeks.
Such scheme helps to minimise the chance of infection or
bleeding but allows also the tumour to recover [51,52].
Cancer patients frequently complain of neurological side
effects [53]. Such effects range from abnormalities in brain
volume and integrity detected by magnetic resonance imag-
ing on patients after chemotherapy to different clinical symp-
toms; manifesting acutely or as delayed neurotoxicities only
becoming apparent years after treatment [40,41,54]. Neu-
rological complications include memory loss and cogni-
tive dysfunction, seizures, vision loss, dementia, leukoen-
cephalopathy, cerebral infarctions, and other problems [41,
53,54]. These symptoms are commonly referred to as Chemo
Brain [53,55]affecting some 4–75% of cancer patients fol-
lowing with chemotherapy [55]. Nearly all frequently used
chemotherapeutic agents can cause adverse neurological
effects [40,41]. Chemotherapy-induced cognitive changes
might be associated with neurotoxic effects of inflammation
and cytokine deregulation. Treatment-induced changes in
the level of oestrogen and testosterone can be related to
cognitive decline. Also, corticosteroids, which are commonly
used as part of chemotherapy regimens or to manage side
effects such as nausea, alter neuroendocrine functioning and
cognition [40].
The most common long-term health problems of adju-
vant chemotherapy include poor memory and concen-
tration, visual deterioration, musculoskeletal complaints
including early onset osteoporosis, poor sleep patterns, skin
changes, sexual dysfunction, and chronic fatigue [3]. This
complex of problems is suggestive of accelerated aging lead-
ing potentially to early onset frailty [3,40]. Such long-term
toxicity can have an impact on the quality of life of cancer
survivals that could last for years [3].
Most chemotherapy drugs are genotoxic likely causing
epigenetic and genetic damage [2,44,53]. Many cancer
patients encounter thus the problem of developing second
malignancies as a result of treatment [44,48,53]. The com-
mon secondary tumours are a variety of acute leukaemias
and non-Hodgkin’s lymphomas, less common are carcino-
mas of the urinary bladder and other malignancies, which are
usually refractory to treatment. Secondary leukaemias con-
stitute approximately 10% of all leukaemias having the
average latent interval from the diagnosis and treatment of
the primary neoplasm to development of acute leukaemia for
four to six years. The International Agency for Research on
Cancer (IARC) has identified 20 single chemotherapeutic
agents or regimens which cause cancer in humans and about
50 others that are suspect [2]. Chemotherapy-associated
immunosuppression can result in an increased rate of
infection by oncogenic viruses which further increase the risk
of secondary cancers [2].
Current treatment protocols often apply multiagent
chemotherapy [54] and this may even increase the extent of
adverse side effects [50]. Several serious complications can
cause discontinuation of therapy, prolong the duration of
stay in hospitals, and may affect the overall prognosis and
outcome of the disease [50]. It is important to bear in mind
that, in general, older cancer patients are more susceptible
to treatment-related complications than younger individuals
[56]. One of the most critical and life-threatening adverse
conditions of chemotherapy needing immediate intervention
is tumour lysis syndrome. It results from the massive and
abrupt destruction and lysis of malignant cells and subse-
quent release of intracellular ions and metabolites into the
bloodstream leading to hyperuricemia, hyperphosphatemia,
hypocalcemia, and hyperkalemia [57,58]. This syndrome is
accompanied by renal failure and metabolic acidosis increas-
ing the risk of death [57]. Although the tumour lysis syn-
drome is most frequently observed in patients with haema-
tologic malignancies, it may also occur in solid tumours
[57,58]. These malignancies share the characteristics of a
high proliferative rate, large tumour burden, or high sensi-
tivity to cytotoxic therapy and in principle, any tumour that
is highly responsive to chemotherapeutic drugs, particularly
if the cancer cells die through the necrotic pathway, can
give rise to this severe metabolic syndrome [2,58]. Most of
the complications can be readily managed when they are
recognised early; however, delay in recognition and treat-
ment of metabolic abnormalities may become fatal [58].
4. Nutritional Approach in Chemotherapy
The efficacy of standard oncologic therapies (involving a
combination of surgery, multiple chemotherapeutic agents,
and ionising radiation) has reached a plateau for most of
solid tumours [48]. General protocol with these therapies is
just to follow a watch-and-wait strategy after the therapeutic
administration is concluded [9]. However, this is a period
when supplemental therapies are highly indicated to result in
a higher percentage of successful outcomes [9]. Cancer
patient must be stocked up with needful nutrients already
before receiving treatment in order to ensure the best health
possible before undergoing chemotherapy [59]. The adverse
side effects of anticancer agents exacerbate the nutritional
problems and the proper nutrition should be an integral part
of the treatment program of every cancer patients [47].
Dietary components may act as adaptogens protecting

4Chemotherapy Research and Practice
organism from the adverse effects of intervention or as
modifiers of biologic response [60] exerting additive or even
synergistic effects with pharmaceutical agents [61].
Thus, nutritional approach may be the means of helping
to raise cancer therapy to a new level of success, whereas sup-
plementing or supporting the body with natural compounds
may be the answer in not only reducing the side effects but
also improving the effectiveness of chemotherapy [2]. At
the same time, it is important to bear in mind that some
nutrients can affect the treatment outcome also adversely
by attenuating or inhibiting the therapeutic effect of certain
drugs. Optimal dietary regimen of cancer patients should
thus be prescribed by a nutritional oncologist considering
each individual case separately, whereas the consumption of
supplements on patient’s own initiative may be dangerous
and should be avoided.
5. Purposes of Nutritional Intervention
Intervention with dietary agents in chemotherapy has several
aims. It increases the efficacy of treatment and decreases its
side effects, improves cancer killing through apoptosis rather
than necrosis, reduces drug resistance or increases drug accu-
mulation within cancer cells, detoxifies body of chemothera-
peutics, decreases weight loss and malnutrition, improves the
quality of life, and reduces severity of comorbid conditions.
Dietary compounds may enhance the efficacy of cancer
therapeutics by modifying the activity of key cell prolifer-
ation and survival pathways [48,61,62]. Multiple antiox-
idants are effective in increasing the tumour response to
chemotherapy improving also the survival time of patients
[9,48,59]. Nutrients can be used also to mitigate the toxicity
of chemotherapy [46,48,62]. Reduction in adverse effects of
anticancer agents has been shown when given concurrently
with antioxidants [9,48,59]. Lowering the side effects may
permit to safely administer a higher and possibly more
effective dose of chemotherapeutic drugs [2]. Combination
of nutrients has generally a better effect getting the optimum
therapeutic response and reducing adverse side effects than
different nutrients separately. However, possible interactions
between the dietary components during chemotherapy need
to be carefully controlled as some supplements can abolish
the beneficial effects of others [2].
Oxidant stress shifts the mechanisms of cell killing away
from apoptosis to necrosis inducing inflammation and pro-
moting cancer progression. Necrosis will increase also the
risk of developing tumour lysis syndrome. Regulating the
oxidant state with specific antioxidants, supporting mito-
chondrial function, and increasing their numbers within
cancer cells can promote the apoptosis-induced death of
chemotherapy. This reduces the side effects associated with
chemotherapy and may also lower the resistance to antican-
cer agents and the progression of tumour [2,9].
Drug resistance is one of the primary obstacles of
successful chemotherapy. Inhibiting the function of ABC
transporters, such as P-gp and MRP-s, may lead to over-
coming drug resistance providing a possible mechanism
to improve chemotherapeutic effects [2,20]. Although co-
administration of transport inhibitors together with the
actual anticancer drug may enhance drug penetration into
the tumour [24], no real solution to multidrug resistance
has been found to date and no chemical P-gp inhibitors with
clinically satisfying results have been described mainly due
to their high toxicity [23,24]. Therefore, several novel com-
pounds including those isolated from natural sources (or the
so-called “fourth generation chemosensitisers”) are actively
explored and may hopefully provide some solution to
overcome these problems [20,23,24].
The body needs to be detoxified of chemotherapeutics
after the treatment is completed. Many of the anticancer
agents are carcinogenic themselves and the patients may suf-
fer secondary cancers following primary remission from the
initial tumour [2].
Nutritional status of cancer patients is associated with the
outcome of malignant disease while weight loss is related to
shortened survival and lowered response to chemotherapy
[2,47]. Malnutrition is the cause of death for the majority of
cancer patients [2]. Therefore, nutritional support enhances
the chances of complete remission of disease and improves
the quality of life [47].
Cancer patients may be antioxidant deficient and chem-
otherapy further generates free radicals that cause oxidative
damage in different organs. It is important to keep comorbid
conditions in mind considering the state of the entire patient
and not just to focus on the cancer. The antioxidant status of
the patient can remain depressed for some months after the
cancer treatment and nutritional support helps to ensure the
best possible general health state [59].
6. Plant-Derived Dietary Agents
in Chemotherapy
The optimal nutritional program proceeds from each indi-
vidual case and considers the needs of a certain patient.
Dietary phytochemical agents influence various aspects of
chemotherapy treatment and their involvement in the cureof
cancer patients is absolutely indicated and needful. Different
natural compounds can improve efficiency of chemother-
apeutic agents, decrease the resistance of chemotherapeu-
tic drugs, lower and alleviate the adverse side effects of
chemotherapy, reduce the risk of tumour lysis syndrome, and
detoxify the body of chemotherapeutics. At the same time,
it is important to be aware that some phytochemical agents
can have also toxic effects and influence the treatment results
adversely.
Effects of plant-derived dietary agents on treatment out-
put have been intensively explored; however, most of the
studies about interactions between dietary phytochemical
agents and chemotherapy drugs are done using either in vitro
cell systems or in vivo animal experiments (see Ta ble 1 ).
Therefore and before more clinical data will be available,
some precaution must be taken in transferring these results
directly to the patients.
Various plant-derived agents like genistein, curcumin,
epigallocatechin gallate (EGCG), resveratrol, indole-3-car-
binol, and proanthocyanidin have been shown to be able to
affect the efficacy of traditional chemotherapeutic agents [48,
61]. Supplementation with bromelain can also increase the

Chemotherapy Research and Practice 5
Tab le 1: Examples of effects of dietary phytochemical agents on chemotherapy.
Compound Dietary source Chemotherapy drug Effect Biological system Reference
Influence on treatment efficacy
Ginsenosides Cisplatin Enhancement of drug-induced antiproliferative
effect Human breast carcinoma MCF-7 cells [63,64]
Ginseng
5-Fluorouracil Increase in antiproliferative effect Human colorectal cancer HCT-116 cells [63,65]
Curcumin Turmeric Vinorelbine Enhancement of chemotherapeutic efficacy Human squamous cell lung carcinoma H520 cells [66,67]
Catechins/theanine Green tea Doxorubicin Enhancement of antitumour activity Ehrlich ascites carcinoma and M5076 ovarian
sarcoma tumour-bearing mice [9,68–70]
Quercetin
Increase in reduction of tumour growth Mice bearing human tumour xenografts [71]
Cisplatin Potentiation of cytotoxic effect Human ovarian and endometrial cancer cell lines [71]
Many foods such as
onions, apples,
berries, and tea Doxorubicin Potentiation of growth-inhibitory activity Doxorubicin-resistant human breast tumour
MCF-7 cells [68,71,72]
Busulfan Synergistic antiproliferative activity Human leukaemia K562 cells [71,73]
Genistein
Cisplatin Increased cytotoxic effect Cisplatin-sensitive and cisplatin-resistant human
2008 ovarian carcinoma cells [9,71]
Attenuation of inhibitory effect of tamoxifen on
tumour cell growth
Oestrogen-dependent human breast cancer
MCF-7 cells [9,74]
Soy foods
Tamo xi fen Attenuation of tamoxifen effect on reducing of
tumour burden
Female Sprague-Dawley rats with induced
mammary tumours [75]
Synergistic growth inhibition Oestrogen receptor-negative human breast
carcinoma MDA-MB-435 cells [9,76]
Daidzein Soy foods Tamoxifen Improvement of drug activity to reduce tumour
burden
Female Sprague-Dawley rats with induced
mammary tumours [9,75]
Tangeretin Tangerine and other
citrus peels Tamo xi fen Complete blocking of growth inhibitory effect of
tamoxifen
Female nude mice inoculated with human
MCF-7/6 mammary adenocarcinoma cells [9,68,77]
Influence on side effects of chemotherapy
Ginsenosides Cyclophosphamide
Protection against drug-induced genotoxicity and
apoptosis in bone marrow cells and peripheral
lymphocytes
Mouse peripheral lymphocytes and bone marrow
cells [78,79]
Ginseng
Cisplatin Attenuation of drug-induced nausea and vomiting Rat model [63,80]
Quercetin
Many foods such as
onions, apples,
berries, and tea
Cisplatin Protection of normal renal tubular cells from drug
toxicity Pig kidney tubular epithelial LLC-PK1 cells [71,81]
Influence on drug resistance
Ginsenosides Ginseng Paclitaxel Chemosensitisation Multidrug-resistant breast cancer cells [63,82]
Catechins/theanine
Doxorubicin Inhibition of drug efflux from tumour cells Drug-resistant M5076 ovarian sarcoma
tumour-bearing mice [9,68,70]
Green tea Daunorubicin Increase in drug accumulation in tumour cells Multidrug-resistant P-gp overexpressing human
epidermal carcinoma KB-C2 cells [20,83]
Irinotecan, SN-38 Inhibiting drug transport into biliary elimination
and prolonging half-lives in plasma Male Sprague-Dawley rats [20,84]

6Chemotherapy Research and Practice
Tab le 1: Continued.
Compound Dietary source Chemotherapy drug Effect Biological system Reference
Quercetin
Vincristine Increase in drug uptake in tumour cells Doxorubicin-resistant human myelogenous
leukaemia K562 cells [20,85]
Tamo xi fen Enhancement of drug bioavailability decreasing the
efflux by MDR transporters Female Sprague-Dawley rats [20,86]
Paclitaxel Enhancement of drug bioavailability Male Sprague-Dawley rats [20,87]
Many foods such as
onions, apples,
berries, and tea Doxorubicin Potentiation of antitumour effect reducing P-gp
expression
Multidrug-resistant human breast cancer MCF-7
cells [9,20,72]
Topotecan Chemosensitisation Mouse fibrosarcoma WEHI-S cells [71,88]
Gemcitabine Chemosensitisation Mouse fibrosarcoma WEHI-S cells [71,88]
Genistein Soy foods Paclitaxel Enhancement in systemic exposure of drug Male Sprague-Dawley rats [20,89]

Chemotherapy Research and Practice 7
cytotoxic activity of several drugs and reduce inflammatory
responses [2,42].
Saponins from Chinese ginseng enhance the therapeutic
effect and behave as adaptogens reducing haematopoietic
complications induced by systemic chemotherapy [60,78].
Laboratory experiments have shown that saponins are able to
protect against cyclophosphamide- (CY-) induced genotoxi-
city and apoptosis in bone marrow cells and peripheral lym-
phocytes [78], some ginsenosides are able to sensitise drug-
resistant breast cancer cells to paclitaxel [63], and American
ginseng can attenuate nausea and vomiting induced by cis-
platin while enhancing its antiproliferative effect on human
breast cancer cells [63]. Notoginseng extract can synergisti-
cally increase the antiproliferative effect of 5-fluorouracil (5-
FU) in human colorectal cancer cell line making it possible
to reduce the dose of 5-FU in combination with notoginseng
and thereby further decrease its dose-related toxicity [63].
Polyphenol quercetin is able to potentiate the cytotoxic
effect of cisplatin while protecting normal renal cells from
cisplatin toxicity. Quercetin can work synergistically with
busulfan against human leukaemia cells and with doxoru-
bicin in cultured multidrug-resistant human breast cancer
cells. It increases cytotoxic effect of CY and decreases resist-
ance to gemcitabine, topotecan, vincristine, tamoxifen, pacli-
taxel, and doxorubicin [9,20,68,71,90]. Quercetin stim-
ulates also the activity of macrophages thereby further
improving the chemotherapeutical efficiency [2].
Catechins from green tea can increase the therapeutic
effect of doxorubicin in drug-resistant tumours in animal
studies [68]. Administration of green tea increases the con-
centration of this chemotherapeutic agent in tumour but not
in normal tissue enhancing its antitumour activity [9].
Curcumin can also enhance the tumoricidal efficacy of
cytotoxic chemotherapy [66] and behave as adaptogen [60].
However, administration of soy isoflavones has led to
contradictory results emphasising the necessity to maintain
caution in excessive consumption of dietary agents and sup-
plements during treatment with chemotherapy. While genis-
tein can potentiate the action of tamoxifen to inhibit the
tumour cell growth in oestrogen receptor-negative human
breast cancer cells, this isoflavone can attenuate the tumorici-
dal activity of tamoxifen in oestrogen-dependent breast car-
cinoma cells (see Tabl e 1). Also, as a combination of daidzein
with tamoxifen produces increased protection against mam-
mary carcinogenesis [9,75], supplementation of genistein
can negate the inhibitory effect of tamoxifen on tumour
burden [75]. The therapeutic effect of tamoxifen can be fully
blocked also by flavonoid tangeretin [9,68] and until the
interactions between flavonoids and tamoxifen will be more
clear, therapeutic doses of flavonoid compounds should be
avoided in nutritional supporting programs of breast cancer
patients treated with tamoxifen [9].
Several naturally occurring plant agents like flavonoids
can enhance the drug bioavailability by inhibiting ATP
transporters-mediated drug efflux in vitro, suggesting that
such interactions could occur also in vivo [20]. It is rec-
ommended therefore that diet of cancer patients treated
with chemotherapy should be rich in herbal constituents
(including quercetin, kaempferol, naringenin, silymarin, cat-
echins), fruits and berries (e.g., grapefruit, orange, apricot,
strawberry), and spices (mint, rosemary, curcumin, garlic,
ginseng, piper nigrum, onion) [20].
To ensure the removal of toxic waste products, it is
important that phase II detoxification enzymes are stimu-
lated and restored. For this purpose, cancer patients should
increase the intake of isothiocyanates (found in various
cruciferous vegetables, particularly Brussels sprouts and red
cabbage), naringin (in grapefruit), and parsley and spice
their food with curcumin [2]. Detoxification program should
be undertaken to eliminate the potentially mutagenic chemo-
therapeutic agents from organism. Various dietary com-
pounds contribute to induce specific detoxification pathways
whereas such multifunctional inducers include many of the
flavonoid molecules found in various fruits and vegetables
[22]. Increase in activity of phase II enzymes supports the
better detoxification and it can be achieved by substances
abundantly found in red grapes, garlic oil, rosemary, soy,
cabbage, Brussels sprouts, and broccoli [2,22].
7. Role of Vitamins in Chemotherapy
It is becoming more and more clear that vitamins can reduce
the side effects of chemotherapy treatment. Thus, vitamin
Areducesadverseeffects of cyclophosphamide in rats [48]
and its coadministration with methotrexate ameliorates
intestinal damage in studies of mice without any inhibition
of antitumour activity [9,68]. Also folic acid (or vitamin
B9) supplementation during chemotherapy may lead to
reduction of toxicity [2]; however, it should not be added
to methotrexate treatment, as this anticancer drug is a folic
acid inhibitor [9]. Oncologists should therefore advise their
patients who undergo chemotherapy with antifolate drugs
(such as methotrexate) not to take folate supplements or
consume folate-rich food in excess. A folate status of the
patient may influence the response to methotrexate and can
possibly support cancer growth [91].
Vitamin C reduces the adverse effects of some chem-
otherapeutic agents on normal cells, such as those from dox-
orubicin. This vitamin can lower tamoxifen-induced hyper-
lipidemia in women with breast cancer and has been shown
to reduce bleomycin-induced chromosomal breakage in
human lymphoid cells in vitro [48]. In experiments carried
out with mice and guinea pigs, vitamin C led to a reduction
in cardiotoxicity of doxorubicin without any reduce in anti-
tumour efficacy [9].
Animal studies carried out mainly with rats and rabbits
have shown the ability of vitamin E to reduce bleomycin-
induced lung fibrosis, doxorubicin-induced cardiac toxicity,
and doxorubicin-induced skin necrosis. It lowers also doxo-
rubicin-induced toxicity in liver, kidney, and intestinal
mucosa. Coadministration of vitamin E and vitamin C can
reduce the tamoxifen-induced hyperlipidemia in women
with breast cancer [48]. The most effective form of vitamin E
is α-tocopheryl succinate that can be used as an adjunct to
standard cancer therapies in order to improve their efficacy

8Chemotherapy Research and Practice
on tumour cells while protecting normal cells against some
of their toxicities [92,93].
Vitamin K3 can act synergistically when combined with
several conventional chemotherapeutic agents [94]. How-
ever, it is important to keep in mind that while this vitamin is
able to induce cell cycle arrest at the G2/M phase, it is useful
as an enhancer of G2 phase-dependent chemotherapeutic
drug etoposide, whereas reduces the cytotoxic activity of S-
phase-dependent agent irinotecan [95].
Last but not least, vitamin-like compound coenzyme
Q10 has also been shown to ameliorate the side effects
of chemotherapies [96]. It helped to prevent doxorubicin-
associated cardiotoxicity in a small human study whereas the
diarrhoea and stomatitis were also significantly reduced. This
compound can lower also daunorubicin-induced adverse
events in leukaemia patients without any reduce in the
therapeutic benefit [9,68].
These data demonstrate the potential of dietary agents to
reduce the symptoms of adverse side effects of chemotherapy
treatment and relieve the situation of patients, improving
their quality of life. Therefore, nutritional support pro-
gramme built upon the personal necessities and clinical pur-
poses is an absolutely important part of treatment scheme for
all cancer patients.
8. Potential Problems
Prescribing Phytochemical
Agents to Chemotherapy Patients
Despite a huge amount of studies published about the ben-
efits of nutrient supplementation in chemotherapy there are
still a lot of sceptics and opponents among both physicians as
well as patients. On the one hand, this can be due to the lack
of knowledge; on the other hand, spread of misconceptions
and false beliefs also play an important role.
It is estimate that roughly 50% of cancer patients use
some kind of dietary supplements [50,97]. Many standard
chemotherapeutic agents mediate their cytotoxic effects by
generating excessive amounts of free radicals [5,6,48,97]
and a long-standing concern with the use of phytochemical
antioxidants has been comprised of their potential theoret-
ical intervention to the effectiveness of chemotherapy [5,6,
9,68]. It might be expected that antioxidants, quenching
the reactive oxygen species, can protect tumour cells as
well as healthy cells from oxidative damage generated by
chemotherapeutic drugs [5,97–99]. This could lead to
reduction in effectiveness of cytotoxic therapy and many
oncologists are of the opinion that taking antioxidants
concurrently with chemotherapeutic drugs might be harmful
[5,48,59,97,99,100]. However, studies involving thousands
of patients have demonstrated that antioxidants and other
herbal nutrients do not interfere with chemotherapy, but
instead provide a wide range of beneficial effects [5,101].
Antioxidants can protect normal tissues from chemotherapy-
induced damage without decreasing oncological efficacy [5,
9,98]. These nutrients reduce the treatment-related side
effects and lower the risk and severity of comorbidities
[5,6,9,59,98,101,102] and improve the quality of life
and overall survival of cancer patients [9,59,101]. Some of
antioxidants may enhance the effects of cytotoxic regimens
improving the response rate of tumour to chemotherapeutic
agents [9,59,98,101,102].
Currently, a number of scientists hold the position that
antioxidants do not interfere with chemotherapy and at
commonly used dosages they enhance the success of the
treatment. Except for some specific interactions (including
flavonoids with tamoxifen) [5,9], the weight of the literature
supports the use of antioxidants during the treatment and
also in maintenance phase [59]. It is better to consume com-
binations of food-based antioxidants rather than synthetic
single compounds (vitamins) [59], whereas the form of a
particular antioxidant as well as dosages and dose schedules
are also important [103]. Physicians need to remain aware
of the large body of evidence showing beneficial effects of
antioxidants on the outcomes of chemotherapy treatment [9]
and apply this knowledge in their everyday clinical practice.
9. Conclusions and Further Perspectives
Developing the rational strategies for fighting the cancer
requires first a clear understanding of the causes and path-
ogenesis of the disease [104]. This comprises a multidimen-
sional approach of the studies at genomic, proteomic, and
metabolomic level considering both the individual vari-
ances as well as interindividual differences. Harnessing the
mutations that cancer cells need to promote their patho-
logical survival and expansion will be the basis of further
therapeutic strategies [19,44]. In the future, each patient
should have his own unique chemotherapy protocol, which
improves the therapeutic quality by selecting and prescribing
well-matched drugs and avoiding ineffective ones [21].
Applying such individualised chemotherapeutics through a
personalised chronotherapy regime will further improve the
final outcome [2,36]. This will be accompanied by the iden-
tification and testing of novel more specific and selective
drugs either via synthetic routes or by purifying from herbal
sources [39].
Although the novel chemotherapeutic agents will be
more and more effective against the tumour cells, their tox-
icity to normal tissues as well as drug resistance remains the
major obstacles for clinical use. Personalised approach using
various phytochemical compounds provides a new dimen-
sion to the standard cancer therapy for improving its out-
come in a complex and complementary way.
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