Download The tell-tale heart: molecular and cellular responses to childhood

Am J Physiol Heart Circ Physiol 307: H1379–H1389, 2014.
First published September 12, 2014; doi:10.1152/ajpheart.00099.2014.
Review
The tell-tale heart: molecular and cellular responses to childhood
anthracycline exposure
Merry L. Lindsey,1 Richard A. Lange,2 Helen Parsons,3 Thomas Andrews,4 and Gregory J. Aune4
1
Department of Physiology and Biophysics, San Antonio Cardiovascular Proteomics Center and Jackson Center for Heart
Research, Mississippi Medical Center, Jackson, Mississippi; 2Division of Cardiology, Department of Medicine, San Antonio
Cardiovascular Proteomics Center, University of Texas Health Science Center San Antonio, San Antonio, Texas; 3Department
of Epidemiology and Biostatistics, University of Texas Health Science Center San Antonio, San Antonio, Texas; and 4Division
of Hematology-Oncology, Department of Pediatrics, Greehey Children’s Cancer Research Institute, University of Texas
Health Science Center San Antonio, San Antonio, Texas
Submitted 12 February 2014; accepted in final form 8 September 2014
anthracyclines; congestive heart failure; cardiomyopathy; cardiomyocytes; fibroblast; extracellular matrix
APPROXIMATELY 325,000 SURVIVORS of pediatric cancer currently
reside in the United States, and 1 in 540 young adults is a
cancer survivor (60). Anthracyclines are components of
most curative combination chemotherapy regimens for
childhood leukemia, lymphoma, and solid tumors, and approximately half of all newly diagnosed pediatric cancer
patients will be treated with an anthracycline-containing
regimen (78). Many of these individuals have, or are at risk
of developing, chronic illnesses related to their childhood
cancer treatments that adversely affect their long-term survival (6, 34, 55, 72, 93, 96). Cardiovascular disease and
secondary malignancies are the two leading causes of premature death in pediatric cancer survivors (6).
Reports of cardiovascular outcomes in pediatric cancer
survivors treated with anthracyclines have focused primarily
Address for reprint requests and other correspondence: G. J. Aune, 8403
Floyd Curl Dr., MSC 7784, San Antonio, TX 78229 (e-mail: aune@uthscsa.
edu).
http://www.ajpheart.org
on clinical outcomes, current preventive strategies, or recommendations for clinical management (9, 22, 25, 38, 43,
44, 48, 68, 77– 83, 125, 126, 140). The rationale for our
review is based on the following three observations. First,
the clinical outcomes in anthracycline-exposed individuals
are not completely explained by the known molecular effects of anthracyclines on the cardiac myocyte. Second, to
our knowledge no recent review has focused on anthracycline cardiotoxicity in the nonmyocyte cell populations of
the heart and those that mediate the myocardial injury
response. Third, additional laboratory models are urgently
needed to better understand the pathogenesis of heart disease in this population, and these models must account for
both the observed clinical outcomes and the events that
occur over time in the collective myocardial cell types that
are responsible for pathological events at the organ level.
Therefore, our review will 1) briefly summarize the clinical
cardiovascular outcomes to provide the necessary clinical
context and 2) focus on the molecular events that occur in
0363-6135/14 Copyright © 2014 the American Physiological Society
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Lindsey ML, Lange RA, Parsons H, Andrews T, Aune GJ. The tell-tale heart:
molecular and cellular responses to childhood anthracycline exposure. Am J Physiol
Heart Circ Physiol 307: H1379 –H1389, 2014. First published September 12, 2014;
doi:10.1152/ajpheart.00099.2014.—Since the modern era of cancer chemotherapy
that began in the mid-1940s, survival rates for children afflicted with cancer have
steadily improved from 10% to current rates that approach 80% (60). Unfortunately, many long-term survivors of pediatric cancer develop chemotherapy-related
health effects; 25% are afflicted with a severe or life-threatening medical condition,
with cardiovascular disease being a primary risk (96). Childhood cancer survivors
have markedly elevated incidences of stroke, congestive heart failure (CHF),
coronary artery disease, and valvular disease (96). Their cardiac mortality is 8.2
times higher than expected (93). Anthracyclines are a key component of most
curative chemotherapeutic regimens used in pediatric cancer, and approximately
half of all childhood cancer patients are exposed to them (78). Numerous epidemiologic and observational studies have linked childhood anthracycline exposure to
an increased risk of developing cardiomyopathy and CHF, often decades after
treatment. The acute toxic effects of anthracyclines on cardiomyocytes are well
described; however, myocardial tissue is comprised of additional resident cell
types, and events occurring in the cardiomyocyte do not fully explain the pathological processes leading to late cardiomyopathy and CHF. This review will
summarize the current literature regarding the cellular and molecular responses to
anthracyclines, with an important emphasis on nonmyocyte cardiac cell types as
well as those that mediate the myocardial injury response.
Review
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CHILDHOOD ANTHRACYCLINE EXPOSURE
Cardiovascular Outcomes in Long-Term Survivors of
Pediatric Cancer Exposed to Anthracyclines
Cardiovascular complications in anthracycline-exposed pediatric cancer survivors may manifest clinically as congestive
heart failure (CHF), ischemic heart disease, stroke, or cardiac
mortality. Cardiac imaging in these subjects may demonstrate
functional or anatomic abnormalities such as cardiomyopathy,
diastolic dysfunction, and valvular disease. These collective
outcomes are important to consider in the context of understanding the interrelated events in anthracycline-exposed myocardial cell populations and the development of relevant preclinical laboratory models of anthracycline cardiotoxicity. A
number of studies have demonstrated an increased risk for
these cardiovascular outcomes, most of which have used the
National Cancer Institute-funded U24 resources of the Childhood Cancer Survivor Study (CCSS). The CCSS is a multiinstitutional effort that has collected treatment and outcome
data on 14,357 long-term childhood cancer survivors and 3,899
sibling controls (72). Oeffinger and colleagues (96) used data
from this cohort to show that the relative risk (RR) of cardiovascular disease is markedly increased in long-term pediatric
cancer survivors compared with matched sibling controls,
including CHF (RR ⫽ 15.1), stroke (RR⫽ 9.3), and coronary
artery disease (RR⫽ 10.4). Importantly, Mulrooney and colleagues (93) completed a study using the CCSS cohort in
which the standardized mortality ratio (SMR) for cardiac death
was 8.2 times higher than expected. These findings have been
reinforced by new analysis of existing human cancer patient
clinical registries by our team (manuscript in preparation.).
These analyses provide further confirmation that childhood
cancer survivors are at significantly higher risk of cardiovascular mortality compared with the general population (Fig. 1).
Examining cardiovascular outcomes in a population-based cohort of childhood cancer survivors enrolled in the Surveillance,
Epidemiology, and End Results Program (SEER) from 1980 to
1989, we found significantly higher cardiac mortality over time
in survivors compared with the general population (Fig. 1A).
Although the SMR for cancer survivors appears to decrease
over time, it remains at least 10 times higher in long-term
cancer survivors compared with the general population. The
lower SMR over time is likely the result of aging of both
survivors and the general population over time, when the
incidence of cardiac events increases in both groups (Fig. 1B).
Fig. 1. Analysis of Surveillance Epidemiology and End Results (SEER)
database to estimate death from cardiac causes in pediatric cancer survivors. A:
standardized mortality ratio (SMR) for cardiac causes in pediatric cancer
survivors compared with the general U.S. population. B: absolute death
number from cardiac causes in pediatric cancer survivors compared with the
general U.S. population.
Cardiac death in children and young adults is extremely rare,
and any event drives large increases in the SMR compared with
the general population of the same age. The important point
remains that even 20 to 30 years after diagnosis, survivors of
childhood and young adult cancers remain more than three
times more likely to experience cardiac mortality compared
with the general population.
Studies using a variety of imaging modalities show that
cardiac anatomic and functional characteristics are frequently
abnormal in long-term survivors of pediatric cancer who have
no clinical symptoms of cardiac disease. Lipshultz and colleagues (81) assessed echocardiographic outcomes in survivors
of childhood cancer and noted lower left ventricular mass, wall
thickness, contractility, and fractional shortening in anthracycline-exposed individuals compared with those who did not
receive an anthracycline. In 277 adult survivors in the CCSS
survey, Brouwer and colleagues (19) showed significantly
higher rates of systolic and diastolic dysfunction in survivors
compared with sibling controls as assessed by echocardiography.
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the cell types that comprise myocardium and those that
direct the responses that occur with injury. Because cardiac
myocytes have historically been the central focus of anthracycline cardiotoxicity research, this review will be heavily
weighted toward molecular events in them. Nevertheless,
our overall goal is to highlight all myocardial cell types and
injury response mechanisms that collectively guide the pathological development of disease in anthracycline-exposed
patients. These cell types include immune cells that are part
of the inflammatory reaction and resident cardiac fibroblasts
that are part of the wound healing response and produce
extracellular matrix (ECM). Developing a more balanced
approach to understanding myocardial anthracycline-induced injury may facilitate the identification of novel targets
to ameliorate the risk for cardiac disease in pediatric cancer
survivors.
Review
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CHILDHOOD ANTHRACYCLINE EXPOSURE
Table 1. Drugs and strategies used to prevent anthracycline-induced cardiotoxicity
Strategy
Deplete iron needed for
ROS production
Counteract ROS effects
Regulate inflammatory response
Miscellaneous or unknown
Target or Mechanism
Reference
Dexrazoxane*
Deferiprone#
Monohydroxyethylrutoside#
Pyroxyl 2-chlorobenzoyl hydrazine#
Amifostine#
CoQ10#
Didox#
Garlic extract#
Glutathione-S-transferase#
HO-3867#
N-acetylcysteine#
Probucol#
Resveratrol#
Schisandrin B#
Tempol#
Telmisartan - angiotensin II blocker#
Trimetazidine#
Vitamin E*
Adiponectin#
Bosentan#
Endothelin-converting enzyme#
PARP inhibitors#
Phosphodiesterase-5 inhibitor#
Pifithrin-␣#
Thrombopoietin#
Erythropoietin#
FGF-2#
Iloprost#
ACE inihibitors*
Administration rate
Berberine#
Liposomal delivery*
Exercise*
Metalloporphyrinic peroxynitrite
decomposition catalyst#
Statins*
Iron chelator
Iron chelator
Iron chelator
Iron chelator
Antioxidant
Antioxidant
Antioxidant
Antioxidant
Antioxidant
Antioxidant
Antioxidant
Antioxidant
Antioxidant
Antioxidant
Antioxidant
Antioxidant
Antioxidant
Antioxidant
Antiapoptosis
Antiapoptosis
Mitochondrial regulation
Antiapoptosis
Antiapoptosis
Antiapoptosis - anti-p53
Antiapoptosis
Antioxidant and anti inflammatory
Cytokine
Synthetic prostaglandin
2Blood pressure/modify ECM remodeling
2Peak serum dose
Unknown
Selective delivery to tumors to limit off-target exposure
1Antioxidant production and reduce ECM remodeling
Anti-nitric oxide
(49, 50, 76, 84, 85, 131)
(3)
(20, 21)
(120)
(13, 14)
(29)
(1)
(2)
(71)
(30)
(94)
(36, 74, 75, 115)
(35)
(24, 137)
(90)
(47)
(124)
(47, 122)
(88)
(12)
(89)
(98)
(63)
(87)
(23)
(4)
(116)
(95)
(15, 16, 51, 109)
(11, 57, 82)
(144)
(104)
(35, 56, 62)
(97)
Antioxidant and anti-inflammatory
(113)
ROS, reactive oxygen species; CoQ10, coenzyme Q10; PARP, poly(ADP-ribose) polymerase; ACE, angiotensin-converting enzyme. *Clinical evidence.
#Preclinical evidence.
Other studies have used more sensitive imaging methods to
screen for subclinical cardiovascular complications in the survivor population. For example, Armstrong and colleagues (7)
recently used cardiac MRI to study 108 anthracycline-exposed
pediatric cancer survivors and found that 14% had a left ventricular ejection fraction of ⬍50% that was classified as normal by
cardiac ultrasonography. Subclinical cardiac dysfunction [i.e.,
abnormal regional wall motion (138) and myocardial performance
index (108)] has also been identified by echocardiographic studies
of anthracycline-treated children, especially in those who received
higher cumulative doses of the drug.
The association between anthracycline exposure in childhood and the development of cardiac dysfunction later in life is
well documented. Because of these studies, current recommendations are not to exceed anthracycline doses of 450 mg/m2.
However, the underlying molecular mechanisms that explain
the late onset of symptoms have not been fully elucidated.
Etiology of Cardiomyopathy in Anthcracycline-Exposed
Patients
Anthracycline exposure in childhood initiates a pathological
progression that may culminate in dilated cardiomyopathy in
adulthood (64). In contrast to almost all other forms of cardiomyopathy, the major myocardial changes that occur after early
anthracycline exposure are predominantly found in the interstitial areas and do not result in extensive hypertrophy. Importantly, fibrosis is a major histologic change that occurs in
survivors who have received anthracycline chemotherapies
(10). Bernaba and colleagues (10) reviewed medical records
from 10 patients who had a history of anthracycline exposure
and available cardiac tissue samples (9 had cardiac transplantation as a result of anthracycline-induced heart failure). Histologic analysis revealed significant interstitial fibrosis in all 10
patients without hypertrophy.
The molecular and cellular mechanisms that direct the development of anthracycline-induced cardiomyopathy remain largely
unknown. With the combination of knowledge of pathological
progression with the range of cellular and molecular effects, it is
possible to speculate on novel targets and therapies for intervention. A number of studies have used existing knowledge to test
protective strategies. A summary of these strategies is listed in
Table 1. To identify new therapeutic strategies, it will be imperative to continue research aimed at elucidating the underlying
molecular events and testing novel inhibitors in the context of the
unique pathology of anthracycline-induced cardiac injury. This
review will summarize what is currently known about the cellspecific effects and molecular events induced by anthracyclines in
the cardiovascular system and heart.
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Prevent apoptosis or regulate
mitochondria
Therapy
Review
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CHILDHOOD ANTHRACYCLINE EXPOSURE
Myocytes
HSF11
Nox2
PARP
NFAT5
TopII β
mTOR
GATA4
HSP90
p38-MapK
BRCA2
Caveolin-3
p-p300/CBP
Caveolin-1
Bcl2:Bax Ratio
cytochrome C
miR-146a
p53
ROS
Neuregulin-1
CCPK-II
Nrdp1
Ub-proteasome
Dystrophin
p21
?
?
Endothelial Cell
Casp3
Bax
Fas
Cardiac Progenitor Cell
telomeres
NFKappaB
?
?
?
endothelin 1
endothelin 1
p16
?
?
?
Extracellular
Matrix
?
Fibroblast
Collagen
Immune Cells
?
Lymphocytes
TLR4
Fibronectin
MMPs
Thrombospondin
Cell-Specific Myocardial Response to Anthracyclines
The major mechanisms of anthracycline-induced myocardial
damage that have been explored focus on the iron-dependent
generation of reactive oxygen species (ROS) and the induction
of cardiomyocyte apoptosis (25), with subsequent loss of
myocytes and replacement fibrosis (31). Whereas these clearly
important mechanisms explain the early loss of cardiac myocytes, they do not fully explain the complex series of events
that occurs later when chemotherapy is completed or the events
that occur in other cardiac cells—such as fibroblasts and
invading immune cells—that are central mediators of the
myocardial injury response (39). Additionally, anthracyclines
may be arrhythmogenic during acute infusion (5, 46, 66, 103),
injure vascular endothelial cells lining the coronary arteries and
endocardium (28, 54, 117, 148), and affect cardiac progenitor
cells (CPCs) (17, 31).
The wide-ranging effects of anthracyclines on individual
myocardial cell types are summarized in Fig. 2. As depicted in
Fig. 2, much more information exists regarding the effects of
anthracyclines on the myocyte than on all of the other cell
types combined. Emerging data from clinical studies and
experiments using cell types and animal models with specific
defects in the injury response strongly suggest an important
role for these distinct cell types in anthracycline-induced cardiac injury. This review will summarize what is currently
known about the molecular responses to anthracyclines in
myocytes, endothelial cells, CPCs, and the cells coordinating
the cardiac injury response.
Myocytes. An extensive amount of experimental data regarding the mechanism of action of anthracyclines in myocytes has
been collected, with most obtained in cultured mouse or rat
cardiomyocyte cell lines isolated from animals ranging from
neonatal age into adulthood. Whereas the generation of ROS
has long been a known biological response to anthracyclines, a
diverse array of other cellular pathways has also been implicated. However, the interactions among these pathways, their
effects on other cell types in the myocardium, and the ECM
remain largely unexplored.
GENERATION OF REACTIVE OXYGEN SPECIES. In cultured cardiomyocytes, antioxidants protect against oxidative stress induced by doxorubicin (32). The Wallace laboratory (146) used
an in vivo model of anthracycline exposure in adult male
Sprague-Dawley rats to show elevated ROS formation in
isolated cardiomyocytes that persisted for 5 wk after exposure
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Fig. 2. Summary of myocardial cellular effects
and the injury response induced by anthracyclines. Blue, absence abrogates cardiac dysfunction or protects from apoptosis; green,
downregulation of mRNA and pathway inhibition; yellow, mediates apoptotic response;
red, expression increases or enhances cardiac
dysfunction; orange, absence enhances cardiac
dysfunction. Anthracycline exposure increases
p53, and global knockout abrogates the cardiotoxic response. HSF11, heat shock factor 11;
Nox2, cofactor for NADPH oxidase; TopII␤,
topoisomerase II-␤; HSP27, heat shock protein
27;
PARP,
poly(ADP-ribose)polymerase;
HSP90, heat shock protein 90; GATA4, transcription factor; NFAT5, nuclear factor of activated T cells; mTOR, mammalian target of rapamycin; p38-MAPK, p38 mitogen-activated protein kinase; p-p300/CBP, phosphorylated p300/
CREB binding protein; BRCA2, breast cancer
susceptibility gene 2; Bcl2:Bax ratio, ratio of
B-cell lymphoma 2 to bcl2-like protein 4; miR146a, microRNA 146a; ROS, reactive oxygen
species; CCPK-II, calcium calmodulin-dependent protein kinase II; Nrdp1, E3 ubiquitin ligase; Ub-proteasome, ubiquitinated proteasome;
Casp3, caspase 3; Bax, bl2-like protein 4; Fas,
ligand for Fas receptor; NF-␬B, nuclear factor-␬
light chain enhancer of activated B cells; MMPs,
matrix metalloproteinases; TLR4, Toll-like receptor 4.
p53
HSP27
Review
CHILDHOOD ANTHRACYCLINE EXPOSURE
induced myocyte toxicity. These studies indicate the following:
1) deficiency in poly(ADP-ribose) polymerase, an enzyme that
repairs DNA single strand breaks, results in protection against
doxorubicin-induced damage (123) and 2) deficiency in breast
cancer susceptibility gene-2 protein, a tumor suppressor protein, results in exaggerated cardiomyocyte apoptosis and cardiac failure in mouse models of anthracycline exposure (114).
These observations highlight the overall importance of cellular
DNA repair mechanisms in the response to anthracycline
exposure. However, mechanisms have not been elucidated that
explain why deficiency of some DNA repair pathways result in
enhanced sensitivity to anthracyclines, whereas others are protective. Thus a greater understanding of how these pathways
affect the response to anthracyclines in individual cell types in
the myocardium may provide important further insights.
NEUREGULIN/ERBB SIGNALING AXIS. Neuregulin-1 is an important growth and survival factor that exerts its function via the
Erb-phosphatidylinositol 3-kinase-AKT pathway in the cardiomyocyte. Numerous in vitro studies have explored its role in
the response to anthracyclines. These studies show the following: 1) treatment with neuregulin-1 protects myocytes from
anthracycline-induced apoptosis (40); 2) HSP90 stabilizes
ErbB2 protein following anthracycline exposure to protect
against myocyte apoptosis (41); 3) heterozygous knockout of
the neuregulin-1 gene in mice exacerbates heart failure caused
by doxorubicin exposure (86); and 4) blocking the neuregulin
axis with antibodies to ErbB2 (e.g., trastuzamab) initiates a
similar apoptotic response to that obtained with daunorubicin
exposure (107). Additionally microRNA-146a overexpression
is induced by doxorubicin exposure and mediates cell death via
interactions with the Erb-neuregulin signaling axis (53).
ALTERATIONS IN TRANSCRIPTION FACTORS. A variety of studies
have investigated the roles that individual transcription factors
play in the cardiomyocyte response to anthracyclines. Krishnamurthy and colleagues (69) showed that ablation of transcription factor HSF-1 results in decreased expression of the
multidrug resistance transporter P-glycoprotein and protection
of cardiomyocytes from doxorubicin injury. Anthracyclines
downregulate GATA4, an important survival factor (26, 99,
111), and decrease nuclear factor of activated T-cells 5
(NFAT5), a transcription factor that regulates osmotic-related
stress. Interestingly, this is not mediated via changes in NFAT5
mRNA (58).
DISRUPTION OF MYOFILAMENTS AND CALCIUM TRAFFICKING. A
number of changes to myocyte filaments occur in response to
anthracyclines exposure. In cultured neonatal rat myocytes,
dose-dependent ultrastructural changes induced by anthracyclines include disorganization and depolymerization of actin
filaments (73). Deng and colleagues (33) investigated cardiotoxicity in dystrophin-deficient mice and found them to be
more sensitive to doxorubicin-induced cardiotoxicity than
matched control mice. More recently, the Maier laboratory
(110) showed that doxorubicin exposure stimulates Ca/calmodulin protein kinase II activation with increased calcium leak
from the sarcoplasmic reticulum.
ACTIVATION OF THE UBIQUITIN-PROTEASOME PATHWAY. The
ubiquitin-proteasome is responsible for degradation of many
cellular proteins and plays an essential role in homeostasis
(105). In animal models, ubiquitin-proteasome activity is increased in cardiomyocytes exposed to anthracyclines (70).
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was discontinued. Subsequent studies showed that disruption
of redox pathways alters the deleterious response to anthracyclines. Turakhia and colleagues (127) used both small interfering RNA knockdown of heat shock protein 27 (HSP27) in
cultured cardiomyocytes and heat shock transcription factor
(HSF)-1⫺/⫺ cells to show that HSP27 protects against doxorubicin damage by preserving catalytic recycling required for
maintaining appropriate redox balance. In cofactor for oxidase
NADPH oxidase (Nox2)-deficient mice that lack NADPH
oxidase, an important ROS source in myocytes, reduced ROS
generation results in abrogated cardiac dysfunction, decreased
myocyte apoptosis, and interstitial fibrosis (145). Metabolic
studies using 13C isotope labeling in cultured cardiomyocytes
demonstrated that oxidative metabolism was significantly increased during anthracyclines exposure, implying a relative
increase in ROS (121). Finally, the Ren laboratory (134) used
ventricular myocytes to show that doxorubicin-induced contractile dysfunction is mediated via p38 MAPK-dependent
oxidative stress mechanisms (134).
APOPTOSIS, DNA DAMAGE, AND DNA REPAIR PATHWAYS. The
cytotoxic mechanisms of anthracyclines have been extensively
studied in in vitro and in vivo tumor model systems. These
studies demonstrate that anthracyclines damage DNA via intercalation and inhibition of topoisomerase II, an enzyme that
relieves torsional strain on the DNA backbone during replication. This results in DNA strand breaks, induction of the DNA
damage and repair pathways, and in the event the damage
cannot be repaired initiation of the apoptotic response. Importantly, functional topoisomerase II has recently been implicated in the cardiotoxic response to doxorubicin. Zhang and
colleagues (142) developed a mouse model with a cardiomyocyte-specific inducible knockout of the topoisomerase II␤ gene
to show that doxorubicin-induced cardiotoxicity is abrogated in
the absence of functional topoisomerase. In contrast, a recent
article published by the Pommier laboratory (65) showed that
absence of mitochondrial topoisomerase I resulted in impaired
mitochondrial function and enhanced toxicity to doxorubicin.
In vitro and in vivo studies have also shown that numerous
cellular intermediates involved in the apoptotic response are
altered in cardiomyocytes during anthracycline treatment.
These include cytochrome c, Bcl-2-to-Bax ratio, and phosphorylation of p300/CREB binding protein (27, 101). In addition,
caveolin 1 and 3 are required for the apoptotic response to
doxorubicin (132). Alternatively, induction of cell survival
pathways such as the WNT-1 pathway has been shown to block
cardiomyocyte death in response to doxorubicin (130). Furthermore, the DNA repair and damage responses appear to be
central to the mechanism of action of anthracycline-induced
myocyte damage and have important functional significance.
This is supported by all of the following: 1) acute doxorubicin
cardiotoxicity is associated with p53-induced inhibition of
mammalian target of rapamycin (147); 2) HSP27 (an important
mediator of the ROS pathway) regulates p53 transcriptional
activity in cultured cardiomyocytes and upregulates p21 to
initiate cell cycle arrest (129); and 3) anthracycline-induced
cardiotoxicity is abrogated in whole body p53-null mice. Interestingly, cardiomyocyte-specific ablation of p53 in mice
using conditional knockdown techniques is not sufficient to
block cardiac dysfunction or reduce cardiac fibrosis (37).
Finally, alterations in pathways that respond directly to DNA
damage have been studied in the context of anthracycline-
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CHILDHOOD ANTHRACYCLINE EXPOSURE
supplementation of an erythropoietin derivative. Yamac and
colleagues (139) treated rats with anthracyclines and observed
extensive degenerative changes in aorta endothelium in nuclei,
ribosomes, and basement membrane.
Using bovine aortic endothelial cells, Wang and colleagues
(133) observed a time- and dose-dependent activation of nuclear factor-␬B (NF-␬B). Activation of NF-␬B and cell apoptosis were significantly decreased by adding glutathione peroxidase to reduce ROS. The findings suggest that in endothelial
cells, anthracyclines induce NF-␬B leading to apoptosis, in
contrast to cancer cells where activation of NF-␬B is antiapoptotic. Finally, Wu and colleagues (135) examined the effects
of anthracycline exposure on the small coronary vessels of rats.
In the endothelial cells that line these vessels, they noted an
increase in proapoptotic caspase-3, Bax, and Fas, as well as a
decrease in antiapoptotic Bcl-2. Collectively, these observations suggest that anthracyclines induce apoptosis in vascular
endothelial cells, possibly leading to increased risk of cardiovascular disease later in life.
Cardiac progenitor cells. A number of recent studies suggest that events in CPCs are an important contributing factor in
the development of anthracycline-induced cardiomyopathy. De
Angelis and colleagues (31) demonstrated that anthracycline
treatment depletes the cardiac stem cell pool and that cardiac
dysfunction can be restored by injecting cardiac stem cells
systemically. In a separate study by the same group, CPCs
grown in culture and exposed to doxorubicin were observed
initiating the DNA damage response and undergoing apoptosis
(100). At later time intervals, shortened telomeres and senescence were observed. In addition, the progeny of doxorubicintreated CPCs exhibited premature expression of p16(INK4a),
an important marker for cellular senescence. This senescence
phenotype is further supported by evidence published by Spallarosa and colleagues who exposed cord blood endothelial
progenitor cells to low doses of doxorubicin and observed
several important changes including increased SA-b-gal activity, decreased telomeric repeat binding factor 2, chromosomal
abnormalities, enlarged cell shape, and disarrangement of Factin stress fibers (117). A recent review summarizes new
observations linking cardiac toxicity from tyrosine kinase inhibitors (an emerging new class of anticancer agents) to cellular targets in CPCs and possibly other myocardial cell types
(102). Collectively, these studies point to CPCs as an important
cell type to study in the context of anthracycline-induced
cardiomyopathy.
The injury response: invading immune cells, fibroblasts, and
ECM. The injury response in the heart is mediated by resident
cardiac fibroblasts and is known to include complex interac-
Table 2. Future research priorities
Attributes of Preclinical Laboratory Models
Needed
Current Deficiency
Lack of pediatric focus
Current models do not account for latent
period between exposure and adverse
cardiac outcomes
Myocardial cell responses poorly
understood, particularly for
nonmyocyte cell types
Acute exposure in young animals with long
latent period before evaluation
Animal models that incorporate exposure in
young animals and evaluation of cellular
and functional parameters as they age
Acute exposure models that differentiate
responses by cell types and can be used
to identify serum biomarkers
Clinical Trial Development
Organized prospective trials need to test long-term efficacy
of novel cardioprotective interventions
Validate biomarkers
Test interventions that slow pathological progression to
overt cardiac disease
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Other studies demonstrate stimulation of 20S proteasomes with
doxorubicin exposure and exacerbation of doxorubicin-induced cardiac dysfunction in mice when the E3-ubiquitin
ligase Nrdp1 is overexpressed (143).
Endothelial cells. Several recent clinical studies have implicated vascular endothelium as an important target of the
cardiovascular changes induced by anthracycline exposure. In
two separate pilot studies, Mulrooney and colleagues (91, 92)
studied 25 long-term survivors of Hodgkin’s lymphoma and 24
survivors of childhood osteosarcoma. Blood samples from
these groups of patients exhibited evidence of vascular inflammation, dyslipidemia, and early atherogenesis. In a similar
study, Brouwer and colleagues (18) studied 277 adult survivors
of pediatric cancer who had received cardiotoxic therapies
including anthracyclines. They observed an increase in arterial
wall thickness, suggesting changes induced by exposure to
systemic chemotherapy. In addition, Jenei and colleagues (61)
studied 96 long-term survivors of pediatric cancer and noted
that these patients had increased vascular stiffness. Zsary and
colleagues (148) measured endothelin-1 levels (a critical regulator of cardiac performance) in 20 one-year survivors of
lymphoma. They observed a decrease in plasma endothelin-1
levels that correlated with decreased ejection fraction and
cardiac function. Collectively, these clinical studies suggest
systemic chemotherapies such as anthracyclines can have deleterious effects on vascular endothelial cells and possibly
contribute to long-term cardiac effects in survivors.
The above clinical observations are further supported by
substantial evidence from numerous preclinical studies that
have investigated the cellular and molecular responses induced
by anthracycline exposure in human endothelial cells. In contrast to clinical studies, Sayed-Ahmed and colleagues (112)
observed an increase in plasma endothelin-1 in rats treated with
anthracyclines. The discrepancy between the clinical and preclinical observations may be attributed to the time at which
endothelin-1 was measured; in the clinical study by Zsary,
endothelin-1 was quantified one year after completion of anthracycline treatment, whereas in the preclinical study measurements were taken at the immediate end of the treatment.
While the direction of the change remains to be determined, the
fact that endothelin-1 is changing in both clinical and preclinical models suggests that it might be an important regulator of
anthracycline-induced cardiomyopathy.
Hoch and colleagues (52) observed impaired endothelial
differentiation in cells isolated from mice treated with doxorubicin. In addition, levels of erythropoietin in the cardiac
microenvironment of these mice were reduced and microvasculature and endothelial differentiation were restored with
Review
CHILDHOOD ANTHRACYCLINE EXPOSURE
Summary and Future Research Priorities
Long-term survivors of pediatric cancer suffer from high
rates of cardiovascular disease and cardiac mortality due to
exposure to cardiotoxic chemotherapy and radiation in childhood. Anthracyclines are one of the most commonly used
classes of chemotherapeutic agents in pediatric oncology, and
their administration is associated with adverse cardiovascular
outcomes that include CHF, cardiomyopathy, vascular disease,
and stroke. Importantly, the widely held views regarding the
molecular mechanisms that result in myocardial damage are
often focused on the cardiomyocyte, although events in this
solitary cell type do not fully explain how anthracycline exposure during childhood results in the clinical outcomes observed
decades later. Collectively, these observations lay the foundation for developing the future research priorities we propose in
Table 2. Consideration of the molecular events in response to
anthracyclines in the various cell types that comprise myocardium is critical to identifying biomarkers of cardiotoxicity and
novel cardioprotective therapeutics. In addition, a systematic
understanding of how anthracyclines affect all myocardial cell
types will allow for the development of novel hypotheses that
are focused on elucidating the temporal and cellular relationships that occur in the heart following anthracycline exposure.
Understanding these relationships will facilitate development
of preclinical laboratory models and new strategies for detection, prevention, and management of cardiac disease in the
large number of pediatric cancer survivors previously exposed
to anthracyclines. The clinical epidemiologic observations
made regarding the long-term cardiac outcomes in survivors of
pediatric cancer and the array of myocardial cellular events
induced by anthracyclines summarized in this review provide
the foundation for a concerted multidisciplinary approach.
ACKNOWLEDGMENTS
Present address of R. A. Lange: Paul L. Foster School of Medicine, Texas
Tech Univ. Health Sciences Ctr. El Paso, El Paso, TX.
GRANTS
This study was supported by National Center for Research Resources and
the National Center for Advancing Translational Sciences, National Institutes
of Health (NIH) Grant 8UL1TR000149 (to G. J. Aune, KL2 Scholar); by
National Cancer Institute Cancer Prevention and Control Career Development
Award K07CA175063 (to H. Parsons); by a St. Baldrick’s Foundation Infrastructure grant (to H. Parsons and G. J. Aune); by NIH HHSN 268201000036C
(N01-HV-00244) for the San Antonio Cardiovascular Proteomics Center,
R01-HL-075360 and HL-051971, and from the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research
and Development Award 5I01BX000505 (to M. L. Lindsey); and by the
Rapoport Foundation for Cardiovascular Research (to R. A. Lange). The
content presented here is solely the responsibility of the authors and does not
necessarily represent the official views of the NIH or any other funding agency.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
M.L.L., R.A.L., H.P., and G.J.A. prepared figures; M.L.L., R.A.L., and
G.J.A. drafted manuscript; M.L.L., R.A.L., H.P., T.A., and G.J.A. edited and
revised manuscript; M.L.L., R.A.L., H.P., T.A., and G.J.A. approved final
version of manuscript.
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