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Review

New advances in molecular mechanisms and the prevention of adriamycintoxicity by antioxidant nutrients

Sergio Granados-Principal a, Jos L. Quiles b, Cesar L. Ramirez-Tortosa c, Pedro Sanchez-Rovira d,MCarmen Ramirez-Tortosa a,*

a Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology Jos Mataix Verd, University of Granada, Granada, Spainb Department of Physiology, Institute of Nutrition and Food Technology Jos Mataix Verd, University of Granada, Granada, Spainc Department of Pathology, Complejo Hospitalario de Jan, Jan, Spaind Department of Oncology, Complejo Hospitalario de Jan, Jan, Spain

a r t i c l e i n f o

Article history:

Received 30 October 2009

Accepted 6 April 2010

Keywords:

Doxorubicin

Antioxidants

Toxicity

Chemoprevention

a b s t r a c t

Anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) are currently the most effective

group of anti-neoplastic drugs used in clinical practice. Of these, doxorubicin (also called adriamycin)

is a key chemotherapeutic agent in cancer treatment, although its use is limited as a consequence of

the chronic and acute toxicity associated with this drug. The molecular mechanisms of doxorubicin

account for both the anti-cancer and the toxic side effects. Many antioxidants have been assayed, with

positive or negative results, to prevent the toxicity of doxorubicin. The present review has two main

goals: (1) to report the latest findings regarding the molecular mechanisms of doxorubicin toxicity; (2)

to update our understanding of the role of natural antioxidants in preventive therapy against doxorubi-

cin-induced toxicity. This review provides new evidence for the chemoprevention of doxorubicin toxicity,

making use of natural antioxidants in particular vitamin E, vitamin C, coenzyme Q, carotenoids, vitamin

A, flavonoids, polyphenol, resveratrol, antioxidant from virgin olive oil and selenium and offers new

insights into the molecular mechanisms of doxorubicin toxicity with respect to DNA damage, free radi-

cals and other parameters.2010 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1426

2. Adriamycin: molecular mechanisms and toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1426

2.1. DNA damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1426

2.2. Mechanisms related to free radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1428

2.3. Other mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1428

3. Natural antioxidants: advances in the prevention of adriamycin toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429

3.1. Vitamin E. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429

3.2. Vitamin C. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14313.3. Carotenoids and vitamin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1431

3.4. Coenzyme Q. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1431

3.5. Flavonoids, polyphenols, and other natural antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1432

3.6. Antioxidant compounds from virgin olive oil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1433

3.7. Selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1434

0278-6915/$ - see front matter 2010 Elsevier Ltd. All rights reserved.doi:10.1016/j.fct.2010.04.007

Abbreviations: AP-1, activator protein-1; Ca2+, calcium; CBR1, carbonyl reductase1; CDK, cyclin dependentkinase; CoQ, Coenzyme Q; DOX, doxorubicin; ERK, extracellular

signal-regulated kinase; H2O2, hydrogen peroxide; HO, hydroxyl radical; iNOS, inducible nitric oxide synthase; IU, international units; LDL, low density lipoprotein; MMP,

matrix metalloproteinase; monoHER, 7-monohydroxyethylrutoside; MPT, mitochondrial permeability transition; NF-jB, nuclear factor kappa B; NOX, NAD(P)H oxidase;O2, superoxide radical; ONOO, peroxynitrite; P-gp, P-glycoprotein; RNS, reactive nitrogen species; ROS, reactive oxygen species; TNF, tumour necrosis factor; TOP2,

topoisomerase II.

* Corresponding author. Address: Instituto de Nutricin y Tecnologa de Alimentos Jos Mataix Verd, Universidad de Granada, Centro de Investigacin Biomdica,

Parque Tecnolgico de Ciencias de la Salud, Avenida del Conocimiento s/n, 18071 Granada, Spain. Tel.: +34 958241000x20316; fax: +34 958819132.

E-mail address: [email protected](MCarmen Ramirez-Tortosa).

Food and Chemical Toxicology 48 (2010) 14251438

Contents lists available at ScienceDirect

Food and Chemical Toxicology

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / f o o d c h e m t o x


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4. Summary and conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1435

Conflict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1435

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1435

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1435

1. Introduction

Chemotherapy is based on the systemic use of drugs with cyto-

toxic activity against cells presenting high proliferation rates, in

the hope of slowing or halting the progression of the primary or

distal tumour (metastasis). The main problem posed by these

drugs is that they target not only the tumour, but also other cells,

thus causing the same damage to both abnormal and normal cells.

Therefore, they are normally only used for treating patients who

fail to respond to other measures or who are not suitable candi-

dates for surgery or primary radiotherapy (Sausville and Longo,

2009).

The cell cycle has been targeted for many years, using various

approaches, such as CDK inhibitors. These inhibitors trigger cell cy-

cle arrest and could induce apoptosis, as occurs with flavonoids.Phase nonspecific agents such as anthracyclines can damage DNA

at any phase but especially at the G2/M phase, before cell division

(Sausville and Longo, 2009).

Chemotherapeutic agents can be grouped into three general

categories: those that influence DNA, microtubules, and those with

effects at the molecular level. On the basis of the mode of action,

these agents can be classified into: (a) DNAdrug direct interaction

(forming DNA covalent adducts) or alkylating agents (cyclophos-

phamide, cysplatin, etc.); (b) anti-neoplastic antibiotics and

topoisomerase poisons (actinomycin D or anthracyclines like doxo-

rubicin, daunorubicin or epirubicin); (c) antimetabolites or DNA

function indirect effectors (5-fluorouracil, metotrexate, etc.); (d)

mitotic spindle inhibitors or anti-mitotic agents (vincristine, vin-

blastine, or taxanes like paclitaxel, docetaxel, etc.); (e) agents tar-geting molecules (bexarotene, which selectively activates retinoid

receptors, or lapatinib, which inhibits HER2 and EGFR) (Li et al.,

2008; Sausville and Longo, 2009).

In contrast to other types of epithelial origin malignant tu-

mours, some cancers, such as breast cancer, respond to various

chemotherapeutic substances, such as anthracyclines, taxanes,

antimetabolites and alkylating agents (Sausville and Longo,

2009). The most effective chemotherapy regimens are those con-

taining anthracyclines, and their efficiency is greater when tamox-

ifen is administered after chemotherapy (Early Breast Cancer

Trialists Collaborative Group, 2005).

Taking into account the above, this review focuses on adriamy-

cin toxicity, molecular mechanisms and preventive therapy, aim-

ing to identify the role of certain antioxidants in preventing thetoxic side effects of this drug.

2. Adriamycin: molecular mechanisms and toxicity

Adriamycin, also called doxorubicin (DOX), is an antibiotic

anthracycline that was isolated from a pigment of Streptomyces

peacetius in the early 1960s but which is now chemically synthes-

ised. Having been employed for more than 30 years in the battle

against cancer, DOX is essential in treating breast and oesophageal

carcinomas, solid tumours in childhood, osteosarcomas, Kaposis

sarcoma, soft tissue sarcomas, and Hodgkin and non-Hodgkin lym-

phomas (Minotti et al., 2004; Quiles et al., 2006).

Anthracyclines (doxorubicin, daunorubicin, epirubicin, and ida-

rubicin) are the most effective anti-neoplastic family in currentclinical practice. Specifically, DOX is a key chemotherapeutic drug

for cancer treatment, although its use is limited by the chronic andacute toxic side effects it produces (Quiles et al., 2006). Acute side

effects related to intravenous injection of DOX appear within min-

utes after infusion, including nausea, vomiting, myelosuppression

and arrhythmia. On the other hand, chronic effects may develop

several weeks or even months after the recurrent administration

of the drug, provoking heart, liver, brain or kidney injury. Since

cardiomyocytes, as well as neurons, are post-mitotic cells, the vast

majority of the damage is irreversible, and unalterably affects

cardiac and brain functions. Furthermore, heart repercussions are

even more prevalent because of this organs greater sensitivity to

damage induced by free radicals, given the high oxidative

metabolism of the heart and its lower level of antioxidant defences.

Adriamycin-related cardiotoxicity may cause dose-dependent car-

diomyopathy and congestive heart failure; moreover, persistentchanges of cognitive function (memory and concentration loss

and difficulty of performing multiple tasks) may occur (Chen

et al., 2007; Quiles et al., 2006).

Dosage-dependent chronic cardiomyopathy associated with

DOX administration generates marked hypotension, tachycardia,

cardiac dilatation and ventricular failure. At the serum level, in-

creased glutamate oxalacetic transaminase, lactate dehydrogenase,

and creatinine phosphokinase enzyme activities have been noted.

At the ultrastructural level, myofibril loss, mitochondrial swelling,

cytoplasmatic vacuolization, and an increased number of lyso-

somes have been reported (Bertinchant et al., 2003; Quiles et al.,

2002). Toxicity associated with DOX therapy in the brain is due

to the indirect action of the drug, because it is not able to cross

the bloodbrain barrier. DOX raises circulating levels of tumournecrosis factor (TNF)-a, which can cross this barrier, reachingand activating glial cells to initiate the local production of TNFaand raise its circulating levels. This TNFa induces the local gener-ation of reactive nitrogen species (RNS) through nitric oxide syn-

thase induction, and therefore intensifies the oxidative stress

responsible for brain injury (Chen et al., 2007).

Molecular mechanisms of DOX account for both its anti-cancer

and its toxic effects (in the heart, brain, kidney, etc.). DOX acts at

two fundamental levels: altering DNA and producing free radicals;

in this respect, too, other mechanisms have been studied ( Fig. 1).

2.1. DNA damage

Anthracyclines, such as DOX, are known as topoisomerase II(TOP2) poisons. DOX can block the synthesis of DNA by intercalat-

ing into the DNA strand; moreover, it inhibits TOP2. This enzyme

modifies DNA topology without altering the structure and se-

quence of deoxynucleotides, causing transient double strand DNA

breaks and then modulating DNA supercoiling. Thus, a suitable

state of DNA is achieved for different cell cycle phases and tran-

scriptional activity (Quiles et al., 2002, 2006). To provoke this

DNA injury, DOX must cross into the cancer cell cytoplasm by sim-

ple diffusion and become bound to the 20S proteosomal subunit,

forming a complex that translocates into the nucleus, where the

complex is dissociated and DOX binds to DNA. Moreover, DOX is

able to bind toTOP2, stabilizing an intermediate reaction in which

the DNA strands are cut and covalently linked to tyrosine residues

ofTOP2, creating a ternary complex DOXDNATOP2 that disturbsthe DNA structure and impedes its synthesis (Minotti et al., 2004).

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DOX is known to be most effective when cells are rapidly prolifer-

ating and expressing high levels ofTOP2. Nevertheless, after treat-

ment with adriamycin, TOP2 undergoes down-regulation. It has

been postulated that such down-regulation may be a major cause

of subsequent chemo-resistance. It is now known that this down-

regulation ofTOP2provoked by DOX is due to the repressive effect

of the transcriptional activator Sp3, while the transcriptional acti-

vator Sp1 is reduced during the cell cycle arrest (Williams et al.,

2007).

It is widely accepted that DNA damage is an early importantevent that takes place in doxorubicin-induced cardiac myocyte

death, where the activation and accumulation of p53 and mito-

chondrial dysfunction are prominent mediators (LEcuyer et al.,

2006). In addition, DOX-mediated p53 activation reportedly leads

to apoptosis (Quiles et al., 2002). It is possible that this effect on

DNA may be related to signalling events of growth arrest and

p53activation; in fact, this activation leads to apoptosis depending

on the tumour and competent p53 status. In this case, proficient

and deficient cells suffer similar rates of damage, becausep53defi-

cient cells have more TOP2 (expressed in the S phase of the cell cy-

cle), and so there are more DNA intercalations. While present in

p53 proficient cells, this tumour suppressor blocks the ligase

capacity of TOP2 and augments the irreversible breakage of DNA

strands. Such genetic disturbances, together with the activationof tumour suppressor p53, and other additional mechanisms, are

responsible for the apoptosis induced by adriamycin. Among those

additional mechanisms, DOX can trigger apoptosis by producing

ceramide (which prompts apoptosis by activating p53 or other

downstream pathways such asJNK), the degradation of Akt by ser-

ine threonine proteases, the mitochondrial release of cytochrome c,

increased FasL (death receptor Fas/CD95 ligand) mRNA production

(Minotti et al., 2004; Ozben, 2007; Quiles et al., 2002, 2006), and a

greater production of free radicals (Chen et al., 2007). It has re-

cently been discovered that DOX-promoted DNA damage triggers

the accumulation of p53 protein in cardiomyocytes through theprior induction of the ATM kinase (Yoshida et al., 2009). The latter

authors also reported p53-dependent cardiomyocyte apoptosis

during chronic cardiotoxicity in p53 heterozygous knockout mice

(Yoshida et al., 2009). Acute DOX-led cardiotoxicity is mediated

by the inhibitory effect of p53 on mTOR (mammalian target of rap-

amycin) activity, an independent effect of cardiomyocyte apoptosis

in transgenic mice (Zhu et al., 2009). Further information is avail-

able on the DOX-induced apoptosis in cardiomyocytes, since we

are now aware of the functional link between extracellular sig-

nal-regulated kinases (ERKs) and p53. This signalling pathway is

closely associated with a lower expression of Bcl-2, increases in

Bax, the activation of caspase-3, poly(ADP-ribose) polymerase

cleavage, and a collapse of mitochondria membrane potential

leading to cardiac cell apoptosis (Liu et al., 2008). The down-mod-ulation of the anti-apoptotic heme oxygenase-1 by DOX was re-

Fig. 1. Molecular mechanisms of doxorubicin toxicity. The main events are: (1) DNA damage, (2) production of free radicals and (3) other mechanisms.

S. Granados-Principal et al./ Food and Chemical Toxicology 48 (2010) 14251438 1427


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cently considered as a ROS-independent cardiomyocyte apoptosis

triggered by exposure to low doses of the drug (Bernuzzi et al.,

2009).

The generation of DNA adducts is another genotoxic mechanism

of DOX, and free radicals originated by DOX are deeply involved.

These radicals promote lipid peroxidation and therefore malondi-

aldehyde production, which reacts with exocyclic amino groups

of deoxyguanosine, deoxyadenosine and deoxycytidine to formalkylated adducts. Furthermore, several types of oxidative injury

in nitrogen bases such as 4,6-diamino-5-formamido-pyrimidine

(FapyAde) or 5-(hydroxymethyl)uracil (5-OH-MeUra) have been

demonstrated. These oxidative adducts are highly mutagenic prod-

ucts that block DNA replication and augment the reading error fre-

quency by DNA polymerase. Moreover, DOX can produce

complexes with formaldehyde through NAD(P)H oxydoreductase

systems and transition metals. Such complexes form covalent links

with DNA and, depending on the intercalation region, can also form

more or less stable intercalations or more stable DNA cross links

(Minotti et al., 2004). A consequence that is probably related to

these cross links is the impossibility of helicase enzymes separat-

ing the DNA strands and interfering with its unwinding, but this ef-

fect might also be due to the direct action of DOX on helicases

(Minotti et al., 2004; Quiles et al., 2002, 2006).

2.2. Mechanisms related to free radicals

The production of free radicals and oxidative stress is closely in-

volved with DOX action, regarding both anti-tumour and toxic ef-

fects. There are four different modes of free radical production by

adriamycin:

(1) Production of semiquinone: DOX is transformed into a semi-

quinone free radical through electron reduction by various

NAD(P)H-dependent reductases in the complex I of the elec-

tron transport chain (cytochrome P-450 reductase). This

semiquinone reacts with molecular oxygen to produce the

superoxide radical (O2

) and it converts DOX into quinone.This quinonesemiquinone cycle generates large amounts of

O2, which subsequently give rise to ROS and RNS species

such as hydrogen peroxide (H2O2), hydroxyl radical (HO)

or peroxynitrite (ONOO) (Chen et al., 2007; Quiles et al.,

2006).

(2) Activation of NAD(P)H oxidases (NOXs): DOX activates NOXs,

which give rise to free radicals that participate in activating

the apoptotic pathway in cardiac cells (Gilleron et al., 2009).

NOX activation may generate ONOO through the mitochon-

drial production of ROS as O2 and the reaction with nitric

oxide (Kimura et al., 2005). ONOO also activates matrix

metalloproteinases (MMPs); these proteases have been

implicated as a major mechanism of the peroxynitrite-

dependent cardiotoxicity of DOX (Bai et al., 2004).(3) Non-enzymatic mechanism: DOX interferes with non-enzy-

matic metabolic reactions in which iron is involved, and

leads to ROS production. Thus, the DOX semiquinone, O2,

and H2O2, can promote the release of iron from ferritin and

cytoplasmic aconitase, thus altering iron metabolism. Subse-

quently, iron can react with DOX and subsequently produce

HO (Chen et al., 2007; Minotti et al., 2004).

(4) Products from the metabolism of DOX: this metabolism leads

to ROS production. On the one hand, the side chain carbonyl

group of the carbon 13 in DOX is converted into a hydroxyl

group by aldoketo reductases, giving rise to a secondary

alcohol (doxorubicinol), which can release iron from cyto-

plasmic aconitase, disturbing the iron metabolism and,

therefore, causing oxidative stress. On the other hand, itcan be metabolised into a lipophilic aglycone capable of dif-

fusing through the mitochondrial membrane and accumu-

lating within it. This aglycone is the starting point for

several reactions that release electrons, producing ROS and

disturbing the functional integrity of the respiratory chain

(Chen et al., 2007).

All the oxidative mechanisms described above are triggered by

DOX to induce cancer cell death and toxic effects in cardiac myo-cytes. Moreover, it is important to take into account that the heart

is very rich in mitochondria. DOX has the ability to modify the

chemical composition, structure and function of biological mem-

branes, mainly at the mitochondrial level, fundamentally due to

the peroxidation generated by DOX (Huertas et al., 1991a,b,

1992). It has been reported that phospholipid peroxidation in-

duced by DOX can cause an exchange of mitochondrial and micro-

somal cholesterol with exogenous pools (Huertas et al., 1992). The

mitochondria contain a phospholipid, cardiolipin, in their inner

membrane, and DOX has a high affinity for this cardiolipin, which

results in the accumulation of adriamycin inside cardiac cells

(Quiles et al., 2002, 2006). This effect may be enhanced by a highly

unsaturated diet, producing a cardiolipin that is very rich in highly

peroxidisable unsaturated fatty acids (Huertas et al., 1991b).Ber-

thiaume and Wallace (2007b) reported a gene expression profile

in the heart of male rats treated with 6 weekly injections of

2 mg/kg DOX followed by a 5-week drug free period. Several path-

ways are closely related to mitochondria, including glycolysis and

fatty acid metabolism, which supports the hypothesis that these

organelles are key targets in DOX toxicity. The same authors

(Berthiaume and Wallace, 2007a) also reviewed the importance

of the mitochondrion in DOX cardiotoxicity, this being an impor-

tant target of this chemotherapeutic drug, which induces ROS pro-

duction due to the adriamycin redox cycling at complex I of the

electron transport chain. This oxidative damage can impair both

short and long term mitochondrial functioning, causing reduced

energy production, oxidation of the mitochondrial DNA and loss

of mitochondrial membrane potential by generating mitochondrial

permeability transition (MPT) pores. It has been suggested that theadenine nucleotide translocator may be the principal component

of those MPT pores, and the concentration of this protein has been

shown to diminish after DOX administration, thus aggravating

mitochondrial dysfunction (Oliveira and Wallace, 2006). In addi-

tion to these events, a decrease in other mitochondrial components

such as coenzyme Q (CoQ) has been reported, as a consequence of

the oxidative stress associated with the administration of DOX

(Huertas et al., 1991a).

2.3. Other mechanisms

Treatment with DOX also causes various disturbances related to

cardiotoxicity, as occurs with alterations in calcium (Ca2+) metab-olism. Such alterations include an increase in intracellular Ca2+,

accumulating in the ventricular myocardium, and even in the

mitochondria, producing transport anomalies in cardiac tissue

and in the Ca2+ release function of the sarcoplasmic reticulum by

affecting the ionic channels (Quiles et al., 2006). Changes in Ca2+

by DOX are also exerted at the muscle response level. It has been

reported that these disturbances in Ca2+ upset the balance in the

response of myotubes and thus disrupt skeletal muscle relaxation

and restrict contraction (van Norren et al., 2009).

The cardiomyopathy created after chronic administration of

DOX displays a down-regulation of the calcium/calmodulin-depen-

dent protein kinase II mRNA. This is correlated with cardiac func-

tion depletion, the reduced expression of sarcomeric proteins,

and greater tissue injury (Little et al., 2009). The use of adenosineA3agonists restores Ca

2+ homeostasis and prevents mitochondrial



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damage that can occur as a result of Ca2+ overload being able to re-

verse the cardiac toxicity (Emanuelov et al., 2009).

Another possible mechanism of DOX toxicity is related to alter-

ations in the metabolism of prostaglandins (Quiles et al., 2006).

The endocannabinoid system has recently been reported to

have a putative role in DOX-induced cardiotoxicity, since the use

of cannabinoid-1-receptor antagonists can reverse the cardiode-

pressive effects of endocannabinoids (Mukhopadhyay et al.,2007). As stated above, MMPs are involved in the mechanism of

the peroxynitrite-dependent cardiotoxicity of DOX (Bai et al.,

2004). Mukhopadhyay et al. (2009) recently demonstrated in-

creases in matrix MMP-2 and MMP-9 gene expression in the cardiac

cells of mice.

Overall, DOX-induced cardiotoxicity has been attributed to sev-

eral events that are probably linked to elevated ROS and risk of oxi-

dative injury. Such effects include mitochondrial dysfunction,

disruption of the sarcoplasmic reticulum function, the direct inhi-

bition of key transporters involved in ion homeostasis, apoptotic

cell loss, and alterations in cellular iron and calcium metabolism

(Berthiaume and Wallace, 2007a). At the brain level, Cardoso

et al. (2008) have reported with respect to experiments on rats that

DOX treatment (2 mg/kg) increases the susceptibility of brain

mitochondria to Ca2+-induced permeability transition pore open-

ing and oxidative stress, predisposing brain cells to degeneration

and death.

3. Natural antioxidants: advances in the prevention of

adriamycin toxicity

This therapy consists in the use of substances or strategies to

protect against or prevent the toxic effects of adriamycin. There

are several ways to achieve this, for example by optimising the

dosage pattern (Chen et al., 2007). Nonetheless, the goal is a diffi-

cult one because even doses of doxorubicin lower than a cumula-

tive dosage of 450550 mg/m2, through continuous infusion, canelevate the risk of cardiotoxicity (Verma et al., 2008). Another

strategy to reduce cardiac toxicity involves the synthesis and use

of DOX analogues with equivalent activity but less toxicity. All

these procedures are intended to reduce levels of DOX-induced

free radicals. In this sense, dexrazoxane is able to chelate the free

iron ions released by DOX, thereby diminishing reactions involving

adriamycin and iron to produce ROS (Chen et al., 2007; Della Torre

et al., 1999a,b; Minotti et al., 2004; Xiang et al., 2009).

Because of their clinical and social relevance, we focus on the

use of various compounds derived from the human diet that have

been demonstrated to protect against adriamycin toxicity, mainly

through their high antioxidant capacity. There is some controversy

surrounding the use of antioxidants either combined with DOX or

previously administered, to prevent the toxic effects of adriamycin.It has been postulated that different antioxidant compounds can

diminish the anti-tumour activity of DOX, by eliminating the oxi-

dative component connected with the toxic and anti-neoplastic ac-

tions, and thus protecting from the side effects but reducing the

efficacy of the drug. Nevertheless, a growing number of authors be-

lieve that drugs such as anthracyclines can exert an effect by addi-

tional forms of oxidative stress. Therefore, these antioxidants

would not diminish the efficacy of DOX, but rather they would pre-

vent some of its toxic side effects. Such claims need to be clarified,

because there are antioxidant compounds that act in synergy with

DOX activity and also weaken its toxicity (Ozben, 2007).

The present review is exclusively focused on the antioxidants

that are derived from the diet, such as vitamin E, vitamin C, carote-

noids, vitamin A, coenzyme Q, flavonoids, antioxidant componentsof virgin olive oil, and selenium. The antagonistic effects of these

antioxidant compounds on the toxicity induced by DOX are sum-

marised inTable 1.

3.1. Vitamin E

Vitamin E has a high antioxidant capacity and plays a funda-

mental biologic role, especially in protecting cells and tissues from

oxidative damage, and membrane lipid and lipoprotein peroxida-tion (Quiles et al., 2002, 2006). In general, preclinical studies in ro-

dents have shown that oral vitamin E tends to increase anti-

tumour actions and protects against the toxic effects of DOX

(Quiles et al., 2006); nevertheless, it has been reported that both

vitamins E and C can increase the expression of P-glycoprotein

(P-gp) and ofhypoxia inducible factor-1alpha in Nox-1overexpress-

ing prostate tumour cells (Wartenberg et al., 2005). Therefore,

these vitamins might fortify resistance to chemotherapy, although

this proposal needs to be more extensively studied. As a beneficial

agent, vitamin E has been found to lengthen the life span of labo-

ratory animals and to diminish the weight loss provoked by che-

motherapy. Moreover, this antioxidant can protect from both

acute and chronic cardiotoxicity caused by DOX, and it increases

antioxidant capacity in the heart (Quiles et al., 2006). With the

aim of testing the cardioprotective effect of vitamin E in doxorubi-

cin-induced acute cardiotoxicity in rats, Puri et al. (2005) pre-

treated them with a high dose of vitamin E intraperitoneally

followed by DOX. The results show that vitamin E pre-treatment

prevents the electrocardiographic changes caused by doxorubicin;

moreover, it helps to lower the levels of creatine phosphokinase

and lactate dehydrogenase raised by DOX. As seen above, adriamy-

cin can provoke mitochondrial permeability transition pores, thus

causing a loss of mitochondrial membrane potential (Berthiaume

and Wallace, 2007a). In this sense, it has been reported that dietary

vitamin E decreases doxorubicin-induced oxidative stress in rats

and enriches cardiac mitochondrial membranes witha-tocopherol,but it cannot prevent the mitochondrial dysfunction caused by

chemotherapeutics (Berthiaume et al., 2005). It seems that the dos-

age and treatment schedule of vitamin E are important if it is to ex-ert a preventive role. Thus, Bjelogrlic et al. (2005) found no

inhibition of DOX-induced acute cardiotoxicity in mice after a sin-

gle dose of oral vitamin E (100 IU/kg). On the other hand, chronic

supplementation with vitamins E and C (400 IU/kg/day and

250 mg/kg/day, respectively) for 30 days in rats reversed the

changes in alanine aminotransferase, lactate dehydrogenase, urea

and creatinine caused by DOX administration, enhancing the sur-

vival rates of the rats (Santos et al., 2007).

At high doses (>90 mg/kg), vitamin E also reduces lipid peroxi-

dation and chromosomal aberrations, the best results being ob-

tained with a dose of 100 mg/kg per body weight in rat bone

marrow cells. It has also been reported that this antioxidant allevi-

ates DOX-induced nephrotoxicity and has positive effects against

skin ulcerations by weakening ulcer aggressiveness and accelerat-ing skin regeneration. In sharp contrast, clinical studies suggest

that vitamin E does not protect against chronic cardiotoxicity in-

duced by DOX, and provides only slight protection against acute

cardiotoxicity (Conklin, 2000; Quiles et al., 2002, 2006). Little evi-

dence has been published in the last five years on the preventive

role of vitamin E against DOX-induced nephrotoxicity. It has been

reported that the intraperitoneal administration of combined vita-

min E and N-acetyl-cysteine (50 mg/kg) 1 day before doxorubicin

counteracts the damage caused by DOX in the rat kidney. Such

combined preventive therapy depresses lipid peroxidation, pre-

vents necrosis caused by DOX, and maintains the activities of the

enzymes superoxide dismutase, catalase, glutathione peroxidase,

glutathione reductase, glucose-6-phosphate dehydrogenase and

glutathione-S-transferase (Kalaiselvi et al., 2005). A surprisingstudy reported that vitamin E (1lg/ml) could make embryonic



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kidney cells more sensitive to genotoxic insults from doxorubicin

by preventing the p53 unfolded isoform. The authors speculatedthat this effect could result from vitamin E reversing the ROS pro-

duction induced by pre-treatment with b-amyloid peptide (Uberti

et al., 2007). In terms of the liver, a study using rats showed thatintraperitoneal vitamin E (100 mg/kg/day) for eight days inhibits

Table 1

Effects of antioxidants on toxicity induced by DOX.

Compound Effects against the action of DOX Organs protected

against DOX toxicity

Effects over

chemo-resistance

Therapeutic

efficacy of DOX

Vitamin E

Decreases ROS Heart Increased Affected?

Lipid peroxidation Liver

Chromosomal aberrations Kidney

Skin ulcerations SkinSerum markers of toxicity

Prevents ECG changes

Increases Skin regeneration

HIF-1aP-gp

Vitamin C

Decreases ROS Heart (weak) Increased Not affected or decreased?

Lipid peroxidation Liver (weak)

Increases P-gp

Carotenoids:b-carotene, lycopene

Decreases ROS Heart unknown Increased (b-carotene)

Lipid peroxidation Kidney

Normalizes the histopathology, and the serum

and tissue markers of toxicity

Vitamin A

Decreases ROS Heart unknown Not affected

Lipid peroxidation Kidney

Chromosomal aberrations Liver

Bone marrow

Brain

Coenzyme Q

Decreases ROS Heart unknown Not affected

Lipid peroxidation

Protects the MTC

Flavonoids: monoHER, catechines, quercetin, ginestein

Iron chelators Heart Reduced Increased

Decreases ROS Liver

Lipid oxidation

Apoptosis of myocytesEfflux pumps

Increases Accumulation of DOX inside the cells

Garlic

Decreases ROS Heart Reduced Increased

Myocardial TNFaP-gp

Polyphenols: curcumin, resveratrol

Decreases ROS Heart Reduced Increased

Lipid oxidation Liver

Protection of membranes Kidney

Efflux pumps

Increases Accumulation of DOX inside the cells

Antioxidant enzymes

Oleuropein from olive oil

Decreases ROS Heart unknown unknown

Lipid and protein oxidation

Serum markers of toxicity

Vacuolisation in myocytes

Restores the distressed energy metabolic

pathways

Selenium

Decreases ROS Heart unknown Increased

Liver (weak)

Increases Antioxidant enzymes Kidney (weak)

Abbreviations:DOX: doxorubicin; ECG: electrocardiogram; HIF-1a: hypoxia inducible factor-1alpha; monoHER: 7-monohydroxyethylrutoside; MTC: mitochondrial transportchain;P-gp:P-glycoprotein; ROS: reactive oxygen species; TNFa: tumour necrosis factor alpha.



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the general toxic and hepatotoxic effects of DOX (Gokcimen et al.,

2007). Similar results were previously obtained by other authors,

who reported that both intravenous vitamin E (200 IU/kg/week)

and intraperitoneal catechin (200 mg/kg/week) for 6 weeks signif-

icantly reduced doxorubicin-induced hepatotoxicity in rats, by

decreasing malondialdehyde, glutathione peroxidase and catalase

activities (Kalender et al., 2005).

In this context, the vast majority of studies have focused on theeffects of vitamin E against DOX-induced cardiotoxicity, although

several have examined other toxic effects. Thus, topical vitamin E

was tested against DOX-induced oral mucositis in paediatric oncol-

ogy. To this end, 2 ml of vitamin E (800 mg ofDL-a-tocopheryl ace-tate diluted with corn oil) was orally administered 24 h after

doxorubicin administration, once daily for 2 weeks. The results ob-

tained show that topical vitamin E does not reduce mucositis in

children receiving doxorubicin as chemotherapy, and the authors

concluded that it should not be used in the clinical context for this

purpose (Sung et al., 2007).Branda et al. (2006)found no mitigat-

ing effect on DOX-induced leucopoenia by dietary vitamin E, either

at low (50 mg/kg) or high (750 mg/kg) doses in rats. Such lack of

effect of vitamin E did not occur with other chemotherapeutic-in-

duced leucopoenia drugs such as docetaxel or cyclophosphamide,

but in the latter case the effect of dietary vitamin E appears to be

dose-dependent.

3.2. Vitamin C

Vitamin C (ascorbic acid) is an effective water soluble antioxi-

dant against lipid peroxidation, scavenging ROS in the aqueous

fraction before these molecules can give rise to lipid oxidation

(Conklin, 2000). An intervention review by van Dalen et al.

(2008) showed that none of the individual studies carried out dem-

onstrated a cardioprotective effect by vitamin C combined with

vitamin E, mainly administered by oral supplementation. Preclini-

cal studies have provoked some controversy about the effects of

vitamin C on the anti-tumour activity of DOX; nevertheless, the

overall view is that ascorbic acid does not increase the anti-neo-plastic action of adriamycin. However, it can lengthen the life span

of laboratory animals and reduce the toxic effects of DOX. This con-

troversy is probably due to the pro-oxidant effect of vitamin C at

high doses (Conklin, 2000; Quiles et al., 2002, 2006). Despite the

controversy, vitamin C is commonly used to compare the protec-

tive activity of other compounds against the toxic effects of DOX.

These kinds of studies still find vitamin C to be a weak protector

against cardiotoxicity and hepatotoxicity in orally supplemented

rats (100 mg/kg/week for 3 weeks) (Injac et al., 2009), H9c2 cardio-

myocytes (Choi et al., 2007; Chularojmontri et al., 2005; Kim et al.,

2006), cardiac myocytes of adult rats (Wold et al., 2005) and in

myocytes of neonate rats (Yamanaka et al., 2003). AlthoughWatt-

anapitayakul et al. (2005) reported that ascorbic acid registers

modest activity in protection against doxorubicin-induced cyto-toxicity by screening several herbal antioxidants in H9c2 cardio-

myocytes, there are several indications that the use of vitamin C

to prevent the toxic effects of DOX may not be an effective choice.

In this sense, a recently published article on mice with lymphoma

cell-derived xenogeneic tumours shows that ascorbic acid

(250 mg/kg dehydroascorbic acid by tail vein) significantly reduced

the therapeutic efficacy of several anti-neoplastic drugs (doxorubi-

cin, cisplatin, vincristine, methotrexate and imatinib). Vitamin C

caused a dose-dependent decrease in apoptosis in cells treated

with anti-tumour drugs, an effect not caused by vitamin C reten-

tion modulated by chemotherapeutics, the antioxidant activity of

ascorbic acid, or the up-regulation of P-gp (Heaney et al., 2008).

This conclusion is corroborated by the fact that vitamin C (at a final

concentration of 10 mmol/l) can decrease the accumulation ofadriamycin in human ovarian carcinoma cells 3AO exposed to

ultrasounds (Yu et al., 2003). Wartenberg et al. (2005)reported

that ascorbic acid raised the expression ofP-gp, a multidrug resis-

tance transporter, in Nox-1 overexpressing prostate tumour cells.

3.3. Carotenoids and vitamin A

Carotenoids such as b-carotene can reduce the lipid peroxida-

tion associated with DOX and augment the anti-tumour effect ofthis drug (Conklin, 2004). Oral supplementation with lycopene

(5 mg/kg/day for 7 weeks), the carotenoid presenting the most

powerful antioxidant activity, has demonstrated a cardioprotective

effect at the myocyte level in rats treated with DOX (4 mg/kg)

intraperitoneally by weeks 3, 4, 5 and 6, but it fails to prevent adri-

amycin-induced cardiac dysfunction (Anjos Ferreira et al., 2007).

Moreover, it has been reported that a tomato oleoresin supplement

containing lycopene (95%), all-trans-b-carotene (5%), and 13-cis-b-

carotene (1%), reduces cardiomyocyte oxidative DNA damage

caused by doxorubicin in rats (Ferreira et al., 2007a). The same

authors reported that DOX maintains levels of lycopene in the

myocardial tissue of rats, and at the same time it raises the antiox-

idant capacity of this tissue. This suggests DOX has an antioxidant

more than a pro-oxidant effect (Ferreira et al., 2007b). The protec-

tion exerted by lycopene against DOX-induced heart and kidney

damage was studied by Yilmaz et al. (2006). Lycopene (4 mg/kg)

was orally administered for 10 days before DOX injection (10 mg/

kg) (pre-treatment group) and for 2 days before and 3 days after

the administration of adriamycin (post-treatment group). The re-

sults show that the lycopene group had higher levels of malondial-

dehyde and lower levels of glutathione, with normalized catalase

activity in heart and kidney tissues. This group also presented nor-

malized levels of plasmatic creatinine and urea, and a normal his-

topathology in heart and kidney tissues. Similar results were

reported for mice receiving intraperitoneal tomato extract (1.2

and 2.4 g/kg) and lycopene (1.7 and 3.5 mg/kg) and a single intra-

peritoneal injection (15 mg/kg) of DOX. Lycopene prevented the in-

crease of serum creatine kinase and ameliorated cardiac cell injury

(Karimi et al., 2005). The benefits derived from lycopene have alsobeen studied at other levels. Thus, it has been reported that pre-

treatment with intraperitoneal lycopene (4 mg/kg) significantly re-

stored malondialdehyde and lowered glutathione levels, and also

reversed the histopathology in rats treated with DOX (10 mg/kg)

(Atessahin et al., 2006). A review of this question has shown that

vitamin A (retinol and some retinol metabolites) also significantly

reduces this lipid oxidation, providing good results in the heart,

brain membranes, liver microsomes and kidney, but it does not

facilitate the anti-tumour action of adriamycin in mice (3.3 mg/

kg of retinol palmitate by intraperitoneal injection) (Quiles et al.,

2006). Vitamin A also has a protective dose-dependent effect

against the chromosomal aberrations induced by doxorubicin in

rat bone marrow cells, 15lg/kg being the most effective dose,

whereas 30lg/kg was found to be clastogenic (Glka et al., 2004).

3.4. Coenzyme Q

Coenzyme Q (CoQ), or ubiquinone, plays a critical role in the

mitochondrial respiratory chain, acting as a redox link between fla-

voproteins andcytochromes, being an essentialcomponent in extra-

mitochondrial redox chains. Its concentration in blood and tissues

depends on biologic requirements, endogenous biosynthesis, and

ofcourse thedietaryintake(Quiles et al., 2002). Due to thehighpres-

ence of CoQin themitochondria, its concentration reflects thecellu-

larcontent of mitochondriaamong differenttissues, being greater in

the heart than in the liver (fivefold more), kidney, pancreas, spleen

(10-fold more), and skeletal muscle (5% more) (Conklin, 2005).

Adriamycin induces cardiotoxicity by lipid peroxidation in cardiacmyocytes, reduces the content of CoQ10 in mitochondrial



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membranes, and inhibitsthe mitochondrial biosynthesis of CoQ10 as

well as respiratory chain CoQ10-dependent enzymes(Conklin, 2000,

2004). Similar effects have been found in rats where the plasma and

mitochondria levels of CoQ10and CoQ9, respectively, were sharply

decreased by the oxidative stress generated by DOX (Huertas et al.,

1991a). Thus, preclinical studies have shown that both supplemen-

tation and treatment with CoQ10 prior to DOX administration de-

creases lipid oxidation and heart toxicity without interfering withthe anti-tumour activity of DOX. Clinical studies have also shown

oral CoQ10 to have a protective effect against the chronic cardiotox-

icity induced by adriamycin (Conklin, 2005; Quiles et al., 2006).

Bryant et al. (2007)reviewed the evidence on the clinical and cost-

effectiveness of cardioprotection against anthracycline-induced

toxiceffects,and found justone studyreporting the cardioprotective

effect of CoQ10(100 mg by oral administration twice daily) on pae-

diatric patients affected by acute lymphoblastic leukaemia or non-

Hodgkinslymphoma,treatedwith adriamycin (250 mg/m2) (Iarussi

et al., 1994). More recently, it has been shown that intraperitoneal

mitoquinone, a triphenylphosphonium-conjugated analogue of

CoQ, either alone (5 mg/kg) or combined (5 mg/kg, twice a week)

with DOX (2.5 mg/kg per week) for 12 weeks in rats, provides car-

dioprotection through a novel mechanism, involving cardiac resto-

ration by the expression ofcytochrome c oxidase subunits IIandVa,

together withthe electronparamagnetic resonancesignal, thussup-

porting the ideathat mitoquinone amelioratesDOX-inducedcardio-

toxicity (Chandran et al., 2009).

3.5. Flavonoids, polyphenols, and other natural antioxidants

Flavonoids are characterised by high antioxidant power, and

have been considered potential protectors against the chronic car-

diotoxicity associated with DOX (Quiles et al., 2002). This protec-

tive effect of flavonoids is closely related to their antioxidant,

iron chelating (Kaiserov et al., 2007) and carbonyl reductase 1

(CBR1)-inhibitory properties (Carlquist et al., 2008). The proposed

mechanism involving iron chelating and antioxidant activities in-

volves two steps: (1) iron is chelated by the flavonoid; (2) ROS pro-duction is quickly scavenged by flavonoids at the place of

generation; such a concept has been termed site-specific scaveng-

ing (Kaiserov et al., 2007). The semisynthetic flavonoid 7-mono-

hydroxyethylrutoside (monoHER) has been extensively studied as

a good cardioprotective compound, both in preclinical (intraperito-

neally administered in mice) (Abou El Hassan et al., 2003a; Bast

et al., 2007b; Bruynzeel et al., 2007d; De Celle et al., 2004) and in

clinical trials (Bruynzeel et al., 2007c; Willems et al., 2006) after

intravenous injection. This flavonoid inhibits negative cardiac ef-

fects in a dose-dependent manner, in accordance with the essential

properties of all flavonoids, i.e. their iron chelating and antioxidant

characteristics. MonoHER reduces lipid peroxidation, the produc-

tion of superoxide anion radical, ferricytochrome creduction, and

oxygen consumption by DOX; it also protects against the negativeionotropic effects of DOX (Bast et al., 2007a; Quiles et al., 2002) and

guards against inflammation by preventing the DOX-mediated

overexpression ofVCAMand E-selectinin neutrophils (Abou El Has-

san et al., 2003c). Recent findings show that the anti-inflammatory

action of monoHER is related to the reduction of N-e-(carboxy-

methyl)-lysine, the accumulation of which is promoted by DOX

during cardiotoxicity (Bruynzeel et al., 2007a). This dose-depen-

dent cardioprotective effect exerted by monoHER does not affect

the anti-tumour capacity of adriamycin (van Acker et al., 1997),

even without interfering with the pharmacokinetics or metabolism

of DOX (Abou El Hassan et al., 2003b). More recently, it has been

determined that monoHER (1 mM) suppresses DOX-induced apop-

tosis in neonatal rat cardiac myocytes, as well as in human endo-

thelial cells, and the ovarian cancer cell lines A2780 and OVCAR-3, this being a caspase-dependent and -independent effect (Bruyn-

zeel et al., 2007b). Finally, monoHER also inhibits the activity of

CBR1 V88 and CBR1 I88 proteins, encoded by polymorphic CBR1

V88 in a concentration-dependent manner (Gonzalez-Covarrubias

et al., 2008).

Other flavonoids, such as catechins, have cardioprotective prop-

erties at low doses, exhibiting an iron chelating activity. These cat-

echins also have beneficial properties for the liver, and Kalender

et al. (2005)reported that catechin (200 mg/kg/week for 6 weeksby intraperitoneal injection) depressed malondialdehyde,

glutathione peroxidase and catalase activities in rats against doxo-

rubicin-induced hepatotoxicity. Two fundamental biochemical

mechanisms of flavonoids can increase the anti-tumour capacity

of DOX when they are administered jointly: (1) the inhibition of

the intracellular metabolism of the drug; (2) the blocking of intra-

cellular drug eliminating mechanisms. In previous in vitro studies,

it has been shown that green tea polyphenols such as caffeine, and

catechins such as epigallocatechin gallate or epigallocatechin can

enhance DOX-induced anti-tumour activity and increase DOX con-

centration in tumours by inhibiting its efflux (Mei et al., 2004;

Quiles et al., 2002). This reversal effect of the multidrug resistance

of green tea polyphenols, and of ()-epigallocatechin gallate in

particular, has been extensively studied, and it is clear that such

compounds can modulate the function of P-gp (Mei et al., 2004,

2003; Wei et al., 2003; Zhang et al., 2004), an effect that is partially

achieved by the regulation of DOX-induced intracellular ROS (Mei

et al., 2005). With respect to the protective effect against DOX-

associated toxicity, Dudka et al. (2005) tested the action of ()-

epigallocatechin gallate, quercetin and resveratrol on the activity

of NADPH-cytochrome P-450 reductase in the human heart, liver

and lungs. The results show that dietary ()-epigallocatechin gal-

late and quercetin may increase the activity of the P-450 reductase

during doxorubicin therapy implying an increased risk of toxicity

while resveratrol has no significant effect.

Quercetin, in addition to its high antioxidant capacity, can inhi-

bit TOP2 and intercalate into DNA strands, thereby boosting the

anti-tumour effect of DOX (Snyder and Gillies, 2002). Quercetin

also inhibits several protein kinases and increases the concentra-tion of adriamycin inside chemotherapy resistant cancer cells, by

blocking efflux pump proteins such as the P-gp and ABCG2 proteins

(Eckford and Sharom, 2009). Moreover, quercetin enormously im-

proves the therapeutic index of DOX in breast cancer cells and in

mice with breast cancer (100 mg/kg by oral gavage for 3 weeks).

The mechanism seems to be related to its inhibitory effect on hy-

poxia inducible factor-1alphain both tumour and normal cells (Du

et al., 2009). It has been reported that quercetin protects rat heart

microsomes and mitochondria against iron-dependent doxorubi-

cin-induced lipid peroxidation (Psotov et al., 2002, 2004). This

cardioprotective effect has been corroborated by Vclavkov

et al. (2008), who reported that quercetin is a potent inhibitor of

DOX-induced toxicity, significantly inhibiting the formation of

doxorubicinol in human liver cytosolic fractions.Oral garlic supplementation decreases the oxidative stress pro-

voked by chronic administration of DOX, and protects against free

radicals, improving the clinical efficacy of adriamycin (Quiles et al.,

2002). Moreover, chronic garlic administration (250 and 500 mg/

kg daily, orally, for 30 days) has been shown to prevent acute adri-

amycin-induced cardiotoxicity and decreases myocardial TNFaexpression (Mukherjee et al., 2003). The garlic-derived volatile

organosulphur compound diallyl sulphide has been shown to be

a non-toxic, selective and highly potent modulator ofP-gp in hu-

man K562 leukaemia cells and in the rodent liver (Arora et al.,

2004).

Other compounds, such as genistein, a soy isoflavone with high

antioxidant capacity, can increase cellular antioxidant status by

scavenging ROS and augmenting the activity of antioxidantenzymes like glutathione peroxidase, glutathione reductase or



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superoxide dismutase. Genistein is also an inhibitor of TOP2, inhib-

iting the binding of ATP to its binding site on the enzyme (Conklin,

2000); furthermore, it is a competitive inhibitor of tyrosine ki-

nases, inhibiting growth factor b signalling pathways, and also

exerting antiproliferative effects in cells and putative anti-cancer

effects, possibly through the induction of apoptosis. Thus, genistein

can be considered a TOP2-specific clastogen (Lynch et al., 2003). Fi-

nally, this isoflavone can enhance the accumulation of doxorubicinin cancer cells, and makes MDA-MB-231 cells more sensitive to

doxorubicin, probably via increasedGRP78(glucose-regulated pro-

tein 78) expression, while having no effects on MCF-7 cells (Lim

et al., 2006).

Curcumin, the main component of the curry spice turmeric, is a

phenolic compound with a high antioxidant effect at several levels:

it prevents the oxidation of low density lipoprotein (LDL) and poly-

unsaturated fatty acids, and the lipid peroxidation of biological

membranes, and affects intracellular systems closely associated

with oxidative processes, such as nuclear factor kappa B (NF-jB),transcription factor, inducible nitric oxide synthase (iNOS), thiore-

doxin, nuclear factor (erythroid-derived 2)-like 2, heme oxygen-

ase-1, hypoxia inducible factor-1, or heat shock protein 70

(Ramirez-Tortosa et al., 2009; Quiles et al., 1998). Curcumin also

induces several antioxidant enzymes, such as glutathioneS-trans-

ferase, NAD(P)H:quinone oxidoreductase 1, glutathione reductase,

glutathione peroxidase, and catalase (Calabrese et al., 2008; Quiles

et al., 2006). This high antioxidant capacity enables oral curcumin

to play a protective role against adriamycin-induced nephrotoxi-

city and cardiotoxicity (Quiles et al., 2006), by three fundamental

mechanisms: (1) inhibiting lipid peroxidation by scavenging free

radicals; (2) raising glutathione levels; (3) stabilizing cardiac cell

membranes (Wongcharoen and Phrommintikul, 2009). A recent re-

port showed that curcumin, administered as an oral turmeric ex-

tract in rats, ameliorated the harmful effects of adriamycin in the

heart and liver, and also blocked nephrotoxicity. With respect to

plasma, turmeric extract effectively inhibited increases in choles-

terol, lactate dehydrogenase and creatine kinase (Mohamad et al.,

2009). Curcumin can also fortify the anti-tumour action of DOXby several mechanisms, one of which consists in raising the intra-

cellular concentration of this chemotherapeutic agent. This mech-

anism is the result of curcumin being a potent modulator of efflux

pump ABCG2 protein (Chearwae et al., 2006) as well as P-gp (Ange-

lini et al., 2008) probably because of the inhibition of the PI3K/Akt/

NF-jB pathway (Choi et al., 2008). Curcumin also sensitizes gliomacells to DOX, among others, by inhibiting the AP-1 (activator pro-

tein-1) and NF-jB transcription factors (Dhandapani et al., 2007).Resveratrol, a non-flavonoid polyphenolic compound, is a

powerful antioxidant found predominantly in peanuts, grapes,

cranberries, turmeric, hops, mulberries, etc., with anti-cancer (neu-

roblastoma, lymphoblastic leukaemia, multiple myeloma, breast,

colorectal and prostate cancer), anti-inflammatory and antioxidant

properties (Udenigwe et al., 2008), although it can exhibit a pro-oxidant capacity under certain experimental conditions (Athar

et al., 2009). Resveratrol exerts its anti-cancer activity at different

levels, affecting cell growth, angiogenesis, invasion, metastasis and

inflammation by targeting tumour suppressors (p53 andRb), cell

cycle mediators (cyclins, CDKs or CDK inhibitors), transcription

factors (NF-jB, AP-1, or c-Jun), or regulators of the apoptotic andsurvival signalling pathways (Bax, Bak, Noxa, TRAIL, survivin, Akt,

Bcl-2, among others) (Athar et al., 2009). The protective role of this

polyphenolic compound against DOX cardiotoxicity is being

studied. It is known that pre-treatment with resveratrol and subse-

quent treatment with doxorubicin in H9c2 cardiomyocytes pro-

tects against the toxicity generated by DOX and can decrease the

intracellular accumulation of ROS induced by xanthine oxidase/

xanthine (Cao and Li, 2004). This protective effect of resveratrolagainst DOX-promoted cardiac toxicity has also been studied in

neonatal rat ventricular myocytes, in which it increases cell viabil-

ity; in addition, it improves electrocardiogram results in mice

(Rezk et al., 2006).Tatlidede et al. (2009)showed that resveratrol

(10 mg/kg was administered intraperitoneally for a total of

7 weeks), in combination with adriamycin (20 mg/kg), markedly

ameliorates the severity of cardiac dysfunction by preventing the

oxidative stress provoked by DOX toxicity in rats. A possible action

mechanism was reported by Danz et al. (2009), who studied theprotective role of resveratrol against DOX-induced cell death in

primary cardiomyocytes. This elegant study shows that resveratrol

protects against DOX-induced mitochondrial depolarization and

cardiomyocyte death by inhibiting ROS production, probably

through the up-regulation of manganese superoxide antioxidant

activity, together with maintenance of mitochondrial function

and the Sirt1 pathway. Sirt1 is a NAD+-dependent class III histone

deacetylase, the overexpression of which protects the heart from

oxidative stress through the up-regulation of antioxidants (Alcen-

dor et al., 2007). More recently, it has been discovered that intra-

peritoneal resveratrol (10 mg/kg) also reverses the vascular

dysfunction caused by DOX in the rat thoracic aorta. The putative

mechanism of this effect could be related to the overexpression

of eNOS (endothelial nitric oxide synthase) and iNOS (Olukman

et al., 2009). Finally, it is important to mention that, apart from

its protective effect, resveratrol also improves the effectiveness of

adriamycin (Rezk et al., 2006) and encourages sensitization to

apoptosis induced by doxorubicin and other chemotherapeutics

in sensitive and multidrug resistant (P-gp positive) promyelocytic

leukaemia HL60 cells (Duraj et al., 2006).

3.6. Antioxidant compounds from virgin olive oil

In comparison with Northern Europe or other Western coun-

tries, Mediterranean countries register a lower rate of mortality

from cardiovascular disease and cancer, attributed at least partly

to the so-called Mediterranean diet (Knoops et al., 2004; Tricho-

poulou et al., 2003). The healthy effects of olive oil consumption

have traditionally been ascribed to its high oleic acid content.However, there is growing evidence that components of olive oil

other than oleic acid could be related to its healthy properties.

The basis for this hypothesis is the presence of minor bioactive

compounds, fundamentally phenols with a strong antioxidant

capacity, such as hydroxytyrosol and oleuropein (Prez-Jimnez

et al., 2007; Aguilera et al., 2003, 2004), and other antioxidants

such as vitamin E (Quiles et al., 2002).

A previous review has highlighted the importance of olive oil in

counteracting the toxic effects exerted by adriamycin. Thus, virgin

olive oil as dietary fat (8 g/100 g of diet) can reduce the damage

caused by DOX in the mitochondria and in liver microsomes

(Mataix et al., 2006; Quiles et al., 2002). Following the idea that

antioxidant compounds from virgin olive oil are beneficial, two

studies were performed in our laboratory using dietary olive oillacking the antioxidant fraction but supplemented with vitamin E

(Quiles et al., 1999a,b). The results obtained show that supplemen-

tation with this antioxidant, up to the normal levels found in virgin

olive oil, greatly improves the response of this edible oil against

adriamycin toxicity in rats. As stated above, other antioxidants,

too, provide virgin olive oil with major healthy properties, and

oleuropein is currently being studied in this sense.

Oleuropein, a hydrophilic phenolic compound belonging to the

secoiridoid family, is found in high concentrations in olives, olive

oil, and the leaves and small branches of the olive tree (Japn-Lujan

and Luque de Castro, 2007). This secoiridoid is the bitter principle

of olive oil, and during ripening and storage, it undergoes hydroly-

sis and yields oleuropein aglycone, elenolic acid and several simple

phenols (such as hydroxytyrosol), which build up the well-knowncomplex taste of olive oil (Visioli et al., 2006) (Fig. 2). Both oleurop-



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ein and hydroxytyrosol present a catechol group that gives these

phenolic compounds a high antioxidant capacity through the for-

mation of intramolecular hydrogen bonds. This antioxidative prop-

erty is even more potent than that exerted by other antioxidants

such as vitamin E, dimethylsulfoxide (DMSO) and butylated

hydroxytoluene. It has been shown that oleuropein and hydroxyty-

rosol can efficiently scavenge free radicals and inhibit LDL oxida-

tionin vitro

(Owen et al., 2000; Visioli et al., 2002). In addition totheir antioxidant effect, both oleuropein and hydroxytyrosol

(orally administered) have demonstrated an antidiabetic activity,

with a hypoglycaemic effect in alloxan diabetic rats (Jemai et al.,

2009) and rabbits (Al-Azzawie and Alhamdani, 2006), and oleurop-

ein could also prevent or slow down the progression of type II dia-

betes (Rigacci et al., 2009). Both oleuropein and hydroxytyrosol

also inhibit lipid and protein oxidation in human plasma (Roche

et al., 2009), and present antiviral activity against hepatitis B (Zhao

et al., 2009) and viral haemorrhagic septicaemia virus (Micol et al.,

2005). Moreover, they are small molecule HIV-1 fusion and integr-

ase inhibitors, interacting with the protein envelope gp41

(Lee-Huang et al., 2007a,b). Oleuropein also interacts with b-amy-

loid peptide, and is a putative inhibitor of the formation of the

neurotoxic b-amyloid peptide assembly associated with

Alzheimers disease. Therefore, oleuropein might profitably be

used against this disease (Benaki et al., 2009). Furthermore, it

inhibits platelet aggregation (Zbidi et al., 2009), acts as an antipar-

asitic agent againstToxoplasma gondii(Jiang et al., 2008), and as an

anti-inflammatory agent (Giamarellos-Bourboulis et al., 2006;

Miles et al., 2005; Puel et al., 2006).

Dietary virgin olive oil, being rich in antioxidants such as phe-

nolic compounds, has been considered an effective protector agent

against cancer (colon, breast or skin), ageing, or cardiovascular dis-

ease (Owen et al., 2000). As an important component in this edible

oil, oleuropein also exhibits an effect against breast cancer. This

phenolic compound has been studied to test its ability to inhibit

the proliferation of breast cancer cells (Han et al., 2009; Menendez

et al., 2007, 2008, 2009), or human urinary bladder carcinoma or

endothelial cells (Goulas et al., 2009). Oleuropein has protectiveproperties against cardiovascular disease, protecting low density

lipoproteins from oxidation (Visioli and Galli, 1994), enhancing ni-

tric oxide production by macrophages (Visioli et al., 1998), inhibit-

ing endothelial activation (Carluccio et al., 2003) through the

down-regulation of adhesion molecules involved in early athero-

genesis (DellAgli et al., 2006), decreasing lipaemia (Jemai et al.,

2008), and preventing the oxidative myocardial injury induced

by ischemia/reperfusion (Manna et al., 2004).

With respect to the protective properties of oleuropein against

doxorubicin-induced cardiotoxicity,Andreadou et al. (2007) have

shown that this secoiridoid, intraperitoneally administered (100

and 200 mg/kg) for 5 or 3 consecutive days, respectively, startingeither 2 days before or on the day of DOX administration, prevents

the acute cardiotoxicity caused by intraperitoneal DOX (20 mg/kg)

in rats. In this study, oleuropein significantly reduced the serum

levels of creatine phosphokinase, creatine phosphokinase-MB, lac-

tate dehydrogenase, aspartate aminotransferase and alanine ami-

notransferase. Moreover, in heart tissue, it not only decreased the

concentrations of lipid peroxidation products (conjugated dienes

and malondialdehyde), protein carbonyls and nitrotyrosine, and

lowered cytoplasmic vacuolisation in cardiomyocytes, but also

boosted the induction of iNOS.

This cardioprotective effect of oleuropein has been supported in

another, more recent, study with the same experimental protocol

and doses of oleuropein and DOX (Andreadou et al., 2009). A nucle-

ar magnetic resonance-based metabolomic approach was used to

analyse acute DOX-induced cardiotoxicity, and found acetate and

succinate to be novel biomarkers applicable to the disturbance of

metabolic energy pathways. Oleuropein at both doses removed

the succinate and acetate accumulation in heart tissue, which indi-

cates that this antioxidant restores distressed energy metabolic

pathways during DOX-associated cardiac toxicity.

3.7. Selenium

In addition to the above mentioned antioxidants, micronutri-

ents such as selenium also present major biological and

antioxidant properties. Selenium has been widely studied for its

anti-cancer effects and the cardioprotective role played against

DOX toxicity. Concerning the former, it has been reported that

selenium induces apoptosis and decreases DNA synthesis, in sev-eral tumour cell lines (breast, colon, prostate, lung, small intestine

and liver) (Vadgama et al., 2000). It also induces massive apoptosis

in a DOX resistant cell line (derived from human small cell lung

carcinoma) in a caspase-3 independent manner (Jnsson-Videster

Fig. 2. Hydrolysis of oleuropein during olive ripening and storage.



11/14

et al., 2004), sensitizes MCF-7 breast cancer cells to DOX-induced

apoptosis by repressing adriamycin-induced Akt activation

(Li et al., 2007b), and induces the Fas death pathway in cooperation

with DOX in MCF-7 cells (Li et al., 2007a). More recently,Tan et al.

(2009)reported that selenium nanoparticles are capable of induc-

ing apoptosis in human hepatic cancer cells Bel7402, and that the

combination of DOX and selenium nanoparticles provides higher

inhibition efficiencies. The cardioprotective effects of seleniumagainst DOX toxicity were reviewed earlier (Quiles et al., 2002),

and it was found that selenium oral supplementation fortifies the

antioxidant defences of cardiac cells and diminishes the heart in-

jury caused by DOX in animals. Recent studies support this idea;

thus,Danesi et al. (2006)reported that a moderate dietary supple-

mentation of selenium (0.1 mg/kg) increases the total antioxidant

activity and glutathione concentration as well as glutathione

peroxidase and catalase activities in the rat heart. Such increases

in endogenous antioxidants lead to reduced ROS production. In a

mouse model of combined therapy (doxorubicin, vincristine and

prednisolone) the administration of selenium decreased catalase

activity, but did not significantly lower xanthine oxidase activity

(Popovic et al., 2007). Weak protective activity of selenium has also

been reported against the nephrotoxicity (Bulucu et al., 2008) and

hepatotoxicity (Bulucu et al., 2009) induced by DOX in rats.

Finally, a recent study shows that a commercial mixture of vita-

mins (C, E and b-carotene) and minerals (copper, selenium and

zinc) administered to Drosophila melanogaster larvae treated with

DOX, was not genotoxic and it also protected against the genotoxic

effects of chemotherapeutic agents (Costa and Nepomuceno,

2006).

4. Summary and conclusions

Adriamycin is one of the most commonly used and effective

drugs against several types of cancer, including breast carcinoma.

Nonetheless, doxorubicin-associated toxicity is a severe problem

in its use in humans, this toxicity occurring mainly in the heart,

kidney and liver. In addition, it provokes DNA alterations and pro-

duces free radicals. Many natural compounds with antioxidant

properties, such as vitamins E, C and A, carotenoids, coenzyme Q,

flavonoids, polyphenols, virgin olive oil compounds, resveratrol

and selenium, have been proposed as promising means of prevent-

ing or reducing such toxic effects, without decreasing the anti-tu-

mour action of adriamycin. Since much of the evidence derives

from in vitrostudies on cell preparations or from laboratory animal

studies, more clinical studies are needed to test the ability of these

compounds to act as chemopreventive agents or to reverse the dis-

turbances provoked by adriamycin. Moreover, the anti-tumour ac-

tion of natural compounds combined with anthracyclines or other

chemotherapeutic drugs should be studied more thoroughly at the

clinical level. It is necessary to establish the appropriate concentra-

tion, dosage and treatment schedule of antioxidants, not only as

dietary supplements, but also probably to be administered as che-

motherapeutic drugs to intensify the anti-tumour action of adria-

mycin, and at the same time to diminish its toxicity.

Conflict of Interest

The authors declare that there are no conflicts of interest.

Acknowledgements

This study was partlyfunded by theExcelentsima Diputacin de

Jan, the CEAS Foundation (30.C0.244500) and Junta de Andaluca

(PI-0210/2007). We thank the Spanish Ministry of Science and Inno-vation (AP2005-144) andthe University of Granada for the personal

support of Dr. S. Granados-Principal. The authors thank Mr. Glenn

Harding for his extensive editing of the manuscript.

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