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Food and Chemical Toxicology 48 (2010) 14251438

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Food and Chemical Toxicology


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Review

New advances in molecular mechanisms and the prevention of adriamycin toxicity 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, Spain Department of Physiology, Institute of Nutrition and Food Technology Jos Mataix Verd, University of Granada, Granada, Spain Department of Pathology, Complejo Hospitalario de Jan, Jan, Spain d Department of Oncology, Complejo Hospitalario de Jan, Jan, Spain
b c

a r t i c l e

i n f o

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 ndings regarding the molecular mechanisms of doxorubicin toxicity; (2) to update our understanding of the role of natural antioxidants in preventive therapy against doxorubicin-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, avonoids, 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 radicals and other parameters. 2010 Elsevier Ltd. All rights reserved.

Article history: Received 30 October 2009 Accepted 6 April 2010

Keywords: Doxorubicin Antioxidants Toxicity Chemoprevention

Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adriamycin: molecular mechanisms and toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. DNA damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Mechanisms related to free radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Other mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Natural antioxidants: advances in the prevention of adriamycin toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Carotenoids and vitamin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Coenzyme Q. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Flavonoids, polyphenols, and other natural antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Antioxidant compounds from virgin olive oil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1426 1426 1426 1428 1428 1429 1429 1431 1431 1431 1432 1433 1434

3.

Abbreviations: AP-1, activator protein-1; Ca2+, calcium; CBR1, carbonyl reductase 1; CDK, cyclin dependent kinase; 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: mramiez@ugr.es (MCarmen Ramirez-Tortosa). 0278-6915/$ - see front matter 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.fct.2010.04.007

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Summary and conclusions . Conflict of Interest . . . . . . . . Acknowledgements . . . . . . References . . . . . . . . . . . . .

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1. Introduction Chemotherapy is based on the systemic use of drugs with cytotoxic 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 candidates 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 cycle arrest and could induce apoptosis, as occurs with avonoids. Phase nonspecic 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 inuence DNA, microtubules, and those with effects at the molecular level. On the basis of the mode of action, these agents can be classied into: (a) DNAdrug direct interaction (forming DNA covalent adducts) or alkylating agents (cyclophosphamide, cysplatin, etc.); (b) anti-neoplastic antibiotics and topoisomerase poisons (actinomycin D or anthracyclines like doxorubicin, daunorubicin or epirubicin); (c) antimetabolites or DNA function indirect effectors (5-uorouracil, metotrexate, etc.); (d) mitotic spindle inhibitors or anti-mitotic agents (vincristine, vinblastine, or taxanes like paclitaxel, docetaxel, etc.); (e) agents targeting 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 tumours, 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 containing anthracyclines, and their efciency is greater when tamoxifen is administered after chemotherapy (Early Breast Cancer Trialists Collaborative Group, 2005). Taking into account the above, this review focuses on adriamycin toxicity, molecular mechanisms and preventive therapy, aiming to identify the role of certain antioxidants in preventing the toxic 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 synthesised. 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 lymphomas (Minotti et al., 2004; Quiles et al., 2006). Anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) are the most effective anti-neoplastic family in current clinical practice. Specically, DOX is a key chemotherapeutic drug

for cancer treatment, although its use is limited by the chronic and acute toxic side effects it produces (Quiles et al., 2006). Acute side effects related to intravenous injection of DOX appear within minutes 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 cardiomyopathy and congestive heart failure; moreover, persistent changes of cognitive function (memory and concentration loss and difculty 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, increased glutamate oxalacetic transaminase, lactate dehydrogenase, and creatinine phosphokinase enzyme activities have been noted. At the ultrastructural level, myobril loss, mitochondrial swelling, cytoplasmatic vacuolization, and an increased number of lysosomes 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 tumour necrosis factor (TNF)-a, which can cross this barrier, reaching and activating glial cells to initiate the local production of TNFa and raise its circulating levels. This TNFa induces the local generation of reactive nitrogen species (RNS) through nitric oxide synthase induction, and therefore intensies 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 intercalating into the DNA strand; moreover, it inhibits TOP2. This enzyme modies DNA topology without altering the structure and sequence 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 transcriptional activity (Quiles et al., 2002, 2006). To provoke this DNA injury, DOX must cross into the cancer cell cytoplasm by simple 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 to TOP2, stabilizing an intermediate reaction in which the DNA strands are cut and covalently linked to tyrosine residues of TOP2, creating a ternary complex DOXDNATOP2 that disturbs the DNA structure and impedes its synthesis (Minotti et al., 2004).

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

DOX is known to be most effective when cells are rapidly proliferating and expressing high levels of TOP2. Nevertheless, after treatment 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 downregulation of TOP2 provoked by DOX is due to the repressive effect of the transcriptional activator Sp3, while the transcriptional activator Sp1 is reduced during the cell cycle arrest (Williams et al., 2007). It is widely accepted that DNA damage is an early important event that takes place in doxorubicin-induced cardiac myocyte death, where the activation and accumulation of p53 and mitochondrial 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 p53 activation; in fact, this activation leads to apoptosis depending on the tumour and competent p53 status. In this case, procient and decient cells suffer similar rates of damage, because p53 decient cells have more TOP2 (expressed in the S phase of the cell cycle), and so there are more DNA intercalations. While present in p53 procient cells, this tumour suppressor blocks the ligase capacity of TOP2 and augments the irreversible breakage of DNA strands. Such genetic disturbances, together with the activation of 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 as JNK), the degradation of Akt by serine 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 recently been discovered that DOX-promoted DNA damage triggers the accumulation of p53 protein in cardiomyocytes through the prior 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 rapamycin) activity, an independent effect of cardiomyocyte apoptosis in transgenic mice (Zhu et al., 2009). Further information is available on the DOX-induced apoptosis in cardiomyocytes, since we are now aware of the functional link between extracellular signal-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-modulation of the anti-apoptotic heme oxygenase-1 by DOX was re-

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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 malondialdehyde production, which reacts with exocyclic amino groups of deoxyguanosine, deoxyadenosine and deoxycytidine to form alkylated 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 products that block DNA replication and augment the reading error frequency 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 separating the DNA strands and interfering with its unwinding, but this effect 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 involved with DOX action, regarding both anti-tumour and toxic effects. There are four different modes of free radical production by adriamycin: (1) Production of semiquinone: DOX is transformed into a semiquinone free radical through electron reduction by various NAD(P)H-dependent reductases in the complex I of the electron 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 mitochondrial 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 peroxynitritedependent cardiotoxicity of DOX (Bai et al., 2004). (3) Non-enzymatic mechanism: DOX interferes with non-enzymatic 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. Subsequently, 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 cytoplasmic aconitase, disturbing the iron metabolism and, therefore, causing oxidative stress. On the other hand, it can be metabolised into a lipophilic aglycone capable of dif-

fusing through the mitochondrial membrane and accumulating 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 myocytes. 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 membranes, 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 induced by DOX can cause an exchange of mitochondrial and microsomal cholesterol with exogenous pools (Huertas et al., 1992). The mitochondria contain a phospholipid, cardiolipin, in their inner membrane, and DOX has a high afnity 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). Berthiaume and Wallace (2007b) reported a gene expression prole 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 pathways 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 important target of this chemotherapeutic drug, which induces ROS production 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 the adenine 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 addition 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+) metabolism. 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-dependent protein kinase II mRNA. This is correlated with cardiac function depletion, the reduced expression of sarcomeric proteins, and greater tissue injury (Little et al., 2009). The use of adenosine A3 agonists restores Ca2+ homeostasis and prevents mitochondrial

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damage that can occur as a result of Ca2+ overload being able to reverse the cardiac toxicity (Emanuelov et al., 2009). Another possible mechanism of DOX toxicity is related to alterations 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 cardiodepressive 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 increases in matrix MMP-2 and MMP-9 gene expression in the cardiac cells of mice. Overall, DOX-induced cardiotoxicity has been attributed to several events that are probably linked to elevated ROS and risk of oxidative injury. Such effects include mitochondrial dysfunction, disruption of the sarcoplasmic reticulum function, the direct inhibition 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 opening and oxidative stress, predisposing brain cells to degeneration and death.

antioxidant compounds on the toxicity induced by DOX are summarised in Table 1. 3.1. Vitamin E Vitamin E has a high antioxidant capacity and plays a fundamental biologic role, especially in protecting cells and tissues from oxidative damage, and membrane lipid and lipoprotein peroxidation (Quiles et al., 2002, 2006). In general, preclinical studies in rodents have shown that oral vitamin E tends to increase antitumour 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 of hypoxia inducible factor-1alpha in Nox-1 overexpressing 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 benecial agent, vitamin E has been found to lengthen the life span of laboratory animals and to diminish the weight loss provoked by chemotherapy. 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 doxorubicin-induced acute cardiotoxicity in rats, Puri et al. (2005) pretreated 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, adriamycin 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 with a-tocopherol, but it cannot prevent the mitochondrial dysfunction caused by chemotherapeutics (Berthiaume et al., 2005). It seems that the dosage and treatment schedule of vitamin E are important if it is to exert a preventive role. Thus, Bjelogrlic et al. (2005) found no inhibition of DOX-induced acute cardiotoxicity in mice after a single 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 survival rates of the rats (Santos et al., 2007). At high doses (>90 mg/kg), vitamin E also reduces lipid peroxidation and chromosomal aberrations, the best results being obtained with a dose of 100 mg/kg per body weight in rat bone marrow cells. It has also been reported that this antioxidant alleviates DOX-induced nephrotoxicity and has positive effects against skin ulcerations by weakening ulcer aggressiveness and accelerating skin regeneration. In sharp contrast, clinical studies suggest that vitamin E does not protect against chronic cardiotoxicity induced by DOX, and provides only slight protection against acute cardiotoxicity (Conklin, 2000; Quiles et al., 2002, 2006). Little evidence has been published in the last ve years on the preventive role of vitamin E against DOX-induced nephrotoxicity. It has been reported that the intraperitoneal administration of combined vitamin 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, prevents 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 surprising study reported that vitamin E (1 lg/ml) could make embryonic

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 difcult one because even doses of doxorubicin lower than a cumulative dosage of 450550 mg/m2, through continuous infusion, can elevate 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 oxidative component connected with the toxic and anti-neoplastic actions, and thus protecting from the side effects but reducing the efcacy of the drug. Nevertheless, a growing number of authors believe that drugs such as anthracyclines can exert an effect by additional forms of oxidative stress. Therefore, these antioxidants would not diminish the efcacy of DOX, but rather they would prevent some of its toxic side effects. Such claims need to be claried, 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, carotenoids, vitamin A, coenzyme Q, avonoids, antioxidant components of virgin olive oil, and selenium. The antagonistic effects of these

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Table 1 Effects of antioxidants on toxicity induced by DOX. Compound Vitamin E Decreases Effects against the action of DOX Organs protected against DOX toxicity Heart Liver Kidney Skin Effects over chemo-resistance Increased Therapeutic efcacy of DOX Affected?

ROS Lipid peroxidation Chromosomal aberrations Skin ulcerations Serum markers of toxicity Prevents ECG changes Skin regeneration HIF-1a P-gp

Increases

Vitamin C Decreases Increases

ROS Lipid peroxidation P-gp

Heart (weak) Liver (weak)

Increased

Not affected or decreased?

Carotenoids: b-carotene, lycopene Decreases ROS Lipid peroxidation Normalizes the histopathology, and the serum and tissue markers of toxicity Vitamin A Decreases

Heart Kidney

unknown

Increased (b-carotene)

ROS Lipid peroxidation Chromosomal aberrations

Heart Kidney Liver Bone marrow Brain

unknown

Not affected

Coenzyme Q Decreases

ROS Lipid peroxidation Protects the MTC

Heart

unknown

Not affected

Flavonoids: monoHER, catechines, quercetin, ginestein Iron chelators Decreases ROS Lipid oxidation Apoptosis of myocytes Efux pumps Increases Garlic Decreases Accumulation of DOX inside the cells

Heart Liver

Reduced

Increased

ROS Myocardial TNFa P-gp Polyphenols: curcumin, resveratrol Decreases ROS Lipid oxidation Protection of membranes Efux pumps Increases Accumulation of DOX inside the cells Antioxidant enzymes

Heart

Reduced

Increased

Heart Liver Kidney

Reduced

Increased

Oleuropein from olive oil Decreases ROS Lipid and protein oxidation Serum markers of toxicity Vacuolisation in myocytes Restores the distressed energy metabolic pathways Selenium Decreases Increases

Heart

unknown

unknown

ROS Antioxidant enzymes

Heart Liver (weak) Kidney (weak)

unknown

Increased

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

kidney cells more sensitive to genotoxic insults from doxorubicin by preventing the p53 unfolded isoform. The authors speculated that 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 that intraperitoneal vitamin E (100 mg/kg/day) for eight days inhibits

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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 significantly 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 the effects 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 oncology. To this end, 2 ml of vitamin E (800 mg of DL-a-tocopheryl acetate diluted with corn oil) was orally administered 24 h after doxorubicin administration, once daily for 2 weeks. The results obtained 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 mitigating 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-induced 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 antioxidant 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 demonstrated a cardioprotective effect by vitamin C combined with vitamin E, mainly administered by oral supplementation. Preclinical 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-neoplastic action of adriamycin. However, it can lengthen the life span of laboratory animals and reduce the toxic effects of DOX. This controversy 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 protective activity of other compounds against the toxic effects of DOX. These kinds of studies still nd 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 cardiomyocytes (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). Although Wattanapitayakul et al. (2005) reported that ascorbic acid registers modest activity in protection against doxorubicin-induced cytotoxicity by screening several herbal antioxidants in H9c2 cardiomyocytes, 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) signicantly reduced the therapeutic efcacy of several anti-neoplastic drugs (doxorubicin, 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 retention 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 nal concentration of 10 mmol/l) can decrease the accumulation of adriamycin in human ovarian carcinoma cells 3AO exposed to

ultrasounds (Yu et al., 2003). Wartenberg et al. (2005) reported that ascorbic acid raised the expression of P-gp, a multidrug resistance transporter, in Nox-1 overexpressing prostate tumour cells. 3.3. Carotenoids and vitamin A Carotenoids such as b-carotene can reduce the lipid peroxidation associated with DOX and augment the anti-tumour effect of this 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 adriamycin-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-bcarotene (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 antioxidant capacity of this tissue. This suggests DOX has an antioxidant more than a pro-oxidant effect (Ferreira et al., 2007b). The protection 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 results show that the lycopene group had higher levels of malondialdehyde and lower levels of glutathione, with normalized catalase activity in heart and kidney tissues. This group also presented normalized levels of plasmatic creatinine and urea, and a normal histopathology 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 intraperitoneal injection (15 mg/kg) of DOX. Lycopene prevented the increase of serum creatine kinase and ameliorated cardiac cell injury (Karimi et al., 2005). The benets derived from lycopene have also been studied at other levels. Thus, it has been reported that pretreatment with intraperitoneal lycopene (4 mg/kg) signicantly restored malondialdehyde and lowered glutathione levels, and also reversed the histopathology in rats treated with DOX (10 mg/kg) (Ates sahin et al., 2006). A review of this question has shown that vitamin A (retinol and some retinol metabolites) also signicantly 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, 15 lg/kg being the most effective dose, whereas 30 lg/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 avoproteins and cytochromes, being an essential component in extramitochondrial redox chains. Its concentration in blood and tissues depends on biologic requirements, endogenous biosynthesis, and of course the dietary intake (Quiles et al., 2002). Due to the high presence of CoQ in the mitochondria, its concentration reects the cellular content of mitochondria among different tissues, being greater in the heart than in the liver (vefold more), kidney, pancreas, spleen (10-fold more), and skeletal muscle (5% more) (Conklin, 2005). Adriamycin induces cardiotoxicity by lipid peroxidation in cardiac myocytes, reduces the content of CoQ10 in mitochondrial

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membranes, and inhibits the 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 CoQ10 and CoQ9, respectively, were sharply decreased by the oxidative stress generated by DOX (Huertas et al., 1991a). Thus, preclinical studies have shown that both supplementation and treatment with CoQ10 prior to DOX administration decreases lipid oxidation and heart toxicity without interfering with the anti-tumour activity of DOX. Clinical studies have also shown oral CoQ10 to have a protective effect against the chronic cardiotoxicity induced by adriamycin (Conklin, 2005; Quiles et al., 2006). Bryant et al. (2007) reviewed the evidence on the clinical and costeffectiveness of cardioprotection against anthracycline-induced toxic effects, and found just one study reporting the cardioprotective effect of CoQ10 (100 mg by oral administration twice daily) on paediatric patients affected by acute lymphoblastic leukaemia or nonHodgkins lymphoma, treated with 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 cardioprotection through a novel mechanism, involving cardiac restoration by the expression of cytochrome c oxidase subunits II and Va, together with the electron paramagnetic resonance signal, thus supporting the idea that mitoquinone ameliorates DOX-induced cardiotoxicity (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 cardiotoxicity associated with DOX (Quiles et al., 2002). This protective effect of avonoids 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 involves two steps: (1) iron is chelated by the avonoid; (2) ROS production is quickly scavenged by avonoids at the place of generation; such a concept has been termed site-specic scavenging (Kaiserov et al., 2007). The semisynthetic avonoid 7-monohydroxyethylrutoside (monoHER) has been extensively studied as a good cardioprotective compound, both in preclinical (intraperitoneally 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 avonoid inhibits negative cardiac effects in a dose-dependent manner, in accordance with the essential properties of all avonoids, i.e. their iron chelating and antioxidant characteristics. MonoHER reduces lipid peroxidation, the production of superoxide anion radical, ferricytochrome c reduction, and oxygen consumption by DOX; it also protects against the negative ionotropic effects of DOX (Bast et al., 2007a; Quiles et al., 2002) and guards against inammation by preventing the DOX-mediated overexpression of VCAM and E-selectin in neutrophils (Abou El Hassan et al., 2003c). Recent ndings show that the anti-inammatory action of monoHER is related to the reduction of N-e-(carboxymethyl)-lysine, the accumulation of which is promoted by DOX during cardiotoxicity (Bruynzeel et al., 2007a). This dose-dependent 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 apoptosis in neonatal rat cardiac myocytes, as well as in human endothelial cells, and the ovarian cancer cell lines A2780 and OVCAR3, 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 avonoids, such as catechins, have cardioprotective properties at low doses, exhibiting an iron chelating activity. These catechins also have benecial properties for the liver, and Kalender et al. (2005) reported that catechin (200 mg/kg/week for 6 weeks by intraperitoneal injection) depressed malondialdehyde, glutathione peroxidase and catalase activities in rats against doxorubicin-induced hepatotoxicity. Two fundamental biochemical mechanisms of avonoids 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 intracellular 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 concentration in tumours by inhibiting its efux (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 DOXassociated 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 gallate and quercetin may increase the activity of the P-450 reductase during doxorubicin therapy implying an increased risk of toxicity while resveratrol has no signicant effect. Quercetin, in addition to its high antioxidant capacity, can inhibit 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 concentration of adriamycin inside chemotherapy resistant cancer cells, by blocking efux pump proteins such as the P-gp and ABCG2 proteins (Eckford and Sharom, 2009). Moreover, quercetin enormously improves 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 hypoxia inducible factor-1alpha in both tumour and normal cells (Du et al., 2009). It has been reported that quercetin protects rat heart microsomes and mitochondria against iron-dependent doxorubicin-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, signicantly inhibiting the formation of doxorubicinol in human liver cytosolic fractions. Oral garlic supplementation decreases the oxidative stress provoked by chronic administration of DOX, and protects against free radicals, improving the clinical efcacy 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 adriamycin-induced cardiotoxicity and decreases myocardial TNFa expression (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 of P-gp in human K562 leukaemia cells and in the rodent liver (Arora et al., 2004). Other compounds, such as genistein, a soy isoavone with high antioxidant capacity, can increase cellular antioxidant status by scavenging ROS and augmenting the activity of antioxidant enzymes like glutathione peroxidase, glutathione reductase or

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superoxide dismutase. Genistein is also an inhibitor of TOP2, inhibiting the binding of ATP to its binding site on the enzyme (Conklin, 2000); furthermore, it is a competitive inhibitor of tyrosine kinases, 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-specic clastogen (Lynch et al., 2003). Finally, this isoavone can enhance the accumulation of doxorubicin in cancer cells, and makes MDA-MB-231 cells more sensitive to doxorubicin, probably via increased GRP78 (glucose-regulated protein 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 polyunsaturated 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), thioredoxin, nuclear factor (erythroid-derived 2)-like 2, heme oxygenase-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 glutathione S-transferase, 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 nephrotoxicity 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 report showed that curcumin, administered as an oral turmeric extract 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 cholesterol, lactate dehydrogenase and creatine kinase (Mohamad et al., 2009). Curcumin can also fortify the anti-tumour action of DOX by several mechanisms, one of which consists in raising the intracellular concentration of this chemotherapeutic agent. This mechanism is the result of curcumin being a potent modulator of efux pump ABCG2 protein (Chearwae et al., 2006) as well as P-gp (Angelini et al., 2008) probably because of the inhibition of the PI3K/Akt/ NF-jB pathway (Choi et al., 2008). Curcumin also sensitizes glioma cells to DOX, among others, by inhibiting the AP-1 (activator protein-1) and NF-jB transcription factors (Dhandapani et al., 2007). Resveratrol, a non-avonoid polyphenolic compound, is a powerful antioxidant found predominantly in peanuts, grapes, cranberries, turmeric, hops, mulberries, etc., with anti-cancer (neuroblastoma, lymphoblastic leukaemia, multiple myeloma, breast, colorectal and prostate cancer), anti-inammatory and antioxidant properties (Udenigwe et al., 2008), although it can exhibit a prooxidant 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 inammation by targeting tumour suppressors (p53 and Rb), cell cycle mediators (cyclins, CDKs or CDK inhibitors), transcription factors (NF-jB, AP-1, or c-Jun), or regulators of the apoptotic and survival 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 subsequent treatment with doxorubicin in H9c2 cardiomyocytes protects 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 resveratrol against DOX-promoted cardiac toxicity has also been studied in

neonatal rat ventricular myocytes, in which it increases cell viability; 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 the protective 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 (Alcendor et al., 2007). More recently, it has been discovered that intraperitoneal 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 countries, 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; Trichopoulou 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 benecial, two studies were performed in our laboratory using dietary olive oil lacking the antioxidant fraction but supplemented with vitamin E (Quiles et al., 1999a,b). The results obtained show that supplementation 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 hydrolysis and yields oleuropein aglycone, elenolic acid and several simple phenols (such as hydroxytyrosol), which build up the well-known complex 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 formation of intramolecular hydrogen bonds. This antioxidative property 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 hydroxytyrosol can efciently scavenge free radicals and inhibit LDL oxidation in vitro (Owen et al., 2000; Visioli et al., 2002). In addition to their 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 oleuropein could also prevent or slow down the progression of type II diabetes (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 integrase inhibitors, interacting with the protein envelope gp41 (Lee-Huang et al., 2007a,b). Oleuropein also interacts with b-amyloid peptide, and is a putative inhibitor of the formation of the neurotoxic b-amyloid peptide assembly associated with Alzheimers disease. Therefore, oleuropein might protably be used against this disease (Benaki et al., 2009). Furthermore, it inhibits platelet aggregation (Zbidi et al., 2009), acts as an antiparasitic agent against Toxoplasma gondii (Jiang et al., 2008), and as an anti-inammatory agent (Giamarellos-Bourboulis et al., 2006; Miles et al., 2005; Puel et al., 2006). Dietary virgin olive oil, being rich in antioxidants such as phenolic compounds, has been considered an effective protector agent against cancer (colon, breast or skin), ageing, or cardiovascular disease (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 protective properties against cardiovascular disease, protecting low density lipoproteins from oxidation (Visioli and Galli, 1994), enhancing nitric oxide production by macrophages (Visioli et al., 1998), inhibiting endothelial activation (Carluccio et al., 2003) through the

down-regulation of adhesion molecules involved in early atherogenesis (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, starting either 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 signicantly reduced the serum levels of creatine phosphokinase, creatine phosphokinase-MB, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase. 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 nuclear 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 indicates that this antioxidant restores distressed energy metabolic pathways during DOX-associated cardiac toxicity. 3.7. Selenium In addition to the above mentioned antioxidants, micronutrients 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 several 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.

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

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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 inducing apoptosis in human hepatic cancer cells Bel7402, and that the combination of DOX and selenium nanoparticles provides higher inhibition efciencies. The cardioprotective effects of selenium against DOX toxicity were reviewed earlier (Quiles et al., 2002), and it was found that selenium oral supplementation forties the antioxidant defences of cardiac cells and diminishes the heart injury caused by DOX in animals. Recent studies support this idea; thus, Danesi et al. (2006) reported that a moderate dietary supplementation 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 signicantly 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 vitamins (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 produces free radicals. Many natural compounds with antioxidant properties, such as vitamins E, C and A, carotenoids, coenzyme Q, avonoids, polyphenols, virgin olive oil compounds, resveratrol and selenium, have been proposed as promising means of preventing or reducing such toxic effects, without decreasing the anti-tumour action of adriamycin. Since much of the evidence derives from in vitro studies 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 disturbances provoked by adriamycin. Moreover, the anti-tumour action 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 concentration, dosage and treatment schedule of antioxidants, not only as dietary supplements, but also probably to be administered as chemotherapeutic drugs to intensify the anti-tumour action of adriamycin, and at the same time to diminish its toxicity. Conict of Interest The authors declare that there are no conicts of interest. Acknowledgements This study was partly funded by the Excelentsima Diputacin de Jan, the CEAS Foundation (30.C0.244500) and Junta de Andaluca (PI-0210/2007). We thank the Spanish Ministry of Science and Innovation (AP2005-144) and the 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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