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Review ArticleChemotherapy-Induced Cardiotoxicity Overview ofthe Roles of Oxidative Stress

Paweorn Angsutararux Sudjit Luanpitpong and Surapol Issaragrisil

Siriraj Center of Excellence for Stem Cell Research Faculty of Medicine Siriraj Hospital Mahidol University Bangkok 10700 Thailand

Correspondence should be addressed to Sudjit Luanpitpong suidjitgmailcom

Received 18 December 2014 Accepted 17 May 2015

Academic Editor Raj Soorappan

Copyright copy 2015 Paweorn Angsutararux et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Chemotherapy-induced cardiotoxicity is a serious complication that poses a serious threat to life and limits the clinical useof various chemotherapeutic agents particularly the anthracyclines Understanding molecular mechanisms of chemotherapy-induced cardiotoxicity is a key to effective preventive strategies and improved chemotherapy regimen Although no reliable andeffective preventive treatment has become available numerous evidence demonstrates that chemotherapy-induced cardiotoxicityinvolves the generation of reactive oxygen species (ROS) This review provides an overview of the roles of oxidative stress inchemotherapy-induced cardiotoxicity using doxorubicin which is one of the most effective chemotherapeutic agents against awide range of cancers as an example Current understanding in the molecular mechanisms of ROS-mediated cardiotoxicity willbe explored and discussed with emphasis on cardiomyocyte apoptosis leading to cardiomyopathy The review will concludewith perspectives on model development needed to facilitate further progress and understanding on chemotherapy-inducedcardiotoxicity

1 Introduction

Chemotherapy is a common treatment for various cancers asan adjuvant or a primary therapy however it also carries arisk of adverse effects thatmight leave an unfavorable damageto cancer patients Chemotherapy-induced cardiotoxicityis a serious complication that limits the clinical use ofchemotherapeutic agents particularly the anthracyclinessince it could eventually culminate in the development of life-threatening cardiomyopathyUnderstanding themechanismsthat are responsible for cardiotoxicity could help lessen theundesirable impact on normal tissues and improve the cancertreatment regimen One of the most widely accepted mecha-nisms of chemotherapy-induced cardiotoxicity involves thegeneration of oxidative stress This review provides anoverview of the roles of oxidative stress in chemotherapy-induced cardiotoxicity Current understanding in the molec-ular mechanisms of oxidative stress-mediated cardiotoxicityis discussed with emphasis on cellular apoptosis leading tocardiomyopathy

2 Chemotherapy-Induced Cardiotoxicity

The basic principle of chemotherapy is to impair mitoticand metabolic process of cancer cells Unfortunately certainnormal cells and tissues are also affected by the chemother-apy leading to various mild and severe adverse effectsincluding nausea and vomiting bone marrow suppressionand cardiovascular side effects namely hypotension tachy-cardia arrhythmias and heart failure [1] The NationalCancer Institute generally defines toxicity that affects theheart as cardiotoxicity Although cardiotoxicity could beaffected by different chemotherapeutic agents as summarizedin Table 1 certain class of chemotherapy for example theanthracyclines induces more common and frequent adverseeffects These drugs should not be administered to patientswith high risk of developing cardiac complications The riskof cardiotoxicity increases in patients with hypertensiondiabetes mellitus liver disease and previous cardiac diseases[2] The risk of cardiotoxicity also depends largely on routeof administration duration of chemotherapy (cumulative

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2015 Article ID 795602 13 pageshttpdxdoiorg1011552015795602

2 Oxidative Medicine and Cellular Longevity

Table 1 Potential cardiotoxicity induced by numerous chemotherapeutic agents

Class Examples of chemotherapeutic agents Possible cardiotoxicityAnthracyclines andanthraquinones DOX mitoxantrone Congestive heart failure left ventricular

dysfunction acute myocarditis and arrhythmia

Antimetabolite agents Capecitabine 5-fluorouracil andcytarabine

Ischemia pericarditis congestive heart failureand cardiogenic shock

Antimicrotubule agents Paclitaxel vinca alkaloidsSinus bradycardia ventricular tachycardiaatrioventricular block hypotension congestiveheart failure and ischemia

Alkylating agents Cyclophosphamide ifosfamide Neurohumoral activation mild mitralregurgitation

Monoclonal antibody againstHER2 Trastuzumab Arrhythmias congestive heart failure

angioedema and left ventricular dysfunctionAntiangiogenic and tyrosinekinase inhibitors Imatinib sorafenib and sunitinib Hypertension arrhythmias

Antivascular endothelial growthfactor Bevacizumab Hypertension thromboembolism

dose) and the dosage regimen For example a combinationof anthracyclines with other potential cardiotoxic agentsnamely paclitaxel or trastuzumab would greatly enhancethe risk of cardiotoxicity that potentially lead to disastrouscongestive heart failure [3ndash6]

Anthracyclines including doxorubicin (DOX) daunoru-bicin epirubicin and idarubicin are highly effective againstacute lymphoblastic and myeloblastic leukemias DOX inparticular has been found to have a much broader spec-trum which includes numerous solid tumors for examplebreast cancer sarcomas and childhood solid tumors (egWilmsrsquo tumor) in addition to hematologicalmalignancies forexample leukemias Hodgkinrsquos disease and non-Hodgkinrsquoslymphomas [1] Anthracycline-induced cardiotoxicity canoccur in an acute or chronicmannerThe acute cardiotoxicitywithin the course of treatment or immediately afterwardsincluding pericarditis-myocarditis or arrhythmias is nor-mally reversible and generally manageable while the chroniccardiotoxicity which may manifest even decades after thecompletion of treatment is serious and clinically significantsubstantially affecting overall morbidity and mortality andrequiring long-term therapy As DOX is an important com-ponent of current cancer treatment that generates high levelof ROS this review mainly emphasizes on the DOX-inducedcardiotoxicity

21 DOX-Induced Cardiotoxicity The cumulative dose ofadministered DOX is an important factor that dictates itscardiotoxicity it cannot exceed 500mgm2 or else the risk ofcongestive heart failure (CHF) would increase tremendously[7] The chance of developing CHF increases from lt4 atthe cumulative dose of 500ndash550mgm2 to lt18 or 36whenthe cumulative dose of DOX is 551ndash600 or over 600mgm2respectively A retrospective analysis revealed that 30-yearchildhood cancer survivors had a 15-fold higher rate ofheart failure and 10-fold higher rate of other cardiovasculardiseases when compared to estimated values in their siblingsCardiac abnormality can be seen as asymptomatic distur-bances in cardiac rhythms [8] changes in blood pressure

[9] thickening of pericardium [10] cardiac dilation [11] andcardiomyopathy

Histologically areas of patchy and interstitial fibrosis withscattered vacuolated cardiomyocytes can be visualized undermicroscope [11 12] There are also partial loss of myofibrilsand the degeneration of myocyte vacuoles [13] resulting inthe remaining peripheral Z disks without filaments and thelarge membrane-bound space accordingly In the nucleuschromatin disorganization with partial replacement of thechromatin by pale staining fibers and filaments could beobserved [11] Ultimately these changes would lead to car-diomyocyte death Since the turnover rate of cardiomyocytesin the heart is very low approximately 1 at the age of 20and lower in older ages [14] the progressive loss of myocytescannot be reversed Subsequently the heart loses its abilityto function properly These pathophysiological changes canlead to dilated cardiomyopathy cardiac hypertrophy andeventually heart failure

DOX is particularly harmful to the heart due to itsexceptional effects on mitochondria Heart as a pump thatcirculates blood throughout the body requires a great amountof energy and thus contains a large amount of energy pro-ducing mitochondria Generally mitochondria are the sitewhere most of reactive oxygen species (ROS) are produced asa consequence of electrons escaping from electron transportchain and captured by oxygen rendering it to be the homeof superoxide production However DOX can drive theseROS production to another level Enzymes within mitochon-dria including NADPH oxidase (also known as NADPHdehydrogenase) cytochrome P-450 reductase and xanthineoxidase (XO) can transform DOX and other anthracyclinesin the form of quinone to semiquinone via one electronreduction of the quinone moiety in ring C [14ndash17] Thissemiquinone can be readily regenerated back to its parentalquinone by reacting with oxygen generating superoxideanion (O2

∙minus) which could be further changed to other ROSor reactive nitrogen species (RNS) [18 19]This redox cyclingthus aids in amplifying the production of oxidative stressApart from mitochondrial enzymes endothelial nitric oxide

Oxidative Medicine and Cellular Longevity 3

synthase (eNOS) which generates nitric oxide (NO) canalso affect the ROS production by DOX [20] Expression andtranscription of eNOS were found to be increased after theDOX administration [19 21] By binding to eNOSrsquos reductasedomain DOX veers its production towards more O2

∙minus andless nitric oxide (NO)

The nature of cardiac tissue that exhibits low level ofantioxidant enzymes such as superoxide dismutase (SOD)and catalase makes it more susceptible to ROS generationand accumulation of oxidative stress [22] Moreover DOXis known to bind to cardiolipin a major phospholipidcomponent of heart mitochondrial inner membranes withhigh affinity [23ndash25] DOX and its major metabolite doxoru-bicinol (DOXol) are abundantly retained inside cardiac cellsattributable to cardiotoxicity [26 27]

3 Oxidative Stress

Major mechanism of chemotherapy-induced cardiotoxicityinvolves the generation of ROS Elevated ROS that causescellular damages and alteration responses referred to asoxidative stress occurs when the delicate balance of theROS-generating system and antioxidant defense system wastipped in favor of the former Immediate systemic oxidativestress and reduced antioxidant status as demonstrated by thedecrease in glutathione (GSH) and total antioxidant capacityof plasma (TRAP) levels were observed in cancer patientsreceiving DOX treatment [28] To discuss the advances inmolecular mechanisms underlying chemotherapy-inducedcardiotoxicity an overview of biochemistry of ROS andantioxidants has provided

Basically ROS are reactive molecules that contain oxygenatom and are primarily generated either bymetabolic processor by physical irradiation as O2

∙minusThe reaction is catalyzed byNADPH oxidase with electron supplied by NADPH as in thefollowing equations

O2 + eminus997888rarr O2

∙minus

2O2 +NADPH 997888rarr 2O2∙minus+NADP+ +H+

(1)

In mitochondrial electron transport chain O2∙minus is also

generated when an electron is transferred from NADH tooxygen molecule by NADH-ubiquinone oxidoreductase orcomplex I

NADH+H+ + 2O2 997888rarr NAD+ + 2H+ +O2∙minus (2)

O2∙minus then undergoes a dismutation a reaction that is

accelerated by SOD enzyme generating less-reactive speciehydrogen peroxide (H

2O2)

2O2∙minus+ 2H SOD997888rarr H2O2 +O2 (3)

The H2O2-removing enzymes include catalase and glu-

tathione peroxidase (GPx)

H2O2Catalase997888997888997888997888997888997888rarr 2H2O+O2

2GSH+H2O2GPx997888rarr GSSG+ 2H2O

(4)

O2∙minus may react with H

2O2and form the highly reactive

hydroxyl radical (∙OH) by Haber-Weiss reaction

O2∙minus+H2O2 997888rarr OHminus +OH∙ +O

2(5)

Since the Haber-Weiss reaction is kinetically slow transi-tionmetals such as iron and copper often serve as its catalystsThe iron-catalyzed Haber-Weiss reaction is called Fentonreaction

Fe2+ +H2O2 997888rarr Fe3+ +OHminus +OH∙ (6)

Under stress conditions O2∙minus facilitates the release of

free iron from iron-containing molecules for example [4Fe-4S]-containing enzymes leading to the generation of ∙OHfrom Fenton reaction Moreover O2

∙minus can facilitate the ∙OHproduction in the reaction by generating ferrous (Fe(II)) fromthe reduction of ferric (Fe(III))

Fe3+ +O2∙minus997888rarr Fe2+ +O2 (7)

With regard toDOX iron has been implicated in its redoxcycling [29 30] When DOX was reduced to semiquinoneradical it can form a complex of semiquinone and iron-free radical which would spontaneously revert back toDOX while generating O2

∙minus [31] and thus it magnifies thegeneration of DOX-derived ROS However under normalsituation iron is sequestered within the cells by ferritinas polynuclear ferric oxyhydroxide [32] DOXrsquos metaboliteDOXol was shown to remove iron from Fe-S cluster ofcytoplasmic aconitase an enzyme in the Krebs cycle andturn it into cluster-free iron regulatory proteins-1 (IRP-1) [33]Then via redox reaction DOX was regenerated and formedcomplex with Fe(II) blocking the conversion of IRP-1 backto aconitase [34] This IRP-1 then bound to iron-responsiveelements (IREs) in ferritin mRNA inhibiting its translationand resulting in the tremendous release of free iron withinthe cells [35 36]

In addition to its direct effects on DNA RNA proteinsand lipids ROS can also act as secondary signalingmoleculesin various pathways that are involved in homeostasis includ-ing cell proliferation and cell death [37 38] Thus it isimperative to maintain the proper level of ROS in the cellularenvironment In the heart oxidative stress could lead tocellular hypertrophy [39] gene expression alterations [40]cell death activation [41] extracellular matrix (ECM) trans-formation [42] ventricular remodeling [41] and calciumtransient perturbation [43] all of which could result in thepathophysiological changes that lead to cardiomyopathy andheart failure

4 Experimental Models

Similar to other abnormalities the ideal and most relevantdata for human cardiotoxicity should be obtained fromsuffering patients However due to the limitation in obtaininghuman myocardial biopsy or necropsy and the complicationfrom patientsrsquo multidrug regimen the meaningful informa-tion for chemotherapy-induced cardiotoxicity comes mostly


from experimental models The commonly used animalsfor in vivo studies include mouse rat rabbit pig and dogThesewhole animal studies enable repeated administration ofchemotherapeutic agents mimicking chronic cardiotoxicityin clinical practice In addition transgenic animal modelswith certain gene modification could aid tremendously tostudy and model cardiotoxicity For example Hfe-deficientmice with excess iron stores exhibited increased susceptibilitytoDOX-induced cardiotoxicity suggesting the significance ofiron in cardiotoxicity [44] On the other hand the simplestand most straightforward approach is the use of in vitro cellculture models including isolated cardiac myocytes partic-ularly primary neonatal rat cardiomyocytes and less oftenadult cardiomyocytes and cardiomyocyte-derived cell linesfor example H9c2 rat embryonic cardiomyoblasts [45]Thesein vitro models offer the advantages of gene manipulationthat provides insight into the molecular mechanisms highthroughput ease of use and low cost

5 Molecular Mechanisms ofChemotherapy-Induced Cardiotoxicity

Extensive researches have been conducted to examine themolecular mechanisms of cardiotoxicity induced by chemo-therapy particularly DOX and oxidative stress was foundto be the major contributor to various potential causes thatultimately lead to cardiomyopathy and heart failure Wewill summarize the current understanding of ROS in suchphenomena and discuss the alterations of key related genesandor proteins with emphasis on cellular apoptosis leadingto cardiomyopathy

51 Cellular Hypertrophy Cellular hypertrophy is charac-terized by an increase in cell size and volume enhancedprotein synthesis and content and heightened organizationof the sarcomere [46 47] At the molecular level there isan induction of cardiac hypertrophic-associated genes suchas ventricular myosin light chain-2 (MLC-2v) alpha-myosinheavy chain (120572-MHC) and atrial natriuretic peptide (ANP)[48]Major signaling cascades of cardiac hypertrophy includetyrosine kinases (Src and focal adhesion kinase) proteinkinase C (PKC) mitogen activated protein kinases (MAPKERK12 p38 and JNK) calcineurin PI3KAkt and NF-120581Bcoupling to the activation of transcriptional expression ofhypertrophic-associated genes It is now evident that ROS arecapable of directmodulation of these cascades [39 41 49ndash52]Additionally ROS were found to activate apoptosis signal-regulating kinase 1 (ASK-1) which in turn stimulates p38and JNK MAPK as well as NF-120581B pathways [53ndash55] Mertenet al reported that DOX-induced H9c2 cardiac hypertrophyinvolved the activation of PI3KAkt and to a lesser extentcalcineurin [56]The role of oxidative stress in DOX-inducedcardiac hypertrophy was supported by the attenuation ofDOX-induced hypertrophy and cardiotoxicity in transgenicmice containing high level of cardiac metallothionein apotent antioxidant [57]

52 ECM Remodeling Microenvironment is crucial to theproper functions of cardiomyocytes ECM microenviron-ment provides a platform for cardiomyocytes to attach alignand orient thereby facilitating efficient cellular contractionproper force transduction and smooth electrical transmis-sion [58] An alteration in ECM structure or compositionwould transform the healthy functional heart to the defectedone [59ndash61] Matrix metalloproteinases (MMPs) are enzymesthat are responsible for the ECM degradation It has pre-viously been demonstrated that ROS activated MMPs andECM degradation via the activation of activator protein-1 (AP-1) and NF-120581B leading to the impairment of cardiacfunctions [62 63] Animal studies in mouse and rat showedthatMMPs particularlyMMP-2 andMMP-9mediatedDOX-induced cardiotoxicity [64ndash66] DOX increased MMP-2 andMMP-9 activities through the mechanisms that involved theactivation of p38 MAPK and NADPH oxidase respectively[67] Further Nox2 NADPH oxidase was found to be a majorsource of DOX-derived ROS Cardiac remodeling induced byDOX was less pronounced in Nox2-deficient mice (Nox2minusminus)compared to the wild-type controls [68] Additionally DOXinduced nitric oxide (NO) in vitro and in vivo [69 70] whichin the presence of O2

∙minus formed peroxynitrite (ONOOminus)leading to an activation of precursors of MMPs (pro-MMPs)and ECM remodeling

53 Impaired Cardiac Contraction Cardiomyocytes (alsoknown as cardiac muscle cells) are myogenic having aninherent rhythmic contraction and relaxation For the wholeheart to properly pump and propel blood into the circula-tion precise control and synchronization of these cells areimperative Each cardiomyocyte is composed of bundles ofmyofibrils which is a chain of several contractile units calledsarcomeres The sarcomeres contain thick (myosin) and thin(actin) myofilaments that process cardiac contraction In therelaxed state tropomyosin wrapped around actin filamentand covered the myosin-binding site Calcium ion generallyresides within sarcomeric reticulum is a key player formyocyte contraction Once released to cytosol calcium ionsbind to troponin which is associated with tropomyosin andshift tropomyosin position on actin filament exposing themyosin-binding site formyosin head of thick filament to bindto the thin filament and resulting in sarcomere shorteningThat being said what control cardiac contraction are themyofilaments and calcium flux

DOX could affect the transcription and expression ofcardiac specific proteins [11 71 72] GATA4 is a transcrip-tion factor critical for regulation of cardiac differentiationsarcomere synthesis and cell survival GATA4 is expressed inthe cardiomyocytes where it functions to regulate many car-diospecific genes including cardiac adriamycin-responsiveprotein (CARP) DOX-derived ROS downregulated GATA4binding activity leading tomyofibrillar deterioration disrup-tion of sarcomere organization and reduction of contractilefunction [73 74]

DOX has been shown to alter calcium homeostasis [7576] This may be in part due to the change of ion channelflux and the functional defect of membrane ion pump [77]


FLIP Bax

C8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bad

BidDeath receptor

Ligands

Pro-

C8TRA

DD

TRAF2RIP

ASK1

JNK C3 6 7P

Bid

t-Bid

Mcl-1

Bcl-xL

Bcl-2

Extrinsic pathway Intrinsic pathway

NF-120581B

For example FasL TNF-120572

Ψ uarr

Figure 1 Major pathways of apoptosis An extrinsic pathway of apoptosis (left) involves the stimulation through binding of death receptor(eg FasR and TNFR) to their respective ligands (eg FasL and TNF-120572) recruiting adaptive proteins such as Fas-associated death-domain(FADD) and pro-caspase-8 (pro-C8) forming death-inducing signaling complex (DISC) and relaying signals to activation of effector caspasessuch as caspase-3 (C3) C6 and C7 In addition Bid is also activated which transduces these death signals to the intrinsic pathway On theother hand an intrinsic pathway of apoptosis is induced in response to cellular stresses such as DNA damage and ROS that increase theexpression of proapoptotic Bcl-2 family proteins (eg Bid Bad and Bax) while repressing antiapoptotic Bcl-2 family proteins (eg Bcl-2Bcl-xL andMcl-1) leading to an alteration in mitochondrial membrane potential and the release of cytochrome C (Cyto C) Proteins such asApaf-1 and caspase-9 (C9) are activated resulting in the formation of an apoptosome which then stimulate the activation of effector caspasesNF-120581B and JNKASK-1 also play a role in apoptotic signaling through the regulation of antiapoptotic molecules such as FLIP and Bcl-2

as a result of lipid peroxidation by DOX-derived ROS ∙OHandH

2O2can readily attack polyunsaturated fatty acids of the

membrane and initiate a redox chain reaction that destroysmembrane lipids [78] thereby disturbing the function ofmembrane-bound protein including mitochondrial calciumchannel [17] Moreover DOX could directly affect the expres-sion level of important component of sarcomeric reticulumcalcium release or uptake channels for example ryanodinereceptor (RYR2) and sarco-endoplasmic reticulum Ca2+ATPase (SERCA2) [79 80] leading to an impaired calciumhandling and subsequent impaired cardiac contraction [81]It has been reported that DOXmodifies the thiol group (ndashSH)of RYR2 [82 83] This modification enhances the probabilityof RYR2 channel to adopt its open state [84 85] makingcytosol overloaded with calcium ions Additionally DOXcould increase the activity of voltage-sensitive L-type calciumchannel (VSCC) on cardiac cell membrane [86] as well asinhibiting the Na+Ca2+ exchanger (NCX) on sarcolemmalmembrane [87] resulting in calcium overload

When cytosolic calcium ions were excessive the relaxedstate after contraction would be undermined and thusthe contraction-relaxation cycle of cardiomyocytes is inter-rupted DOXrsquos major metabolite DOXol was shown to havemore profound effect on contraction-relaxation cycle ascompared to DOX [26] DOXol could inhibit RYR2 Na+K+

pump on the cell membrane and proton pump onmitochon-dria resulting in the impairment of relaxation [26 88]

54 Cardiac Cell Death Programmed cell death or apoptosisis a critical cellular process occurring when a cell commitssuicide as it is no longer needed no longer processesproperly or senses the cytotoxic signals Damage to geneticDNA proteins cellular organelles or membrane integritythat is beyond repair would trigger apoptosis in order toreserve resources and energy for other normal cells andprevent neighboring cells from its death signals Apoptosisis a tightly regulated process involving multiple signalingcascades commonly in extrinsic death receptor and intrinsicmitochondrial apoptosis pathways (Figure 1)

The death receptor pathway involves the binding of deathligands for example Fas ligand (FasL) and TNF-120572 to theirrespective membrane-bound death receptors for exampleFas receptor or apoptosis antigen-1 (APO-1) or CD95 andTNF-120572 receptor (TNFR) resulting in the recruitment ofsecondary proteins that will relay the signals to variousproteins mediating the caspase cascade leading to apoptosisIn particular when FasL binds to Fas receptor the receptoroligomerizes and recruits an adaptor protein Fas-associateddeath-domain (FADD) and pro-caspase-8 assembling thedeath-inducing signaling complex (DISC) and activating


the initiator caspase-8 (FLICE) which in turn activateseffector caspase-3 [89] Caspase-3 catalyzes the cleavage ofpoly(ADP-ribose) polymerase (PARP) causing apoptosis ascharacterized by chromatin condensation DNA fragmenta-tion and membrane blebbing [90] Alternatively caspase-8 can cleave Bid to become truncated Bid (t-Bid) that willtranslocate to mitochondria thus linking the death recep-tor and mitochondrial pathways [91 92] Similar to FasLthe binding of TNF-120572 to TNFR recruits TNFR-associateddeath domain protein (TRADD) adaptor protein which willthen recruit either FADD or receptor-interacting protein(RIP) These two pathways result in two different situationsthat are TRADDFADD activates caspase-8 and inducesapoptosis while TRADDRIPTRAF2 activates NF-120581B andprosurvival pathway [93] NF-120581B could induce the expressionof antiapoptotic proteins such as FLIP and Bcl-2 [94] Onthe other hand TRAF-2 can activate ASK-1JNK pathway viaan ROS-dependent manner and induce apoptotic signalingcascades [95] An active phosphorylated JNK can translocateto nucleus and increase the expression of proapoptotic genesOr else it can translocate to mitochondria and phospho-rylate Bcl-2 to antagonize its activity as well as releasingthe cytochrome C and SmacDiablo (Smac) which is aTRAF2IAP1 inhibitor

The mitochondrial pathway relies on the changes inmitochondrial transmembrane potential (120595) which is a keyindicator of mitochondrial membrane permeability Bcl-2family proteins includes antiapoptotic proteins such as Bcl-2 Bcl-XL and Mcl-1 and proapoptotic proteins such asBid Bad Bax Bak Bok and Bim The proapoptotic pro-teins facilitate the release of cytochrome C from mitochon-dria by dimerizing and forming transition pores [96] Thereleased cytochrome C subsequently binds to caspase adap-tor molecule Apaf-1 and recruits initiator pro-caspase-9 toform a complex called apoptosome which activates effectorcaspase-3 The oligomerization of proapoptotic Bcl-2 familyproteins can be prevented by antiapoptotic Bcl-2 familyproteins

When the number of cardiomyocytes available to func-tion in the heart was remarkably reduced the heart can nolonger effectively and efficiently pump blood sequentiallyleading to ventricular remodeling and heart failure [97ndash100]DOXhas been demonstrated to cause cardiomyocyte apopto-sis by various means It can activate mitochondrial apoptosispathway by disrupting the cardiolipin an important com-ponent of mitochondrial inner membrane [99] Cardiolipincontrols energy metabolism and thereby its alteration canpotentially lead to heart failure [101] Apoptosis can also beactivated by the damage to cellular lipid membrane DNAor mitochondrial DNA induced by DOX [102ndash105] ROSare believed to be responsible for the apoptotic effect ofDOX An increase in ROS level as measured by electronspin resonance spectroscopy was observed in cardiac cellsafter exposing to DOX in agreement with an increase inmalondialdehyde a product of lipid peroxidation driven byROS [106 107]MitochondrialDNA is particularly vulnerableto DOX toxicity due to its proximity to DOX and sourcesof ROS generation within mitochondrial membrane [108] Inaddition to the amplification of ROS signals as mentioned

earlier DOX suppressed the antioxidant defense systemDOX reduced the levels and activities of antioxidant GSHGPx-1 and sulfhydryl groups within enzyme complex as wellas the cytosolic SOD making cells vulnerable to oxidativestress [22 31 49 108ndash113] A large amount of O2

∙minus producedwithin mitochondria cannot pass through its membrane andthus can easily damage mitochondrial DNA that does nothave the protective complex chromatin organization likehistone proteins and introns and has limited repair capability[114]

With regard to apoptosis pathways DOX-derived ROSwas reported to activate p53 as well as p38 and JNK MAPKand NF-120581B signaling pathways resulting in an imbalancebetween pro- and anti-apoptotic Bcl-2 family proteins forexample an increase in Bax to Bcl-2 ratio [115 116] (Figure 2)Such imbalance disrupted mitochondrial membrane poten-tial causing cytochrome C release Notably JNK can alsotranslocate to nucleus after being activated by DOX-derivedROS and phosphorylate c-Jun that subsequently binds toAP-1 and initiates FasL transcription [95] Inhibition ofFLIP by DOX-derived ROS further rendered cardiac cellsto apoptosis induced by FasL providing another potentialmechanism for DOX-mediated apoptosis [117] AdditionallyDOX-derivedROSwere shown to cause calcium leakage fromsarcoplasmic reticulumwhich then activated calcineurin andpromoted apoptosis via NFATFasL activation or Bcl-XL andAkt pathway inhibition by Bad [118] Several studies reportedthatDOX induced the loss of phospholipaseCdelta-1 (PLCD-1) and PLCD-3 that simultaneously led to cardiomyocyteapoptosis and the development of cardiomyopathy [118 119]Additionally DOX could directly induce the mitochondrialrelease of cytochrome C and activate caspase-3 or p53accumulation leading to the proapoptotic signaling cascades[120 121]

55 Autophagy The role of autophagy towards cell fatemay vary depending on cellular environment and stimuliUnder normal physiological condition autophagy enhancescellular function and overall viability by eliminating damagedandor unnecessary proteins and organelles while main-taining cellular integrity and inhibiting apoptosis Underpathological condition autophagy could either promote cellsurvival or induce cell death Several studies demonstratedcardiac autophagy upon DOX administration as evaluatedby an increase of autophagic vacuoles and expression ofautophagosome markers [122ndash127] however its precise rolein DOX toxicity still remains controversial Many groupsagreed that inhibition of autophagy resulted in a decreasein DOX toxicity [122 125 127 128] in correspondence witha decrease in mitochondrial membrane potential and ROSgeneration [127] On the other hand Kawaguchi et al andSishi et al observed the protective effect of autophagy towardsDOX cardiotoxicity [124 129] likely through the reduction inmitochondrial ROS [129]

6 Preventive Strategies

Cardiotoxicity could be life threatening and thus severalattempts have been made to attenuate and minimize such


FLIP

BaxC8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bax

Bax

Pro-

C8

FasR

DOX

Calcineurin

C3

Bcl-2


FasLDOX

ROS

transcriptionFasL

Bax

DOX

DOX

ROS

PARP

BaxBcl-2 uarr

MAPK uarrp53 uarrNF-120581B uarr

Ca2+Ca2+

Ψ uarr

Figure 2 Schematic representation of DOX-induced apoptosis and the involvement of ROS DOX-derived ROS could affect the regulationof calcium homeostasis resulting in cytosolic calcium (Ca2+) overload that can activate calcineurin and increase the transcription of Fasligand (FasL) DOX-derived ROS could also inhibit the expression of caspase-8 (C8 also known as FLICE) inhibitory protein FLIP renderingcells to apoptosis Additionally DOX-derived ROS could act as an intrinsic stress that activates mitogen activated protein kinases (MAPK)p38 and JNK and NF-120581B pathways as well as intracellular p53 accumulation leading to an alteration in the ratio of proapoptotic proteins toantiapoptotic proteins (eg Bax to Bcl-2) cytochrome C (Cyto C) release and caspase-9 and -3 (C9C3) activation

toxicity induced by chemotherapy particularly the mostcommon DOX Clinical practice suggests close monitoringand evaluation of patient risks for developing complicationsafter treatment Early detection and immediate proper med-ication could reverse the condition in time that minimizescardiotoxic effects Analogues of DOX with some changes inmolecular structures including epirubicin idarubicin andmitoxantrone have been developed and became anotherappealing alternative as studies in cancer patients showedcomparable drug efficacy with lower cardiotoxicity to con-ventional DOX [130ndash132] Liposomal DOX is another strat-egy to reduce the drug toxicity as encapsulating DOX wasrestricted to the site with tight capillary junction like inthe heartrsquos wall while readily penetrating through the morefragile tumor vasculature [133]

Dexrazoxane is the only FDA-approved cardioprotectiveagent against cardiotoxicity induced by anthracyclines Dueto the potential risk of developing secondary tumors andinterfering effect of dexrazoxane towards anticancer activityof DOX Dexrazoxane clinical use is limited only to somecertain groups of patients [134 135] namely adult patientswith breast cancer who have received cumulative dose of atleast 300mgm2 doxorubicin or 540mgm2 epirubicin

7 Conclusions and Perspectives

Adverse effects of chemotherapeutic agents limit their clinicalbenefits For instance DOX one of the most effective and

frequently used chemotherapeutic agents to treat a varietyof cancers poses serious problem of cardiotoxicity whenadministered over certain critical dosage Several studiesdemonstrate that ROS are the main contributor of DOX-induced cardiotoxicity DOX-derived ROS affected variousmajor cellular processes leading to cardiomyopathy andeventually congestive heart failure including cellular hyper-trophy ECM remodeling impaired cardiac contraction andremarkable cardiac cell death Specifically to cell deathDOX-derived ROS served as a secondary signaling moleculeengaged in numerous pathways of apoptosis The protectiveeffect of antioxidants against DOX-induced apoptosis in cellculture and animal models support the notion that DOX-induced cardiotoxicity is caused mainly by ROS Otherchemotherapeutic agents that induce ROS and high degreeof cardiotoxicity include all other anthracyclines alkylatingagents and vinca alkaloids However the nonprotective effectof antioxidants against cardiotoxicity induced by DOX andother chemotherapeutic agents was observed particularly inchronic studies using animal models or in clinical trials Suchfailure of antioxidants may be due to (i) a complexity of ROSnetwork that partly interruptions or inhibitions by antioxi-dants cannot totally reverse its effects and (ii) a variety of dif-ferent mechanisms governing in chemotherapy-induced car-diotoxicity A key to effective preventive strategies is a betterunderstanding of molecular mechanisms of chemotherapy-induced cardiotoxicity which requires the development of


more predictive experimental models Much of our under-standing on chemotherapy-induced cardiotoxicity was basedon animal models and neonatal rat cardiomyocyte culturethus strengthening the notion that the experimental modelsthat mimic human heart physiology and allow mechanisticstudies are currently lacking The newly developed humaninduced pluripotent stem- (iPS-) derived cardiomyocytesor three-dimensional (3D) organ culture is promising andmight provide us with the different facet of this complicatedproblem In addition the drug concentrations and regimenused during each preventive study should faithfully reflect thereal scenario of drug administration during cancer therapy sothat its results could be better appreciated and reliable

Abbreviations

120572-MHC Alpha-myosin heavy chain3D Three-dimensionalANP Atrial natriuretic peptideAP-1 Activator protein-1APO-1 Apoptosis antigen-1ASK-1 Apoptosis signal-regulating kinase 1C3 C8 C9 Caspase-3 caspase-8 caspase-9CARP Cardiac adriamycin-responsive proteinCHF Congestive heart failureCyto C Cytochrome CDISC Death-inducing signaling complexDOX DoxorubicinDOXol DoxorubicinolECM Extracellular matrixFADD Fas-associated death-domainFe(II) FerrousFe(III) FerriceNOS Endothelial nitric oxide synthaseFasL Fas ligandGPx Glutathione peroxidaseGSH GlutathioneH2O2 Hydrogen peroxide

iPS Induced pluripotent stemIREs Iron-responsive elementsIRP-1 Iron regulatory proteins-1MAPK Mitogen activated protein kinasesMLC-2v Ventricular myosin light chain-2MMPs Matrix metalloproteinasesNO Nitric oxideO2∙minus Superoxide anion

∙OH Hydroxyl radicalONOOminus PeroxynitritePARP Poly(ADP-ribose) polymerasePKC Protein kinase CPLCD Phospholipase C deltapro-MMPs Precursors of matrix metalloproteinasesRIP Receptor-interacting proteinRNS Reactive nitrogen speciesROS Reactive oxygen speciesRYR2 Ryanodine receptorSERCA2 Sarco-endoplasmic reticulum Ca2+ ATPaseSOD Superoxide dismutaset-Bid Truncated Bid

TNFR TNF-120572 receptorTRADD TNFR-associated death domain proteinVSCC Voltage-sensitive L-type calcium channel

Conflict of Interests

No potential conflict of interests was disclosed

Acknowledgments

This work was supported by Grants from Thailand ResearchFund (RTA 488-0007) and the Commission on HigherEducation (CHE-RES-RG-49)

References

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[2] D L Hershman R B McBride A Eisenberger Y T Wei V RGrann and J S Jacobson ldquoDoxorubicin cardiac risk factorsand cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkinrsquos lymphomardquo Journal of Clinical Oncology vol 26 no19 pp 3159ndash3165 2008

[3] L Gianni E Munzone G Capri et al ldquoPaclitaxel by 3-hourinfusion in combinationwith bolus doxorubicin in womenwithuntreated metastatic breast cancer high antitumor efficacy andcardiac effects in a dose-finding and sequence-finding studyrdquoJournal of Clinical Oncology vol 13 no 11 pp 2688ndash2699 1995

[4] E A Eisenhauer and J B Vermorken ldquoThe taxoids Compar-ative clinical pharmacology and therapeutic potentialrdquo Drugsvol 55 no 1 pp 5ndash30 1998

[5] A Giantris L Abdurrahman A Hinkle B Asselin and SE Lipshultz ldquoAnthracycline-induced cardiotoxicity in childrenand young adultsrdquo Critical Reviews in OncologyHematologyvol 27 no 1 pp 53ndash68 1998

[6] V B Pai andMCNahata ldquoCardiotoxicity of chemotherapeuticagents Incidence treatment and preventionrdquo Drug Safety vol22 no 4 pp 263ndash302 2000

[7] E A Lefrak J Pitha S Rosenheim and J A Gottlieb ldquoA clini-copathologic analysis of adriamycin cardiotoxicityrdquoCancer vol32 no 2 pp 302ndash314 1973

[8] V J Ferrans J R Clark J Zhang Z-X Yu and E H HermanldquoPathogenesis and prevention of doxorubicin cardiomyopathyrdquoTsitologiya vol 39 no 10 pp 928ndash936 1997

[9] F L Medrano A S Munoz V S Sanchez and J R CPerez-Herrero ldquoCardiotoxicity of 5-fluorouracil ischemia ormyocardial toxicityrdquo Revista Clınica Espanola vol 201 no 2pp 106ndash107 2001

[10] C Lestuzzi ldquoNeoplastic pericardial disease old and currentstrategies for diagnosis and managementrdquo World Journal ofCardiology vol 2 no 9 p 270 2010

[11] G Takemura and H Fujiwara ldquoDoxorubicin-induced car-diomyopathy from the cardiotoxic mechanisms to manage-mentrdquo Progress in Cardiovascular Diseases vol 49 no 5 pp330ndash352 2007

[12] L M Buja V J Ferrans R J Mayer W C Roberts andE S Henderson ldquoCardiac ultrastructural changes induced bydaunorubicin therapyrdquo Cancer vol 32 no 4 pp 771ndash788 1973

[13] M E Billingham J W Mason M R Bristow and J R DanielsldquoAnthracycline cardiomyopathy monitored by morphologic


changesrdquo Cancer Treatment Reports vol 62 no 6 pp 865ndash8721978

[14] N R Bachur S L Gordon M V Gee and H Kon ldquoNADPHcytochrome P-450 reductase activation of quinone anticanceragents to free radicalsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 76 no 2 pp 954ndash957 1979

[15] V Berlin and W A Haseltine ldquoReduction of adriamycin toa semiquinone-free radical by NADPH cytochrome P-450reductase produces DNA cleavage in a reaction mediated bymolecular oxygenrdquoThe Journal of Biological Chemistry vol 256no 10 pp 4747ndash4756 1981

[16] K J A Davies and J H Doroshow ldquoRedox cycling of anthracy-clines by cardiac mitochondria I Anthracycline radical forma-tion by NADH dehydrogenaserdquo Journal of Biological Chemistryvol 261 no 7 pp 3060ndash3067 1986

[17] K J M Schimmel D J Richel R B A van den Brink andH Guchelaar ldquoComplications of treatment cardiotoxicity ofcytotoxic drugsrdquo Cancer Treatment Reviews vol 30 pp 181ndash1912004

[18] J H Doroshow ldquoEffect of anthracycline antibiotics on oxygenradical formation in rat heartrdquo Cancer Research vol 43 no 2pp 460ndash472 1983

[19] J Vasquez-Vivar P Martasek N Hogg B S S Masters K APritchard Jr and B Kalyanaraman ldquoEndothelial nitric oxidesynthase-dependent superoxide generation from adriamycinrdquoBiochemistry vol 36 no 38 pp 11293ndash11297 1997

[20] D M Weinstein M J Mihm and J A Bauer ldquoCardiac per-oxynitrite formation and left ventricular dysfunction followingdoxorubicin treatment in micerdquo Journal of Pharmacology andExperimental Therapeutics vol 294 no 1 pp 396ndash401 2000

[21] B Liu H Li H Qu and B Sun ldquoNitric oxide synthaseexpressions in ADR-induced cardiomyopathy in ratsrdquo Journalof Biochemistry and Molecular Biology vol 39 no 6 pp 759ndash765 2006

[22] J H Doroshow G Y Locker and C E Myers ldquoEnzymaticdefenses of themouse heart against reactive oxygenmetabolitesAlterations produced by doxorubicinrdquo The Journal of ClinicalInvestigation vol 65 no 1 pp 128ndash135 1980

[23] M A Parker V King and K P Howard ldquoNuclear magneticresonance study of doxorubicin binding to cardiolipin contain-ing magnetically oriented phospholipid bilayersrdquo Biochimica etBiophysica Acta vol 1514 no 2 pp 206ndash216 2001

[24] G M Hatch and G McClarty ldquoRegulation of cardiolipinbiosynthesis in H9c2 cardiac myoblasts by cytidine 51015840-triphosphaterdquo The Journal of Biological Chemistry vol 271 no42 pp 25810ndash25816 1996

[25] E Goormaghtigh P Chatelain J Caspers and J M Ruyss-chaert ldquoEvidence of a specific complex between adriamycin andnegatively-charged phospholipidsrdquo Biochimica et BiophysicaActa vol 597 no 1 pp 1ndash14 1980

[26] R D Olson P S Mushlin D E Brenner et al ldquoDoxorubicincardiotoxicity may be caused by its metabolite doxorubicinolrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 85 no 10 pp 3585ndash3589 1988

[27] D J Stewart D Grewaal R M Green et al ldquoConcentrationsof doxorubicin and its metabolites in human autopsy heart andother tissuesrdquo Anticancer Research vol 13 pp 1945ndash1952 1993

[28] C Panis A C S A Herrera V J Victorino et al ldquoOxidativestress and hematological profiles of advanced breast cancerpatients subjected to paclitaxel or doxorubicin chemotherapyrdquo

Breast Cancer Research and Treatment vol 133 no 1 pp 89ndash972012

[29] C F Thorn C Oshiro S Marsh et al ldquoDoxorubicin pathwayspharmacodynamics and adverse effectsrdquo Pharmacogenetics andGenomics vol 21 no 7 pp 440ndash446 2011

[30] G Minotti S Recalcati P Menna E Salvatorelli G Cornaand G Cairo ldquoDoxorubicin cardiotoxicity and the control ofiron metabolism quinone-dependent and independent mech-anismsrdquoMethods in Enzymology vol 378 pp 340ndash361 2004

[31] Y Chen P Jungsuwadee M Vore D A Butterfield and D KS Clair ldquoCollateral damage in cancer chemotherapy oxidativestress in nontargeted tissuesrdquoMolecular Interventions vol 7 no3 pp 147ndash156 2007

[32] E C Theil G L Eichorn and L Marzili ldquoFerritin structurefunction and regulation in iron binding proteins withoutcofactors and sulfur clustersrdquo Annual Review of Biochemistryvol 56 pp 289ndash315 1987

[33] G Minotti R Ronchi E Salvatorelli P Menna and G CairoldquoDoxorubicin irreversibly inactivates iron regulatory proteins1 and 2 in cardiomyocytes evidence for distinct metabolicpathways and implications for iron-mediated cardiotoxicity ofantitumor therapyrdquo Cancer Research vol 61 no 23 pp 8422ndash8428 2001

[34] G Minotti G Cairo and E Monti ldquoRole of iron in anthra-cycline cardiotoxicity new tunes for an old songrdquo The FASEBJournal vol 13 no 2 pp 199ndash212 1999

[35] G Minotti S Recalcati A Mordente et al ldquoThe secondaryalcohol metabolite of doxorubicin irreversibly inactivatesaconitaseiron regulatory protein-1 in cytosolic fractions fromhuman myocardiumrdquo The FASEB Journal vol 12 pp 541ndash5521998

[36] G Minotti C Mancuso A Frustaci et al ldquoParadoxical inhi-bition of cardiac lipid peroxidation in cancer patients treatedwith doxorubicin Pharmacologic and molecular reappraisal ofanthracycline cardiotoxicityrdquo The Journal of Clinical Investiga-tion vol 98 no 3 pp 650ndash661 1996

[37] T P A Devasagayam J C Tilak K K Boloor K S Sane SS Ghaskadbi and R D Lele ldquoFree radicals and antioxidants inhuman health current status and future prospectsrdquo Journal ofAssociation of Physicians of India vol 52 pp 794ndash804 2004

[38] DGDeavall EAMartin JMHorner andRRoberts ldquoDrug-induced oxidative stress and toxicityrdquo Journal of Toxicology vol2012 Article ID 645460 13 pages 2012

[39] A Sabri H H Hughie and P A Lucchesi ldquoRegulation ofhypertrophic and apoptotic signaling pathways by reactiveoxygen species in cardiac myocytesrdquo Antioxidants and RedoxSignaling vol 5 no 6 pp 731ndash740 2003

[40] D A Siwik J D Tzortzis D R Pimental et al ldquoInhibitionof copper-zinc superoxide dismutase induces cell growthhypertrophic phenotype and apoptosis in neonatal rat cardiacmyocytes in vitrordquo Circulation Research vol 85 no 2 pp 147ndash153 1999

[41] S H Kwon D R Pimentel A Remondino D B SawyerandW S Colucci ldquoH

2O2regulates cardiac myocyte phenotype

via concentration-dependent activation of distinct kinase path-waysrdquo Journal of Molecular and Cellular Cardiology vol 35 no6 pp 615ndash621 2003

[42] DA Siwik P J Pagano andW S Colucci ldquoOxidative stress reg-ulates collagen synthesis and matrix metalloproteinase activityin cardiac fibroblastsrdquoTheAmerican Journal of PhysiologymdashCellPhysiology vol 280 no 1 pp C53ndashC60 2001


[43] N S Dhalla R M Temsah and T Netticadan ldquoRole of oxida-tive stress in cardiovascular diseasesrdquo Journal of Hypertensionvol 18 no 6 pp 655ndash673 2000

[44] C J Miranda H Makui R J Soares et al ldquoHfe defi-ciency increases susceptibility to cardiotoxicity and exacerbateschanges in iron metabolism induced by doxorubicinrdquo Bloodvol 102 no 7 pp 2574ndash2580 2003

[45] T Simunek M Sterba O Popelova M Adamcova R Hrdinaand V Gersi ldquoAnthracycline-induced cardiotoxicity overviewof studies examining the roles of oxidative stress and freecellular ironrdquo Pharmacological Reports vol 61 no 1 pp 154ndash171 2009

[46] N Frey H A Katus E N Olson and J A Hill ldquoHypertrophyof the heart a new therapeutic targetrdquo Circulation vol 109 no13 pp 1580ndash1589 2004

[47] S Mouli G R Nanayakkara R Fu et al ldquoThe role of frataxinin doxorubicin-mediated cardiac hypertrophyrdquo The FASEBJournal vol 28 no 1 supplement 6486 2014

[48] T C Karagiannis A J E Lin K Ververis et al ldquoTrichostatinA accentuates doxorubicin-induced hypertrophy in cardiacmyocytesrdquo Aging vol 2 no 10 pp 659ndash668 2010

[49] J-M Li N P Gall D J Grieve M Chen and A M ShahldquoActivation of NADPH oxidase during progression of cardiachypertrophy to failurerdquo Hypertension vol 40 no 4 pp 477ndash484 2002

[50] M O Date T Morita N Yamashita et al ldquoThe antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hyper-trophy in in vivo murine pressure-overload modelrdquo Journal ofthe American College of Cardiology vol 39 no 5 pp 907ndash9122002

[51] Y Higuchi K Otsu K Nishida et al ldquoInvolvement of reactiveoxygen species-mediated NF-120581B activation in TNF-120572-inducedcardiomyocyte hypertrophyrdquo Journal of Molecular and CellularCardiology vol 34 no 2 pp 233ndash240 2002

[52] D R Pimentel J K Amin L Xiao et al ldquoReactive oxygenspecies mediate amplitude-dependent hypertrophic and apop-totic responses to mechanical stretch in cardiac myocytesrdquoCirculation Research vol 89 no 5 pp 453ndash460 2001

[53] S Hirotani K Otsu K Nishida et al ldquoInvolvement of nuclearfactor-120581B and apoptosis signal-regulating kinase 1 inG-protein-coupled receptor agonist-induced cardiomyocyte hypertrophyrdquoCirculation vol 105 no 4 pp 509ndash515 2002

[54] K Nakamura K Fushimi H Kouchi et al ldquoInhibitory effectsof antioxidants on neonatal rat cardiac myocyte hypertrophyinduced by tumor necrosis factor-alpha and angiotensin IIrdquoCirculation vol 98 no 8 pp 794ndash799 1998

[55] Y Izumiya S Kim Y Izumi et al ldquoApoptosis signal-regulatingkinase 1 plays a pivotal role in angiotensin II-induced cardiachypertrophy and remodelingrdquo Circulation Research vol 93 no9 pp 874ndash883 2003

[56] K EMerten Y JiangW Feng andY J Kang ldquoCalcineurin acti-vation is not necessary for doxorubicin-induced hypertrophy inH9c2 embryonic rat cardiac cells involvement of the phospho-inositide 3-kinase-akt pathwayrdquo Journal of Pharmacology andExperimental Therapeutics vol 319 no 2 pp 934ndash940 2006

[57] X Sun Z Zhou and Y J Kang ldquoAttenuation of doxorubicinchronic toxicity in metallothionein-overexpressing transgenicmouse heartrdquo Cancer Research vol 61 no 8 pp 3382ndash33872001

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the diseased cardiac microenvironmentrdquo Tissue Engineering ampModeling vol 2 no 1 2014

[59] M L McCain H Yuan F S Pasqualini P H Campbelland K K Parker ldquoMatrix elasticity regulates the optimalcardiac myocyte shape for contractilityrdquo American Journal ofPhysiologymdashHeart and Circulatory Physiology vol 306 no 11pp H1525ndashH1539 2014

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[63] F G Spinale M L Coker C V Thomas J D WalkerR Mukherjee and L Hebbar ldquoTime-dependent changes inmatrix metalloproteinase activity and expression during theprogression of congestive heart failure relation to ventricularand myocyte functionrdquo Circulation Research vol 82 no 4 pp482ndash495 1998

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[67] P Spallarossa P Altieri S Garibaldi et al ldquoMatrix metallo-proteinase-2 and -9 are induced differently by doxorubicin inH9c2 cells the role of MAP kinases and NAD(P)H oxidaserdquoCardiovascular Research vol 69 no 3 pp 736ndash745 2006

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[70] T Okamoto T Akaike T Sawa Y Miyamoto A van der Vlietand H Maeda ldquoActivation of matrix metalloproteinases byperoxynitrite-induced protein s-glutathiolation via disulfide s-oxide formationrdquo The Journal of Biological Chemistry vol 276no 31 pp 29596ndash29602 2001

[71] H Ito S C Miller M E Billingham et al ldquoDexorubicinselectively inhibits muscle gene expression in cardiac musclecells in vivo and in vitrordquo Proceedings of the National Academy ofSciences of the United States of America vol 87 no 11 pp 4275ndash4279 1990

[72] R Jeyaseelan C Poizat H-Y Wu and L Kedes ldquoMolecularmechanisms of doxorubicin-induced cardiomyopathy Selective


suppression of Reiske iron-sulfur protein ADPATP translo-case and phosphofructokinase genes is associated with ATPdepletion in rat cardiomyocytesrdquo Journal of Biological Chem-istry vol 272 no 9 pp 5828ndash5832 1997

[73] Y Kim A-G Ma K Kitta et al ldquoAnthracycline-inducedsuppression of GATA-4 transcription factor implication in theregulation of cardiacmyocyte apoptosisrdquoMolecular Pharmacol-ogy vol 63 no 2 pp 368ndash377 2003

[74] A Aries P Paradis C Lefebvre R J Schwartz and M NemerldquoEssential role of GATA-4 in cell survival and drug-inducedcardiotoxicityrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 101 no 18 pp 6975ndash69802004

[75] S-S Takahashi M A Denvir L Harder et al ldquoEffects ofin vitro and in vivo exposure to doxorubicin (adriamycin)on caffeine-induced Ca2+ release from sarcoplasmic reticulumand contractile protein function in rsquochemically-skinnedrsquo rabbitventricular trabeculaerdquo Japanese Journal of Pharmacology vol76 no 4 pp 405ndash413 1998

[76] D A Dodd J B Atkinson R D Olson et al ldquoDoxorubicincardiomyopathy is associated with a decrease in calcium releasechannel of the sarcoplasmic reticulum in a chronic rabbitmodelrdquo The Journal of Clinical Investigation vol 91 no 4 pp1697ndash1705 1993

[77] J I Kourie ldquoInteraction of reactive oxygen species with iontransport mechanismsrdquo The American Journal of PhysiologymdashCell Physiology vol 275 no 1 pp C1ndashC24 1998

[78] C Mylonas and D Kouretas ldquoLipid peroxidation and tissuedamagerdquo In Vivo vol 13 no 3 pp 295ndash309 1999

[79] M Arai K Tomaru T Takizawa et al ldquoSarcoplasmic reticu-lum genes are selectively down-regulated in cardiomyopathyproduced by doxorubicin in rabbitsrdquo Journal of Molecular andCellular Cardiology vol 30 no 2 pp 243ndash254 1998

[80] P Kaplan E Babusikova J Lehotsky and D Dobrota ldquoFreeradical-induced protein modification and inhibition of Ca2+-ATPase of cardiac sarcoplasmic reticulumrdquo Molecular andCellular Biochemistry vol 248 no 1-2 pp 41ndash47 2003

[81] M Arai A Yoguchi T Takizawa et al ldquoMechanism ofdoxorubicin-induced inhibition of sarcoplasmic reticulumCa2+-ATPase gene transcriptionrdquo Circulation Research vol 86no 1 pp 8ndash14 2000

[82] A V Zima and L A Blatter ldquoRedox regulation of cardiaccalcium channels and transportersrdquo Cardiovascular Researchvol 71 no 2 pp 310ndash321 2006

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[84] S R M Holmberg and A J Williams ldquoPatterns of interactionbetween anthraquinone drugs and the calcium-release channelfrom cardiac sarcoplasmic reticulumrdquoCirculation Research vol67 no 2 pp 272ndash283 1990

[85] K Saeki I Obi N Ogiku M Shigekawa T Imagawa and TMatsumoto ldquoDoxorubicin directly binds to the cardiac-typeryanodine receptorrdquo Life Sciences vol 70 no 20 pp 2377ndash23892002

[86] E C Keung L Toll M Ellis and R A Jensen ldquoL-typecardiac calcium channels in doxorubicin cardiomyopathy inrats morphological biochemical and functional correlationsrdquoJournal of Clinical Investigation vol 87 no 6 pp 2108ndash21131991

[87] P Caroni F Villani and E Carafoli ldquoThe cardiotoxic antibioticdoxorubicin inhibits the Na+Ca2+ exchange of dog heart

sarcolemmal vesiclesrdquo FEBS Letters vol 130 no 2 pp 184ndash1861981

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[89] I N Lavrik and P H Krammer ldquoRegulation of CD95Fassignaling at the DISCrdquo Cell Death and Differentiation vol 19no 1 pp 36ndash41 2012

[90] A G Porter and R U Janicke ldquoEmerging roles of caspase-3 inapoptosisrdquo Cell Death and Differentiation vol 6 no 2 pp 99ndash104 1999

[91] C Kantari and H Walczak ldquoCaspase-8 and Bid caught in theact between death receptors and mitochondriardquo Biochimica etBiophysica Acta vol 1813 no 4 pp 558ndash563 2011

[92] T Kaufmann A Strasser and P J Jost ldquoFas death receptorsignalling roles of Bid and XIAPrdquo Cell Death amp Differentiationvol 19 no 1 pp 42ndash50 2012

[93] F Van Herreweghe N Festjens W Declercq and P Vanden-abeele ldquoTumor necrosis factor-mediated cell death to breakor to burst thatrsquos the questionrdquo Cellular and Molecular LifeSciences vol 67 no 10 pp 1567ndash1579 2010

[94] H Wajant and P Scheurich ldquoTNFR1-induced activation of theclassical NF-120581B pathwayrdquoThe FEBS Journal vol 278 no 6 pp862ndash876 2011

[95] D N Dhanasekaran and E P Reddy ldquoJNK signaling inapoptosisrdquo Oncogene vol 27 no 48 pp 6245ndash6251 2008

[96] J K Brunelle and A Letai ldquoControl of mitochondrial apoptosisby the Bcl-2 familyrdquo Journal of Cell Science vol 122 no 4 pp437ndash441 2009

[97] D B Sawyer X Peng B Chen L Pentassuglia and C C LimldquoMechanisms of anthracycline cardiac injury can we identifystrategies for cardioprotectionrdquo Progress in CardiovascularDiseases vol 53 no 2 pp 105ndash113 2010

[98] S Kotamraju E A Konorev J Joseph and B KalyanaramanldquoDoxorubicin-induced apoptosis in endothelial cells and car-diomyocytes is ameliorated by nitrone spin traps and ebselenRole of reactive oxygen and nitrogen speciesrdquo The Journal ofBiological Chemistry vol 275 no 43 pp 33585ndash33592 2000

[99] L Wang W Ma R Markovich J-W Chen and P H WangldquoRegulation of cardiomyocyte apoptotic signaling by insulin-like growth factor IrdquoCirculation Research vol 83 no 5 pp 516ndash522 1998

[100] O J Arola A Saraste K Pulkki M Kallajoki M Parvinen andLM Voipio-Pulkki ldquoAcute doxorubicin cardiotoxicity involvescardiomyocyte apoptosisrdquo Cancer Research vol 60 no 7 pp1789ndash1792 2000

[101] R H Houtkooper and F M Vaz ldquoCardiolipin the heartof mitochondrial metabolismrdquo Cellular and Molecular LifeSciences vol 65 no 16 pp 2493ndash2506 2008

[102] C Thollon J P Iliou C Cambarrat F Robin and J PVilaine ldquoNature of the cardiomyocyte injury induced by lipidhydroperoxidesrdquo Cardiovascular Research vol 30 no 5 pp648ndash655 1995

[103] N Rathore S John M Kale and D Bhatnagar ldquoLipid per-oxidation and antioxidant enzymes in isoproterenol inducedoxidative stress in rat tissuesrdquo Pharmacological Research vol 38no 4 pp 297ndash303 1998


[104] T Hemnani and M S Parihar ldquoReactive oxygen species andoxidative DNA damagerdquo Indian Journal of Physiology andPharmacology vol 42 no 4 pp 440ndash452 1998

[105] N SuematsuH Tsutsui JWen et al ldquoOxidative stressmediatestumor necrosis factor-120572-induced mitochondrial DNA damageand dysfunction in cardiac myocytesrdquo Circulation vol 107 no10 pp 1418ndash1423 2003

[106] L Costa V Malatesta F Morazzoni R Scotti E Monti andL Paracchini ldquoDirect detection of paramagnetic species inadriamycin perfused rat heartsrdquo Biochemical and BiophysicalResearch Communications vol 153 no 1 pp 275ndash280 1988

[107] P K Singal and G N Pierce ldquoAdriamycin stimulates low-affinity Ca2+ binding and lipid peroxidation but depressesmyocardial functionrdquo American Journal of PhysiologymdashHeartandCirculatory Physiology vol 250 no 3 ppH419ndashH425 1986

[108] P K Singal R J Segstro R P Singh andM J Kutryk ldquoChangesin lysosomal morphology and enzyme activities during thedevelopment of adriamycin-induced cardiomyopathyrdquo Cana-dian Journal of Cardiology vol 1 no 2 pp 139ndash147 1985

[109] J Serrano CM Palmeira DW Kuehl andK BWallace ldquoCar-dioselective and cumulative oxidation of mitochondrial DNAfollowing subchronic doxorubicin administrationrdquo Biochimicaet Biophysica Acta vol 1411 no 1 pp 201ndash205 1999

[110] R D Olson J S MacDonald C J van Boxtel et al ldquoRegulatoryrole of glutathione and soluble sulfhydryl groups in the toxicityof adriamycinrdquo Journal of Pharmacology and ExperimentalTherapeutics vol 215 no 2 pp 450ndash454 1980

[111] G C Pereira A M Silva C V Diogo F S Carvalho PMonteiro and P J Oliveira ldquoDrug-induced cardiac mitochon-drial toxicity and protection from doxorubicin to carvedilolrdquoCurrent Pharmaceutical Design vol 17 no 20 pp 2113ndash21292011

[112] A L Odom C A Hatwig J S Stanley and A M BensonldquoBiochemical determinants of adriamycin toxicity in mouseliver heart and intestinerdquo Biochemical Pharmacology vol 43no 4 pp 831ndash836 1992

[113] H M Abd El-Gawad and M M El-Sawalhi ldquoNitric oxide andoxidative stress in brain and heart of normal rats treated withdoxorubicin role of aminoguanidinerdquo Journal of Biochemicaland Molecular Toxicology vol 18 no 2 pp 69ndash77 2004

[114] D C Wallace ldquoMitochondrial defects in cardiomyopathy andneuromuscular diseaserdquoAmerican Heart Journal vol 139 no 2pp S70ndashS85 2000

[115] C D Venkatakrishnan A K Tewari L Moldovan et al ldquoHeatshock protects cardiac cells from doxorubicin-induced toxicityby activating p38 MAPK and phosphorylation of small heatshock protein 27rdquo The American Journal of PhysiologymdashHeartand Circulatory Physiology vol 291 no 6 pp H2680ndashH26912006

[116] J Ghosh J Das P Manna and P C Sil ldquoThe protectiverole of arjunolic acid against doxorubicin induced intracellularROS dependent JNK-p38 and p53-mediated cardiac apoptosisrdquoBiomaterials vol 32 no 21 pp 4857ndash4866 2011

[117] J Nitobe S Yamaguchi M Okuyama et al ldquoReactive oxy-gen species regulate FLICE inhibitory protein (FLIP) andsusceptibility to Fas-mediated apoptosis in cardiac myocytesrdquoCardiovascular Research vol 57 no 1 pp 119ndash128 2003

[118] Y-C Lien T Noel H Liu A J Stromberg K-C Chenand D K St Clair ldquoPhospholipase C-1205751 is a critical targetfor tumor necrosis factor receptor-mediated protection againstadriamycin-induced cardiac injuryrdquo Cancer Research vol 66no 8 pp 4329ndash4338 2006

[119] Y Nakamura K Kanemaru R Kojima et al ldquoSimultaneousloss of phospholipase C1205751 and phospholipase C1205753 causescardiomyocyte apoptosis and cardiomyopathyrdquo Cell Death andDisease vol 5 no 5 article e1215 2014

[120] A C Childs S L Phaneuf A J Dirks T Phillips andC Leeuwenburgh ldquoDoxorubicin treatment in vivo causescytochrome c release and cardiomyocyte apoptosis as wellas increased mitochondrial efficiency superoxide dismutaseactivity and Bcl-2Bax ratiordquo Cancer Research vol 62 no 16pp 4592ndash4598 2002

[121] M Ueno Y Kakinuma K-I Yuhki et al ldquoDoxorubicin inducesapoptosis by activation of caspase-3 in cultured cardiomyocytesin vitro and rat cardiac ventricles in vivordquo Journal of Pharmaco-logical Sciences vol 101 no 2 pp 151ndash158 2006

[122] L Lu W Wu J Yan X Li H Yu and X Yu ldquoAdriamycin-induced autophagic cardiomyocyte death plays a pathogenicrole in a rat model of heart failurerdquo International Journal ofCardiology vol 134 no 1 pp 82ndash90 2009

[123] P Dimitrakis M-I Romay-Ogando F Timolati T M Suterand C Zuppinger ldquoEffects of doxorubicin cancer therapy onautophagy and the ubiquitin-proteasome system in long-termcultured adult rat cardiomyocytesrdquoCell andTissue Research vol350 no 2 pp 361ndash372 2012

[124] T Kawaguchi G Takemura H Kanamori et al ldquoPriorstarvation mitigates acute doxorubicin cardiotoxicity throughrestoration of autophagy in affected cardiomyocytesrdquo Cardio-vascular Research vol 96 no 3 pp 456ndash465 2012

[125] S Kobayashi P Volden D Timm K Mao X Xu and Q LiangldquoTranscription factor GATA4 inhibits doxorubicin-inducedautophagy and cardiomyocyte deathrdquo The Journal of BiologicalChemistry vol 285 no 1 pp 793ndash804 2010

[126] A J Smuder A N Kavazis K Min and S K PowersldquoDoxorubicin-induced markers of myocardial autophagic sig-naling in sedentary and exercise trained animalsrdquo Journal ofApplied Physiology vol 115 no 2 pp 176ndash185 2013

[127] Y Zhang C Meng X Zhang et al ldquoOphiopogonin D atten-uates doxorubicin-induced autophagic cell death by relievingmitochondrial damage in vitro and in vivordquo The Journal ofPharmacology amp Experimental Therapeutics vol 352 no 1 pp166ndash174 2014

[128] X Xu K Chen S Kobayashi D Timm and Q Liang ldquoResver-atrol attenuates doxorubicin-induced cardiomyocyte death viainhibition of p70 S6 kinase 1-mediated autophagyrdquoThe Journalof Pharmacology and Experimental Therapeutics vol 341 no 1pp 183ndash195 2012

[129] B J N Sishi B Loos J van Rooyen and A-M EngelbrechtldquoAutophagy upregulation promotes survival and attenuatesdoxorubicin-induced cardiotoxicityrdquo Biochemical Pharmacol-ogy vol 85 no 1 pp 124ndash134 2013

[130] G N Hortobagyi H-Y Yap S W Kau et al ldquoA comparativestudy of doxorubicin and epirubicin in patients with metastaticbreast cancerrdquo American Journal of Clinical Oncology CancerClinical Trials vol 12 no 1 pp 57ndash62 1989

[131] R B Weiss ldquoThe anthracyclines will we ever find a betterdoxorubicinrdquo Seminars in Oncology vol 19 no 6 pp 670ndash6861992

[132] L A Smith V R Cornelius C J Plummer et al ldquoCardiotoxicityof anthracycline agents for the treatment of cancer systematicreview andmeta-analysis of randomised controlled trialsrdquoBMCCancer vol 10 article 337 2010


[133] A A Gabizon ldquoStealth liposomes and tumor targeting onestep further in the quest for the magic bulletrdquo Clinical CancerResearch vol 7 no 2 pp 223ndash225 2001

[134] C K Tebbi W B London D Friedman et al ldquoDexrazoxane-associated risk for acute myeloid leukemiamyelodysplasticsyndrome and other secondary malignancies in pediatricHodgkinrsquos diseaserdquo Journal of Clinical Oncology vol 25 no 5pp 493ndash500 2007

[135] S M Swain F S Whaley M C Gerber et al ldquoCardioprotec-tion with dexrazoxane for doxorubicin-containing therapy inadvanced breast cancerrdquo Journal of Clinical Oncology vol 15 no4 pp 1318ndash1332 1997

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Potential cardiotoxicity induced by numerous chemotherapeutic agents

Class Examples of chemotherapeutic agents Possible cardiotoxicityAnthracyclines andanthraquinones DOX mitoxantrone Congestive heart failure left ventricular

dysfunction acute myocarditis and arrhythmia

Antimetabolite agents Capecitabine 5-fluorouracil andcytarabine

Ischemia pericarditis congestive heart failureand cardiogenic shock

Antimicrotubule agents Paclitaxel vinca alkaloidsSinus bradycardia ventricular tachycardiaatrioventricular block hypotension congestiveheart failure and ischemia

Alkylating agents Cyclophosphamide ifosfamide Neurohumoral activation mild mitralregurgitation

Monoclonal antibody againstHER2 Trastuzumab Arrhythmias congestive heart failure

angioedema and left ventricular dysfunctionAntiangiogenic and tyrosinekinase inhibitors Imatinib sorafenib and sunitinib Hypertension arrhythmias

Antivascular endothelial growthfactor Bevacizumab Hypertension thromboembolism

dose) and the dosage regimen For example a combinationof anthracyclines with other potential cardiotoxic agentsnamely paclitaxel or trastuzumab would greatly enhancethe risk of cardiotoxicity that potentially lead to disastrouscongestive heart failure [3ndash6]

Anthracyclines including doxorubicin (DOX) daunoru-bicin epirubicin and idarubicin are highly effective againstacute lymphoblastic and myeloblastic leukemias DOX inparticular has been found to have a much broader spec-trum which includes numerous solid tumors for examplebreast cancer sarcomas and childhood solid tumors (egWilmsrsquo tumor) in addition to hematologicalmalignancies forexample leukemias Hodgkinrsquos disease and non-Hodgkinrsquoslymphomas [1] Anthracycline-induced cardiotoxicity canoccur in an acute or chronicmannerThe acute cardiotoxicitywithin the course of treatment or immediately afterwardsincluding pericarditis-myocarditis or arrhythmias is nor-mally reversible and generally manageable while the chroniccardiotoxicity which may manifest even decades after thecompletion of treatment is serious and clinically significantsubstantially affecting overall morbidity and mortality andrequiring long-term therapy As DOX is an important com-ponent of current cancer treatment that generates high levelof ROS this review mainly emphasizes on the DOX-inducedcardiotoxicity

21 DOX-Induced Cardiotoxicity The cumulative dose ofadministered DOX is an important factor that dictates itscardiotoxicity it cannot exceed 500mgm2 or else the risk ofcongestive heart failure (CHF) would increase tremendously[7] The chance of developing CHF increases from lt4 atthe cumulative dose of 500ndash550mgm2 to lt18 or 36whenthe cumulative dose of DOX is 551ndash600 or over 600mgm2respectively A retrospective analysis revealed that 30-yearchildhood cancer survivors had a 15-fold higher rate ofheart failure and 10-fold higher rate of other cardiovasculardiseases when compared to estimated values in their siblingsCardiac abnormality can be seen as asymptomatic distur-bances in cardiac rhythms [8] changes in blood pressure

[9] thickening of pericardium [10] cardiac dilation [11] andcardiomyopathy

Histologically areas of patchy and interstitial fibrosis withscattered vacuolated cardiomyocytes can be visualized undermicroscope [11 12] There are also partial loss of myofibrilsand the degeneration of myocyte vacuoles [13] resulting inthe remaining peripheral Z disks without filaments and thelarge membrane-bound space accordingly In the nucleuschromatin disorganization with partial replacement of thechromatin by pale staining fibers and filaments could beobserved [11] Ultimately these changes would lead to car-diomyocyte death Since the turnover rate of cardiomyocytesin the heart is very low approximately 1 at the age of 20and lower in older ages [14] the progressive loss of myocytescannot be reversed Subsequently the heart loses its abilityto function properly These pathophysiological changes canlead to dilated cardiomyopathy cardiac hypertrophy andeventually heart failure

DOX is particularly harmful to the heart due to itsexceptional effects on mitochondria Heart as a pump thatcirculates blood throughout the body requires a great amountof energy and thus contains a large amount of energy pro-ducing mitochondria Generally mitochondria are the sitewhere most of reactive oxygen species (ROS) are produced asa consequence of electrons escaping from electron transportchain and captured by oxygen rendering it to be the homeof superoxide production However DOX can drive theseROS production to another level Enzymes within mitochon-dria including NADPH oxidase (also known as NADPHdehydrogenase) cytochrome P-450 reductase and xanthineoxidase (XO) can transform DOX and other anthracyclinesin the form of quinone to semiquinone via one electronreduction of the quinone moiety in ring C [14ndash17] Thissemiquinone can be readily regenerated back to its parentalquinone by reacting with oxygen generating superoxideanion (O2

∙minus) which could be further changed to other ROSor reactive nitrogen species (RNS) [18 19]This redox cyclingthus aids in amplifying the production of oxidative stressApart from mitochondrial enzymes endothelial nitric oxide





3 Oxidative Stress





∙minus


(1)






2O2)






(4)





2(5)























FLIP Bax

C8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bad

BidDeath receptor

Ligands

Pro-

C8TRA

DD

TRAF2RIP

ASK1

JNK C3 6 7P

Bid

t-Bid

Mcl-1

Bcl-xL

Bcl-2


NF-120581B


Ψ uarr




















FLIP

BaxC8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bax

Bax

Pro-

C8

FasR

DOX

Calcineurin

C3

Bcl-2


FasLDOX

ROS

transcriptionFasL

Bax

DOX

DOX

ROS

PARP

BaxBcl-2 uarr


Ca2+Ca2+

Ψ uarr









Abbreviations







Acknowledgments


References

























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















3 Oxidative Stress





∙minus


(1)






2O2)






(4)





2(5)























FLIP Bax

C8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bad

BidDeath receptor

Ligands

Pro-

C8TRA

DD

TRAF2RIP

ASK1

JNK C3 6 7P

Bid

t-Bid

Mcl-1

Bcl-xL

Bcl-2


NF-120581B


Ψ uarr




















FLIP

BaxC8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bax

Bax

Pro-

C8

FasR

DOX

Calcineurin

C3

Bcl-2


FasLDOX

ROS

transcriptionFasL

Bax

DOX

DOX

ROS

PARP

BaxBcl-2 uarr


Ca2+Ca2+

Ψ uarr









Abbreviations







Acknowledgments


References

























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























FLIP Bax

C8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bad

BidDeath receptor

Ligands

Pro-

C8TRA

DD

TRAF2RIP

ASK1

JNK C3 6 7P

Bid

t-Bid

Mcl-1

Bcl-xL

Bcl-2


NF-120581B


Ψ uarr




















FLIP

BaxC8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bax

Bax

Pro-

C8

FasR

DOX

Calcineurin

C3

Bcl-2


FasLDOX

ROS

transcriptionFasL

Bax

DOX

DOX

ROS

PARP

BaxBcl-2 uarr


Ca2+Ca2+

Ψ uarr









Abbreviations







Acknowledgments


References

























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















FLIP Bax

C8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bad

BidDeath receptor

Ligands

Pro-

C8TRA

DD

TRAF2RIP

ASK1

JNK C3 6 7P

Bid

t-Bid

Mcl-1

Bcl-xL

Bcl-2


NF-120581B


Ψ uarr




















FLIP

BaxC8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bax

Bax

Pro-

C8

FasR

DOX

Calcineurin

C3

Bcl-2


FasLDOX

ROS

transcriptionFasL

Bax

DOX

DOX

ROS

PARP

BaxBcl-2 uarr


Ca2+Ca2+

Ψ uarr









Abbreviations







Acknowledgments


References

























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























FLIP

BaxC8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bax

Bax

Pro-

C8

FasR

DOX

Calcineurin

C3

Bcl-2


FasLDOX

ROS

transcriptionFasL

Bax

DOX

DOX

ROS

PARP

BaxBcl-2 uarr


Ca2+Ca2+

Ψ uarr









Abbreviations







Acknowledgments


References

























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















FLIP

BaxC8

C9Apaf-1

Apoptosis

Cyto C

FAD

D

Bax

Bax

Pro-

C8

FasR

DOX

Calcineurin

C3

Bcl-2


FasLDOX

ROS

transcriptionFasL

Bax

DOX

DOX

ROS

PARP

BaxBcl-2 uarr


Ca2+Ca2+

Ψ uarr









Abbreviations







Acknowledgments


References

























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Abbreviations







Acknowledgments


References

























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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Review Article Chemotherapy-Induced Cardiotoxicity ...downloads.hindawi.com/journals/omcl/2015/795602.pdf · Chemotherapy-induced cardiotoxicity is a serious complication that poses