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Novel insights in pathophysiology of antiblastic drugs-induced cardiotoxicity and cardioprotection

Deidda, Martino; Madonna, Rosalinda; Mango, Ruggiero; Pagliaro, Pasquale; Bassareo, Pier P.; Cugusi, Lucia; Romano, Silvio; Penco, Maria; Romeo, Francesco; Mercuro, Giuseppe

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Journal of Cardiovascular Medicine: May 2016 - Volume 17 - Issue - p e76-e83
doi: 10.2459/JCM.0000000000000373
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Cardiotoxicity (CTX) induced by drugs poses a serious risk to human health and is becoming an increasingly important topic.1 To date, the conventional indexes and biomarkers of CTX often show evident changes only after heart damage has occurred. In recent decades, basic research focused on the mechanisms that underlie CTX have been performed to identify new signaling pathways that may be useful as possible biomarkers of early cardiac damage and as new therapeutic targets. More recently, a translational scientific approach has led to new opportunities for the investigation of the mechanisms of CTX as well as innovative strategies to address its screening and treatment.

In this article, we examine the role of stem cells and specific molecular pathways in CTX and cardioprotection and discuss the potential clinical utility of ‘omics" approaches for identifying CTX and individual responses to antineoplastic drugs.

Genomics and epigenetics

The identification of genetic and epigenetic contributions to the variability of the response to drugs may be essential for realizing personalized medicine, in particular, in cancer patients for whom CTX generates the most important adverse reactions.2 Established risk factors for CTX include a greater cumulative dose (e.g. for anthracycline), concomitant cardiac irradiation, higher individual doses, shorter infusion time, older than 65 years of age, female sex and cardiovascular comorbidity.3 However, demographic and clinical profiles alone are not sufficient to accurately stratify patients into groups that are at high and low risk for anthracycline-induced CTX (A-CTX).4 A-CTX can occur idiosyncratically in patients without obvious risk factors, suggesting a predisposition to susceptibility that may be genetically determined. Moreover, the genetic contribution to the variability among patients regarding their sensitivity to anthracyclines is further supported by the relatively higher heritability of A-CTX.5,6

The first analysis of genetic predisposition to A-CTX in humans was published in 2005 by Wojnowski et al.7 In this case–control study, 109 cases (55 acute A-CTX and 54 chronic A-CTX) and 363 matched controls were drawn from the German non-Hodgkin lymphoma study (NHL-B). Single-nucleotide polymorphisms (SNPs) from 82 genes were evaluated using a candidate gene approach. The genotyped genes were selected considering their role in reactive oxygen species (ROS) generation, doxorubicin (DXR) transport and development of congestive heart failure. The authors identified five significant SNPs within NAD(P)H oxidase as well as DXR efflux transporter genes associated with a higher risk of developing A-CTX. In particular, chronic ACT was associated with a variant of the NAD(P)H oxidase p40phox subunit (NCF4 gene, SNP rs1883112, −212A>G). Acute A-CTX was associated with an SNP of the NAD(P)H oxidase p22phox subunit (CYBA gene, SNP rs4673 c.242C>T), leading to the missense variation His72Tyr, and with an SNP of the NAD(P)H oxidase RAC2 subunit (RAC2 gene, SNP rs13058338 c.7508T>A). In addition, acute A-CTX was associated with an SNP located in DXR efflux transporter multidrug resistance protein 1 (ABCC1/MRP1 gene, SNP rs45511401, c.2012G>T, p.Gly671Val) and two missense variations located in multidrug resistance protein 2 (ABCC2/MRP2 gene, SNP rs8187694, c.3563T>A, p.Val1188Glu and SNP rs8187710, c. 4554G>A, p.Cys1515Tyr). In a subsequent study, Rossi et al.8 confirmed the role of the NCF4 rs1883112 SNP as an independent predictor of A-XCT (OR: 0.37) in 106 consecutive patients with diffuse large B-cell lymphoma treated with R-CHOP21 (rituximab with cyclophosphamide, DXR, vincristine and prednisone).

Interestingly, Cascales et al.9 explored the possible association of the NAD(P)H oxidase subunit SNPs: NCF4 rs1883112 (−212A>G), CYBA rs4673 (c.242C>G) and RAC2 rs13058338 (c.7508T>A) with the cardiac histological lesions related to anthracycline treatment. Interestingly, the authors observed a strong association between NCF4 rs1883112 SNP and cardiac interstitial fibrosis; thus, confirming the role of this variation in CTX, particularly in the chronic form, as previously reported.7 Moreover, an association between the CYBA rs4673 SNP and patched myocardial fibrosis was observed. Carriers of the C allele at the CYBA rs4673 SNP had a higher incidence of patched myocardial fibrosis than T carriers. No association was observed for the RAC2 rs13058338 variation.9 These studies confirm and expand the role of NAD(P)H oxidase and oxidative stress as major determinants of heart damage by anthracyclines.

Other mechanisms, such as variability in anthracycline metabolism, have been proposed as significant contributors to A-CTX, either through the generation of free radicals or toxic metabolites.10 In this context, Lubieniecka et al.11 using a multi-SNP-based approach, examined 60 genes coding for proteins involved in drug metabolism and efflux in 286 patients with acute myeloid leukemia. The authors identified three SNPs (rs2868177, rs13240755 and rs4732513) in the P450 oxidoreductase (POR) gene that were significantly associated with the drop of the left ventricular ejection fraction after daunorubicin administration through their linear interaction with the cumulative drug dose.

More recently, Wasielewski et al.12 starting with an observation of two patients affected by anthracycline-induced cardiomyopathy with multiple family members diagnosed with dilated cardiomyopathy (DCM), explored the hypothesis that a genetic predisposition for DCM could be a potential risk factor for A-CTX. The genetic screening of six DCM families revealed three mutations (c.1633G>A, p.Asp545Asn; c.2863G>A, p.Asp955Asn and c.4125T>A, p.Tyr1375X) in the MYH7 sarcomeric gene in two patients with anthracycline-induced DCM and a positive familiar history of DCM. On the basis of these data and because of the multifactorial genetic model that leads to A-CTX, a systematic analysis of nucleotide variations in DCM genes might be useful to confirm and further expand this new mechanistic link to A-CTX.

Although these studies have generated new insight and an original approach to understanding the genetic mechanism predisposing individuals to A-CTX, the data are not yet sufficiently clear and are often discordant, especially when pediatric and adult populations are compared.

Visscher et al.3 carried out a study of 2977 SNPs in 220 key drug biotransformation genes in two cohorts of 156 and 188 anthracycline-treated children with a replication of the top SNPs in a third cohort of 96 patients. The authors identified a highly significant association of a synonymous coding variant, rs7853758 (c.1381C>T, p.Leu461=), within the solute SLC28A3 gene that conferred significant protection against A-CTX. Moreover, additional associations with risk and protective variants in other genes (SLC28A1, ABCB1, ABCB4 and ABCC1) were found. However, the study failed to confirm the previously associated SNPs in the ABCC1 and NCF4 genes observed in the adult population. Patient age is one of the most important confounding demographic factors that has been shown to limit the success of genetic studies in A-CTX susceptibility.1 The following are other important confounding factors: the complexity of the A-CTX phenotype with many genes involved; the use of a standard singlevariant-based association test, which is often unable to detect the modest effect of each variant and is not suitable for the exploration of gene–environment interactions; a small sample size; ethnic differences in allele frequencies and epigenetic modifications.2,6,11

In addition to genetic variants, epigenetic systems, which are heritable genomic features that do not change the DNA sequence [e.g. cytosine modifications, microRNAs (miRNAs) and histone modifications], are known to play crucial roles in gene regulation. Recent studies have demonstrated that epigenetic mechanisms not only regulate the expression of protein-encoding genes but also miRNAs, which are noncoding RNAs involved in the posttranscription regulation of gene expression.13 Conversely, a specific group of miRNAs (defined as epi-miRNAs) can directly target effectors of the epigenetic machinery and indirectly affect the expression of genes, whose expression is controlled by epigenetic factors. This complex network of feedback between miRNAs and epigenetic pathways appears to form an epigenetics-miRNA regulatory circuit and to organize the whole gene expression profile.14 When this regulatory circuit is disrupted, the normal physiological functions are interrupted, contributing to various disease processes or to variability in drug responses.

Although miRNAs have been shown to play important regulatory roles in both cardiovascular disease and cancer, less data are available regarding A-CTX and epigenetics.15–19 Only a deeper exploration of this new field of knowledge may promote the understanding of the molecular mechanisms of cytotoxicity induced by anticancer agents.

DNA topoisomerases play important roles in cell cycle events, such as chromosome condensation/decondensation, DNA replication and sister chromatid segregation.18 Topoisomerase II α (Top2α) is highly expressed in proliferating cells, and the high anticancer efficacy of DXR, a Top2-targeting drug, is likely due to the high expression of Top2α in cancer cells. However, Top2β is also expressed in postmitotic cells, including cardiomyocytes,20 and DXR CTX comprises Top2β-dependent alterations in the expression of genes involved in the regulation of mitochondrial biogenesis and function. Indeed, mitochondrial alterations affect oxidative phosphorylation, leading to the exaggerated production of ROS, which may be responsible for CTX.21,22

All of these findings, although still not suitable for clinical application, lay the foundation for the development of personalized medicine based on the prevention of A-CTX with the use of genetic testing. The ability to identify optimal patient groups by their genetic make-up could significantly impact the care of cancer patients by reducing the rate of unnecessary side-effects.


The first proteomics approach to antiblastic CTX was attempted in 2004 by Petricoin et al.,23 who studied the potential clinical utility of using diagnostic proteomics patterns to identify CTX signals. They analyzed the mass spectra obtained from more than 200 serum samples from spontaneously hypertensive rat challenged with DXR or with mitoxantrone ± dexrazoxane to assess whether high-resolution serum proteomic patterns could outperform the serum cardiac troponin T (cTnT) for detecting early cardiac damage. The spectra were divided into four datasets that were used in as many experiments to generate proteomic results that were compared with both pathological and serum biomarkers of cardiac injury (histological changes and concentrations of cTnT, respectively). The authors concluded that proteomic analysis was able to identify the natural history of the treatment, the serum cTnT levels and the histological pattern of prior cardiac damage.

Ohyama et al.24 applied proteomic analysis to heart tissue from control, docetaxel (DOC) and adriamycin (ADR) intermittent (DOC-ADR) and simultaneous-dosing (ADR and DOC) groups. The analysis of heart samples identified nine proteins that were differentially expressed in the control and two treatment groups; seven of these proteins were involved in energy production pathways, including glycolysis, the Krebs cycle, and the mitochondrial electron transport chain. Remarkably, glyceraldehyde-3-phosphate dehydrogenase expression was higher in the group with a lower death rate.

The involvement of energy metabolism was confirmed in 2011 by Stěrba et al.25 They investigated a model of CTX induced in rabbits with daunorubicin (3 mg/kg weekly, 10 weeks). The proteomics results were compared with functional, morphological and biochemical data. The most important alterations were found in mitochondrial proteins involved in oxidative phosphorylation, energy channeling and antioxidant defense. Moreover, desmin resulted in a distinct upregulation, and the expression of the myosin light chain isoforms was decreased. In addition, the activation of proteolytic mechanisms and an increased abundance of chaperones and proteins involved in autophagy, membrane repair and apoptosis were found.

In the same year, Kumar et al.26 used a rat model of DXR-induced CTX to demonstrate the differential regulation of several key proteins, including proteins that are stress responsive (ATP synthase, enolase alpha, alpha B-crystallin, translocation protein 1 and stress-induced phosphoprotein 1), and apoptotic/cell damage markers (p38 alpha, lipocortin, voltage-dependent anion-selective channel protein 2, creatine kinase and MTUS1).


The sensitivity of metabolomics, that is the study of the small-molecule metabolite profile of a biological organism,27 represents a very promising basis for its application in the field of CTX and cardioprotection.

In 2009, Andreadou et al.28 carried out NMR-based metabolomics profiling of acute DXR-induced CTX in rats. The hearts were excised 72 h after DXR treatment, and 1H-NMR spectra of aqueous myocardium extracts were recorded. Principal component analysis and partial least square discriminant analysis revealed differences between the control and DXR groups. In detail, the myocardial levels of acetate and succinate were increased in DXR, whereas the levels of branched amino acids were decreased. Moreover, they investigated the role of oleuropein, a phenolic antioxidant present in olive trees, and reported that it conferred protection against DXR CTX. The authors concluded that acetate and succinate could be useful as CTX biomarkers and that oleuropein treatment could reduce energy metabolic pathways distress.

The role of oleuperin in preventing CTX was confirmed by a successive study in which Andreadou et al.29 compared a metabolomic analysis with cardiac geometry and function data assessed by echocardiography, cardiac histopathology, nitro-oxidative stress (Malondialdehyde, protein carbonyls, nitrotyrosine), inflammatory cytokines (IL-6, Big ET-1), Nitric Oxide homeostasis [inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expressions] and kinases involved in apoptosis (Akt, 5′ adenosine monophosphate-activated protein kinase).

The importance of energetic metabolic reactions in the development of CTX was confirmed in 2011 by a gas chromatography-mass spectrometry metabolomic study conducted by Tan et al.30 In a rat model of DXR-induced CTX, they found that a CTX fingerprint composed of 24 metabolites was involved in glycolysis, the citrate cycle and the metabolism of some amino acids and lipids.

To reduce the cumulative CTX of pirarubicin (THP), an anthracycline used in acute leukemia, malignant lymphoma and several solid tumors, a liposomal drug delivery system was developed. Cong et al.31 investigated the urinary metabolomic profiles of Sprague-Dawley rats after three successive doses of THP liposome powder (L-THP) or free THP (F-THP). Metabolomic analysis showed only minimal metabolic alterations in L-THP compared with F-THP, and these findings correlated with the biochemical and cardiac histopathologic indexes of heart injury. Moreover, successive doses of THP led to severe metabolic disturbances, particularly at the level of the well known target of cell energy production pathways. In detail, in the drug treatment groups, the expression of citrate (Krebs cycle), lactate (glycolysis), D-gluconate-1-phosphate (pentose phosphate pathway), N-acetylglutamine and N-acetyl-DL-tryptophan (amino acid metabolism) was downregulated. Furthermore, F-THP treatment caused a greater downregulation of intermediary metabolites compared with L-THP treatment.

More recently, Li et al. created a murine model of CTX that was induced by DXR (20 mg/kg), isoproterenol (5 mg/kg) and 5-fluorouracil (125 mg/kg). The metabolomic analysis of plasma samples was carried out using ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry. The authors applied multivariate statistical and integration analyses and identified 39 biomarkers that were able to predict CTX earlier than other biochemical analyses and histopathological assessments.

Drugs with different toxicities can induce metabolic changes similar to each other, although they differ when compared to other non-CTX models (hepatotoxic and nephrotoxic). Therefore, the identified biomarkers were processed for verification and optimization, combined with hepatotoxicity and nephrotoxicity, to filter out exclusive CTX biomarkers. Ten metabolites, among which L-carnitine, 19-hydroxydeoxycorticosterone, lysophosphatidylcholine (14 : 0) and LPC (20 : 2) were the most highly specific, had a prediction rate of up to 90.0%.32

The proteomics and metabolomics findings suggest that energy metabolism is a key target in A-CTX development. Therefore, research aimed to investigate these pathways could lead to the identification of early markers of CTX and the development of innovative cardioprotective agents.

Redox and NO pathways in cardiotoxicity

In the cardiovascular system, ROS can be generated by different cell types, including cardiomyocytes. Different enzyme/mechanisms can produce ROS (Fig. 1), including NADPH oxidase, uncoupled NOS and electrons leaked from mitochondrial complexes.32,33 Cardiomyocyte mitochondria represent 36 to 40% of the cellular mass, and the mitochondrial respiratory chain at complex I and III is the main source of superoxide anions (O2•–).33,34 These radicals can be converted to H2O2 (hydrogen peroxide) and to OH•– (hydroxyl radical) by several processes within and outside of mitochondria.33–35

Fig. 1
Fig. 1:
Anthracyclines, such as doxorubicin, trigger the generation of reactive oxygen species and affect enzyme activity, including mitochondrial enzyme complexes, nitric oxide synthase, NAD(P)H-oxidases and glutathione peroxidase, leading to cell damage. Anthracyclines via different mechanisms (arrows) favor lipid peroxidation and DNA damage and affect mitochondrial function; thus, reducing energy production within the cell. See the text for other details. GPX, glutathione peroxidases; NOS, nitric oxide synthase; RNS, reactive nitrogen species; ROS, reactive oxygen species.

Another biologically important redox species is nitric oxide (NO•), which also has antioxidant properties.34,35 It is generated by three different isoforms of NOS, endothelial (eNOS or NOS3) and neuronal (nNOS or NOS1), which are constitutively expressed in cardiomyocytes and, possibly, within mitochondria, as well as by inducible NOS2 (iNOS), which is not present in the healthy/naïf myocardium, but may be stimulated from proinflammatory mediators or ischemic preconditioning.36–38 Nitric oxide regulates heart and coronary function by the spatial confinement of NOS isoforms. However, NO• can also be produced by other reactions in the biological systems, which are collectively called ‘non-NOS’ processes. These include reactions catalyzed by ‘non-NOS enzymes’, such as cytochrome C, hemoglobin and xanthine oxidoreductase, and reactions due to‘nonenzymatic’ process under acidic conditions, such as the reduction of nitrite to NO•. Nitrite and NO• can produce different biological actions by direct or indirect posttranslational nitration (3-nitrotyrosine formation) or the nitrosation/nitrosylation of specific targets, such as metals and cysteine thiol residues.33,39 NO• and ROS lead to the formation of reactive nitrogen species (RNS), including peroxynitrite (ONOO−). These molecules (ROS/RNS) and their interactions affect coronary and myocardial function and are able to modulate pathophysiological signaling pathways in a redox-dependent way.33,38,39

A strong ROS source is represented by the NADPH oxidase system, namely, isoforms NOXs 1–5 and dual oxidases DUOX1/2. Increasing evidence suggests that myocardium NOX2 (usually quiescent) produces O2•– and NOX4 (constitutively active) and only generates H2O2. Together with the antioxidant defense systems and the capacity of redox buffers, NOXs contribute to the creation of a delicate ROS homeostasis, which can be disturbed by a weak insult and by antiblastic treatments (see infra).38,40–42 In fact, the cytosol and organelles also contain redox buffers and antioxidant enzymes, among which the most important are catalases, superoxide dismutases (SOD1 and SOD2) and glutathione peroxidases.42–44 The latter may also be targets of antiblastic agents (see infra). Mitochondrial, nonmitochondrial ROS/RNS sources and redox buffer systems dictate the overall ROS/RNS homeostasis and hence also the switch from physiological oxidative/nitrosative signaling to pathological oxidative/nitrosative stress.38,40,42 In fact, stimulated ROS/RNS and NOX-related damage contribute to both the initiation and progression of many solid and hematopoietic cancers,45 whereas antiblastics, and in particular anthracyclines, may induce CTX via altered ROS/RNS production and/or an endogenous antioxidant system disturbance within the cardiovascular system.46,47

Anthracyclines in the heart trigger both ROS-independent and ROS-dependent pathways that may lead to substantial apoptosis and necrosis of cardiomyocytes.41 In ROS-dependent pathways, it has been reported that DXR binds to iron (Fe), both in the ferric (Fe3+) and ferrous (Fe2+) forms, generating Dox:iron complexes that can favor the formation of O2•–, but can also reduce H2O2 to the more dangerous OH•–.46 Disorders of the respiratory chain are considered to be responsible for the generation of ROS, even after treatment with anthracyclines is terminated. In fact, exposure to anthracyclines may depress the activity of cardiac glutathione peroxidases and induce alterations of the respiratory chain, leading to ROS-mediated mitochondrial-DNA damage.48,49 This ROS production may also induce cardiomyocyte apoptosis.50 Actually, a portion of cardiac injury triggered by anthracyclines is due to their high affinity for cardiolipin, a mitochondrial membrane phospholipid that is involved in apoptotic pathways.51,52 The initial phases of apoptosis ROS can lead to peroxidation of cardiolipin,53 which may induce the release of cytochrome C and other mitochondrial apoptogenic factors. Interestingly, cytochrome C can trigger cardiolipin peroxidation; thus, triggering a vicious cycle that exacerbates anthracycline-induced damage.51 Intriguingly, NO• can inhibit the peroxidase activity of the cytochrome C/cardiolipin complex and can block cardiolipin oxidation.54 Thus, it can be argued that site-specific and appropriate amounts of NO•, which has antioxidant properties, may counteract the toxic effects of anthracyclines. Indeed, gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences.55,56

Although redox stress is essential for A-CTX, different redox inhibitors given together with anthracyclines were not cardioprotective. The failure of these agents to protect against anthracycline-induced cardiac injury may be due to a plethora of reasons, including the important physiological role of ROS/RNS, which is disturbed by large-spectrum oxidant scavengers. Nevertheless, it is likely that A-CTX is not exclusively caused by redox stress.52 If DXR-dependent energetic and oxidative stress depends upon a vicious cycle triggered by late sodium current hyperactivation, it is likely that ranolazine, a potent and selective late sodium current inhibitor, may stop this vicious cycle. On these basis, ranolazine has been proposed to be a cardioprotective agent that is capable of sustaining ATP production and ROS scavenging without affecting the DXR-dependent antiblastic effects41,57 In C57BL6 mice, DXR treatment for 7 days produced LV dilation and decreased echo-measured fractional shortening, instead by elevations in atrial and brain natriuretic peptides, connective tissue growth factor and matrix metalloproteinase 2 mRNAs, whereas ranolazine, coadministered with DXR, prevented all these events; noteworthy, similar protective results were obtained with the Na+/Ca2+ exchanger inhibitor KB-R7943.58

Intriguingly, experimental studies have shown that neuregulin-1 attenuates DXR damage in rat cardiomyocytes via a redox mechanism.59 Although the role (beneficial vs. detrimental) of hydrogen sulfide (H2S) in cancer diseases is still controversial, a novel redox modulator approach can be conceived by the observation that the ROS-mediated inhibition of cystathionine-γ-lyase, a key enzyme in the generation of H2S, is involved in DXR-induced cytotoxicity in H9c2 cardiomyocytes and that exogenous H2S can confer protection against DXR-induced CTX.60 Of course, these observations and hypotheses require experiments in appropriate animal models and comparative studies with other already approved cardioprotective drugs (e.g. dexrazoxane), as well as randomized trials in the context of antiblastic CTX.

The role of cardiovascular stem cells in cardiotoxicity and cardioprotection

In the failing heart, not only adult cardiac cells but also stem (CSCs) and progenitor cells (CPCs) can undergo degenerative changes, such as necrosis and apoptosis.61 Thus, these cell populations may be implicated in the onset and development of the cardiovascular effects of anticancer strategies.61,62 The possibility of preventing CTX by the preservation and/or expansion of the resident stem cell pool that is responsible for cardiac repair may open new therapeutic options. Among cardiac stem cell populations, one of the best characterized was first isolated by Beltrami et al.63 by virtue of its expression of stem cell growth factor receptor c-kit, which is involved in stem cell mobilization into the injury area.64 c-Kit positive cells are multipotent and demonstrate self-renewal and clonogenic capacities. In addition, these cells have remarkable regenerative potential when injected into rat hearts following surgically induced myocardial infarction.63 Recently, the work of Giacomello and Marban isolated and expanded another type of CSC from biopsies of human and murine hearts in primary culture. These cells form multicellular clusters, dubbed cardiospheres (CSp), in suspension culture. Approximately 30% of CSp express the c-kit marker and are composed of clonally derived cells, consisting of proliferating c-kit+ cells primarily in their core as well as differentiating cells expressing cardiac and endothelial cell markers on their periphery.65 In-vivo experiments have shown that injected CSp can functionally improve the heart. The location of CSCs and CPCs in the heart is not random, but is well organized in a fixed compartment named the ‘stem cell niche,’66 which has the capability to protect and maintain the stem cells under well defined microenvironmental conditions. The stem cell niche is an interactive anatomical structure consisting of stem cells, supporting cells, the extracellular matrix and, most importantly, a wide range of molecular, chemical and mechanical signals whose balance influences the fate of stem cells and protects them from stimuli that might interfere with their ‘stemness’, including apoptotic stimuli.67 CSCs and their niche may be sensitive to the interference of anthracyclines on DNA replicative machinery, resulting in the inhibition of CSC/CPC proliferation.61 This phenomenon may be operative in anthracycline-induced cardiomyopathy, so that the repeated administration of the drug may affect the population of CSCs/CPCs that are activated in an attempt to repair the damaged myocardium. In fact, recent data have shown that exposure to DXR over a period of 6 weeks led to an almost complete depletion of the CSC/CPC pool within the myocardium due to the inhibition of CSC/CPC division in combination with the accumulation of oxidative DNA damage, growth arrest, cellular senescence and apoptosis.61 In addition, tyrosine kinase receptor inhibitors sunitinib and sorafenib inhibit c-kit expression, with consequent impairment of CSC and CPC mobilization into the injury area.64,68 CSCs and CPCs offer a novel and promising cardioprotective strategy for cancer therapy-induced CTX, mainly through their paracrine effects.61,69–74 CADUCEUS75 has used c-kit+/Sca-1+ cells and CSp, and has demonstrated promising results following the application of CSCs. In preclinical models of DXR-induced cardiomyopathy, the transplantation of syngeneic CPCs via intramyocardial injection improves heart function.61 Several signaling pathways, including Akt 1373 and Notch,71 are advocated to mediate the cardioprotective effects of CSCs and CPCs. On the basis of these promising results, myocardial biopsies of neoplastic patients may be obtained before antineoplastic drugs are given, and autologous CSCs or CPCs can be isolated and expanded from these myocardial samples and injected back into the cardiomyopathic heart, where these cells can contribute to myocardial protection, neovascularization and the reduction of cardiac fibrosis by the secretion of growth factors (Fig. 2).71,73

Fig. 2
Fig. 2:
The mechanisms of stem cell-based cardioprotection and cardiotoxicity.


Animal models, which consider risk factors for cardiovascular disease and comorbidities, are currently essential for adequate successive clinical translation.76 Hopefully, the large body of pathophysiological data provided by such investigations may allow improved a priori stratification and early identification of CTX risk. Moreover, in the near future, basic and translational studies may also identify novel and highly effective therapeutic strategies to potentially prevent antiblastic-induced CTX.

There are no conflicts of interest.


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cardiotoxicity; genomics; proteomics; metabolomics; NO pathways; stem cells

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