Renu 2017
Renu 2017
Renu 2017
www.elsevier.com/locate/ejphar
PII: S0014-2999(17)30692-1
DOI: https://doi.org/10.1016/j.ejphar.2017.10.043
Reference: EJP71481
To appear in: European Journal of Pharmacology
Received date: 24 July 2017
Revised date: 11 October 2017
Accepted date: 20 October 2017
Cite this article as: Kaviyarasi Renu, V.G. Abilash, P.B. Tirupathi Pichiah and
Sankarganesh Arunachalam, Molecular Mechanism of Doxorubicin-Induced
Cardiomyopathy – An Update, European Journal of Pharmacology,
https://doi.org/10.1016/j.ejphar.2017.10.043
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Molecular Mechanism of Doxorubicin-Induced Cardiomyopathy – An Update
1
Department of Biomedical Sciences, School of Biosciences and Technology, VIT University,
2
Department of Animal Science, School of Life Sciences, Bharathidasan University,
3
Department of Biotechnology, Kalasalingam University, Krishnankoil-626126, Tamil Nadu,
India
Corresponding Author:
1. SankarganeshArunachalam, Ph.D.,
Department of Biotechnology,
Kalasalingam University,
INDIA.
Email: [email protected]
2. Abilash V.G, Ph.D.,
VIT University,
India.
Email: [email protected]
Abstract:
Doxorubicin is utilized for anti-neoplastic treatment for several decades. The utility of
this drug is limited due to its side effects. Generally, doxorubicin toxicity is originated from the
myocardium and then other organs are also ruined. The mechanism of doxorubicin is intercalated
with the DNA and inhibits topoisomerase 2. There are various signalling mechanisms involved
to oxidative stress. Cardiac mitochondrial damage is supposed after few hours following the
revelation of doxorubicin. This has led important new uses for the mechanism of doxorubicin-
and interventions for the impediment of cardiotoxicity. The idea of this review is to bring up to
date the recent findings of the mechanism of doxorubicin cardiomyopathies such as calcium
Keywords:
consequences
3.2.1. Elevated fatty acid uptake and decreased glucose uptake in heart
reticulum
4. Immune response, oxidative stress, and tissue injury
5.1. Apoptosis
5.2. Necrosis
5.3. Autophagy
5.4. Fibrosis
6. Other mechanisms
7. Conclusion
1. Introduction
chemotherapeutic drug for the treatment of a wide range of cancers including both the solid and
hematogenous cancers since 1969 (Damiani et al., 2016). This antibiotic was first discovered
from a mutated strain of Streptomyces peucetius. The clinical utility of this drug is limited for its
side effects especially, cardiotoxicity when it exceeds the cumulative dosage of 400 mg/m2 - 700
mg/m2 for adults and 300mg/m2 in the cases of children. Upon crossing the mentioned
thresholds, the chances of developing cardiotoxicity increases, with 400 mg/m2 there is a 5%
incidence of cardiotoxicity, with 550mg/m2 26% risk, and with 700 mg/m2, there is a risk as high
as 48% (Li and Hill, 2014). Doxorubicin is biphasic in nature depends on the concentration of it
(Ondrias et al., 1990). Determination of acute toxicity within two or 3 days of drug
administration and chronic cardiotoxicity found in several weeks or even several months after
dysfunction and congestive heart failure (Mitry and Edwards, 2016). Doxorubicin acquaintances
robustly with cellular nuclei and intercalate with deoxyribonucleic acid (DNA) bases to mediate
doxorubicin-DNA complexes, ensuing in cell demise (Cheung et al., 2015; Trouet and Deprez-
breakage and mitotic catastrophe generation (Eom et al., 2005). Doxorubicin mediates dsDNA
breakage through reticence of Top2β (Topoisomerase 2-beta), and knockout of Top2β gene in
al., 2012). Reactive oxygen species (ROS) apparently plays a key role in doxorubicin-induced
elusive. The other mechanism contributes to doxorubicin cardiotoxicity are iron regulatory
protein, nitric oxide (NO) release, Mitochondrial dysfunction, impaired adenosine triphosphate
(ATP ) level, hampered cardiac progenitor cells, calcium dysregulation, inflammatory mediators,
endothelial dysfunction, activation of ubiquitin protease system, autophagy and cell death.
Though a number of mechanisms have been shown to be involved in cardiotoxicity the exact
mechanism is indistinct. This review is aimed at comprehending the cellular and molecular
failure. Spotlight more on the cellular and molecular mechanism of doxorubicin on the
myocardium with the rationale of innovative copious delineating the essential molecular
consequences
stress is the imbalance between the production of reactive oxygen species, reactive nitrogen
species (RNS) and intrinsic antioxidant mechanisms. The reactive oxygen species, reactive
nitrogen species produced within the cardiomyocytes are not effectively removed/neutralized by
the inherent antioxidant mechanisms of the cells (Tham et al., 2015). When the cumulative
dosage of doxorubicin exceeds 500mg/m2 body surface area it leads to the increased oxidative
stress (C Pereira et al., 2011). This oxidative stress is triggered through any of the following
mechanisms.
elevated reactive oxygen species production through the reduction of the redox cycling in
complex I of electron transport chain (ETC) (Alexieva et al., 2014; Davies and Doroshow, 1986;
Davies et al., 1983; Doroshow and Davies, 1986). Any structural modification in the
equipped with 35 - 40% higher mitochondrial number when compared to other tissues. (Goffart
et al., 2004).
charge and doxorubicin has a cationic charge they have a mutual affinity. Therefore,
doxorubicin and cardiolipin make an irreversible complex. (Parker et al., 2001) Subsequently,
oxidation of protein, fat and signalling molecules (Kuznetsov et al., 2011). Cardiolipin is
important for the activation of enzymes present in electron transport chain such as cytochrome C
doxorubicin it is unavailable for activating above mentioned enzymes which are essential
1980).
free radicals from mitochondria (Pani et al., 2000). MnSOD is situated in a mitochondrial matrix
which acts as a superoxide scavenger in the mitochondria (Fridovich, 1995). Knock out of
MnSOD would decrease the survival and mitochondrial function and its integrity which leads to
cell death further myocardial dysfunction (Li et al., 1995). Doxorubicin-induced apoptosis is
through elevated superoxide dismutase (SOD) and haem oxygenase and preserving
Doxorubicin thereby suppresses the mitochondrial metabolism and production of the end product
which leads to the apoptosis. This process can be retrieved by allowing the mice to inhale carbon
monoxide which is responsible for the coding of the gene responsible for the mitochondrial
metabolism and also up-regulating gene which is responsible for the heme oxygenase (Piantadosi
et al., 2008; Suliman et al., 2007). The result of increased reactive oxygen speciesproduction is
pathological alterations in the lipid, protein, nucleic acids and signalling molecules (Berthiaume
2.2. Role of Iron regulatory protein in the production of reactive oxygen species
The non-enzymatic reaction such as Fe3+ (ferric iron) reacts with the ketone and hydroxy
group of doxorubicin forms doxorubicin-Fe2+ free radical complexes (Olson and Mushlin,
1990). These complexes interact with the negatively charged cell membranes and cause lipid
peroxidation. Lipid peroxidation occurs when there is a high production of free radicals near to
the cell membranes which contain more phospholipid (Chichuk et al., 1998; Markin et al., 1996).
Doxorubicin increases the intracellular iron pool and normally, iron represents less than 5% of
total cellular iron (Xu et al., 2005). This transition iron metal is involved in the generation of free
radicals. To control the process of free radical generation, the iron bound to storage protein
and/or transport protein (Dorr, 1996). The doxorubicin-induced apoptosis in cardiac is due to the
changes in the iron homeostasis and accumulates iron in mitochondria. Homeostatic changes are
regulated by transferrin receptor (TfR) and this homeostatic changes induced by the release of
administration of 24mg/kg in 5 injections for 5 days would down-regulates the ABCB8 protein
thereby affecting the export of iron from mitochondria. Administration of iron chelators such as
DFO-50mg/kg and DXZ – 60mg/kg before 2hrs of administration of DOX would protect from
transport protein involved in the import of iron into the mitochondria. There is no change in
Mfrn-2 expression levels and therefore uptake of iron into the mitochondria remains unaltered.
With no change in import, iron export is affected leading to a disturbed state of iron homeostasis
in mitochondria (Ichikawa et al., 2014). There are also additional mechanisms which result in
altered iron homeostasis. Doxorubicin treatment in rat embryonic H9c2 would inactivate both
iron regulatory protein 1(IRP1) and IRP2 in cardiomyocytes permanently. Doxorubicin effects
the post-translational modification of IRP1. 4Fe/S cluster of IRP1 is affected and therefore IRP1
loses its ability to bind to iron-responsive element (IRE) thereby resulting in distortion of iron
IRPs via post-transcriptional modification and communication with the 4Fe/S cluster in IRP1
(Kwok and Richardson, 2002; Minotti et al., 2001). Doxorubicin increases the iron incorporate
into the cells and decreasing the release of iron from sub-cellular organelles by altering the
protein trafficking inside the cells. Doxorubicin also affects the import of iron into the cells by
suppressing IRPs. Top-2β is also acting as a mediator in the doxorubicin cardiotoxicity
in human hemochromatosis protein (HFE) iron regulatory gene show heightened susceptibility to
ruptures the lysosomes rich in iron and also degrades ferritin in lysosomes which further leads to
the cardiac toxicity in hemochromatosis with increased iron (Terman et al., 2008). Even though
many iron chelators like dexrazoxane (DXZ), deferoxamine (DFO), deferiprone, deferasirox
failed to export the iron from mitochondria during doxorubicin cardiotoxicity. So, the novel iron
the activation of reactive oxygen species. These free radicals are produced by the doxorubicin
II (Ang II) activates the level of NADPH oxidase and mediates reactive oxygen species
production during doxorubicin treatment at the 1μM concentration (Gilleron et al., 2009). The
(Sacco et al., 2009). Cardiomyoblast treated with doxorubicin shows an increased level of
NADPH oxidase (NOX) and flavin-containing enzymes such as P450 reductase, nitric oxide
synthase leading to increased level of reactive oxygen species and subsequently oxidative stress
Nitric Oxide is a vasodilator and it mediates contraction in heart significantly. Nitric oxide is
found in higher quantities in the diseased heart. Increased level of NO is found during
(nNOS). Preferably, cardiac NO synthesis is carried by eNOS and iNOS. There is an increased
level of iNOS along with the NO quantity during doxorubicin treatment in cardiac cells. During
doxorubicin treatment, generation of superoxide anions by the activated NOXs reacts with the
peroxynitrite oxides leads to mitochondrial oxidative stress, apoptosis, and necrosis. The
inhibition of iNOS by its inhibitors and amino guanidine protects form doxorubicin-induced
cardiotoxicity (Bahadır et al., 2014). Doxorubicin treatment for 3h, 15mg/kg would increase the
al., 2004).
Nuclear factor erythroid 2-related factor 2 (Nrf2), a basic leucine zipper protein, is involved
in regulation of the expression of a number of antioxidant proteins. Nrf2 also plays a crucial role
cardiac function. Agents which can increase the expression of Nrf2 shows a protective effect
against doxorubicin-induced cardiomyopathy. For example, sulforaphane and dioscin have
overexpressing Nrf2. Doxorubicin impairs the activity of autophagy which leads to toxicity in
the heart. Nrf2 prevents oxidative stress by inducing autophagy which happens during
doxorubicin treatment also. Nrf2 mediates the balance between oxidative stress and autophagy,
Lipid peroxidation is the formation of a free radical chain by causing damage to phospholipid
layer of the cell through oxygen derived-free radicals (Chichuk et al., 1998; Markin et al., 1996).
Lipid peroxidation alters the membrane permeability and cell function. The formation of lipid-
lipid and lipid-protein moieties (Bruch and Thayer, 1983), the ratio of cholesterol to
increase in the formation of free radicals which further leads to lipid peroxidation. Lipid
peroxidation occurs by both intracellular- and extracellular-derived free radicals. During high
concentration of doxorubicin, vacuoles are formed. Vacuoles formed are the product of lipid
metabolism and lipid peroxidation (Hiroyuki et al., 1984; Terman and Brunk, 2005). There is an
increased level of malondialdehyde which is the product of lipid peroxidation (Myers et al.,
cytochrome P450 and glutathione transferases are found less in heart compared to the other
organs like kidney, liver. Selenium and zinc normally reduce the free radical production, which
acts as a cofactor for antioxidant enzymes (Koenig et al., 1997). Doxorubicin lowers the level of
activity of Cu/Zn superoxide dismutase, which results in the decreased level of the antioxidants
system (RAAS) activation is available, but a recent report suggests that the RAS antagonist
products (AGE) activation, and the subsequent end result of cardiomyopathy. Doxorubicin
causes hyperglycemia and mimics type 2 diabetic condition (Arunachalam et al., 2013). There is
an increase in the AGE metabolites (Moriyama et al., 2010), and activation of the reactive
oxygen species (Shi et al., 2011) and also it causes the cardiomyopathy (Carvalho et al., 2014;
Octavia et al., 2012). Therefore, cardiomyopathy may be the result of increased AGE metabolites
and reactive oxygen specieswhich are attributable to hyperglycemia. The activated reactive
oxygen species level would mediate the sympathetic nervous system (SNS) and RAAS activity.
endothelial cell activation leads to left ventricular dysfunction further induces cardiomyopathy
(Jungsuwadee, 2016).
3. Involvement of sub-cellular organelles associated oxidative stress doxorubicin-
increase in the number of lysosomes (Minotti et al., 2004), disruption of cristae in mitochondria
(Ascensão et al., 2005), myocyte disruption, fibrosis (Bristow et al., 1981)(Torti et al.,
1986)(Billingham et al., 1978). Doxorubicin treatment to H9C2 cell lines caused degradation of
both the lamins A and B (Sardão et al., 2009) leading to changes in the morphology of nucleus,
filaments and distortion of mitochondrial network (Grimmond and Beerman, 1982; Iwasaki and
Suzuki, 1991; Jang et al., 2004; Jones et al., 1990; Ueno et al., 2006)(Arola et al., 2000). These
troponin C, alpha-actin. The specific gene which is responsible for the cell integrity and
contraction of the heart include α-tropomyosin (α-TM) and myosin heavy and light chains are
contractile protein, found near the Z line of the sarcomere (Chen et al., 2008; Gewirtz, 1999).
Connexin (CX) 40, CX43, CX45 are the gap junction protein and hemichannels. CX43, a
protein found in the heart in relatively higher quantities, is involved in protecting the heart from
expression of CX40 along with endothelial dysfunction (Idris-Khodja et al., 2013). In addition,
doxorubicin down-regulates some other genes including Ca2+ ATPase, ryanodine receptor 2
3.2.1. Elevated fatty acid uptake and decreased glucose uptake in the heart.
Heart due to its extreme energy demands is equipped with a high number of mitochondria.
(Jeyaseelan et al., 1997). Doxorubicin treatment reduces glucose uptake was determined using
on fatty acid for survival (Takemuraet al., 2007). This might be possible since Adriamycin
et al., 2012). Since there is no hormonal regulation for fatty acid uptake by the heart (Ajay and
Prabhakaran, 2010; Bayeva et al., 2013) the main source of fatty acid for cardiomyocytes is
circulating fatty acids, the hematogenous chain fatty acid, triacylglycerol (TAG), cholesterol and
transporter for lipids such as very low density lipoprotein (VLDL) and low-density lipoprotein
(LDL) are also increased both in heart disease condition and doxorubicin cardiomyopathy(Hong
Doxorubicin impedes the expression of genes encoding enzymes conscientious for energy
electron transport chains such as adenosine diphosphate (ADP)/ATP translocase and Rieske iron-
sulphur protein are found to be abridged. (Jeyaseelan et al., 1997). As a result, there is a
(PCr) and total adenine nucleotide in cardiomyocytes. The reduced level of ATP impairs the
attraction of cardio-protective protein heat shock protein (HSP90) towards erEb2. This cardio-
protein kinase (AMPK)signalling due to bio-energetic failure, genotoxic stress, and oxidative
stress and finally, leads to the increased energetic stress and hypertrophy. The AMPK inhibition
is due to the regulatory cross-talk such as AKT signalling (Gratia et al., 2012). In contrast, there
is an upregulation of AMPK signalling and leads to the activation of caspase 3 and ATP loss
mitochondrial function (Praet and Ruysschaert, 1993). (Boudina et al., 2007; Duncan, 2011;
How et al., 2006; Mazumder et al., 2004). The decreased ATP production is connected with the
impedes the mitochondrial membrane potential and mitochondrial permeability transition pore
(Wallace, 2003). Doxorubicin alters the respiratory components and also decreases respiratory
state 3 (Muhammed et al., 1983). As discussed above that there is an increased uptake of fatty
acid by the myocardium. Doxorubicin also alters the ATP production (Neri et al., 1991; Pelikan
et al., 1986; Sayed - Ahmed et al., 2000) and also increases the oxidative stress in mitochondria
by enhancing the production of reactive oxygen species(Octavia et al., 2012). The lipid content
such as cardiolipin in mitochondrial is enhanced by the oxidative stress (Minotti et al., 2004;
mitochondria leads to changes in the Ca2+ homeostasis of the myocardium (Cardoso et al., 2008;
Outomuro et al., 2007; Singal et al., 2000b). It also affects the fatty acid oxidation (FAO) which
is induced by fatty acid metabolism, calcium signalling, oxidative stress, lipid content leads to
reticulum
Under pathological conditions of the heart, there is myocardial endoplasmic reticulum stress
(Lakshmanan et al., 2013; Li et al., 2007; Xu et al., 2009). Doxorubicin treatment induces ER
stress as marked by the elevation of 78-kDa glucose-regulated protein (GRP78) and C/EBP
homologous protein (CHOP) (Wang et al., 2012). Increased ER stress also triggers the
phospholamban, and calcium storage gene such as calsequestrin in rabbits (Arai et al., 1998;
Kim et al., 2006b). The change in the expression of calcium regulating genes impairs the both
acetyl glucosamine) such as calcium / calmodulin-dependent protein kinase 2 (CAMK II) which
leads to the changes in genes involved in calcium signaling (Erickson et al., 2013; Luo et al.,
cardiomyopathy (Wallace, 2003). These changes cause an alteration in the calcium homeostasis
Doxorubicin treatment induces the immune system to release a variety of cytokines. The
Further it stops the natural killer (NK) cell activity, stimulates the responses of cytotoxic T
immune cell affect the cardiac function during doxorubicin treatment. (Ehrke et al., 1984;
ligand produced by damaged tissue. Toll-like receptors 2 and Toll-like receptors 4 are mainly
involved in cardiac pathogenesis. Cardiomyopathy induced by the doxorubicin has an increased
oxidative stress associated with increased Toll-like receptors 2. These toll-like receptors 2
induces the nuclear factor kappa B (NF-kappa B) which ultimately leads to apoptosis (Frantz et
The toll-like receptors 4 during doxorubicin treatment causes apoptosis, oxidative stress, and
cardiac inflammation and increased endothelial – 1 causes left ventricular dysfunction. The
knockdown of toll-like receptors 4 decreases the formation of reactive oxygen species in the
myocardium and prevents transcription factor GATA-4 (GATA-4) down-regulation. With the
causing the viscous cycle. (Riad et al., 2008) The toll-like receptors 4 also increases the level of
Toll-like receptors 3 receptor has the ability to stimulate the type1 interferon (IFN) based on
the efficacy of doxorubicin and also produces the IFN – stimulated genes. The dying tumour
cells release the self RNA during doxorubicin treatment. This self RNA further triggers the toll-
like receptors 3 receptor signalling (Sistigu et al., 2014). The recombinant human interleukin
IL-1β (Guo et al., 2013a; Sauter et al., 2011), IL-6 (Guo et al., 2013a; Sauter et al., 2011;
Zordoky et al., 2011), TNF-α (Guo et al., 2013a; Riad et al., 2009; Sauter et al., 2011; Zordoky et
al., 2011) and p38 mitogen-activated protein kinase (p38 MAPK)/NF-κB (Guo et al., 2013b).
The inhibitors such as SB203580, an inhibitor of p38 MAPK or siRNAs specific for p38 (sip38)
or pyrrolidine dithiocarbamate (PDTC) reduced the inflammation caused by doxorubicin (Guo et
al., 2013a). Doxorubicin also increases the level of macrophage (Haskill, 1981). Recombinant
IL-1 receptor antagonist protects form doxorubicin-induced cardiotoxicity (Zhu et al., 2010). The
treatment with sodium hydrosulfide (NaHS) ameliorates inflammation caused by the doxorubicin
Doxorubicin activates NFĸB through oxidative stress, which eventually mediates Bmx
SMAT3 pathway and enhances inflammatory mediators such as IL-1, IL-6, IL-7, TNF receptor
2, vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP2). Activation
of SMAT3 pathway induces stress-mediated cardiac remodelling and left ventricular dysfunction
through mTOR. The establishment of cardiac remodeling leads to cardiomyopathy (Chau et al.,
2002; Gottar-Guillier et al., 2011; Holopainen et al., 2015; Mitchell-Jordan et al., 2008; Suwei et
al., 2002; Tavora et al., 2014; Tsai et al., 2000; Zelarayan et al., 2009).
5.1. Apoptosis
Under pathological conditions such as infracted and reperfused myocardium, diabetes, left
ventricular dysfunction and hypertrophy apoptosis occurs along with necrosis. (Freude et al.,
2000; Guerra et al., 1999; Sam et al., 2000; Tea et al., 1999; Zhou et al., 2000). Oxidative stress
results in the release of cytochrome c through voltage-dependent anion channels (VDAC) and
apoptosis is increased by b-cell lymphoma 2 –(Bcl 2): Bcl-2-like protein 4 (bax) ratio. The
efficiency of mitochondria is increased (P/O ratio) and an increase in the activity of SOD (Childs
et al., 2002). Reactive oxygen speciesgeneration increases apoptotic level by activating the
mediates apoptosis through the enhancement of p53, decrease the GATA-4 expression level and
p300 degradation (Aries et al., 2004; Kawamura et al., 2004; Kim et al., 2003; Liu et al., 2008;
Liu et al., 2004; Park et al., 2010; Poizat et al., 2005). In doxorubicin cardiotoxicity, there is an
activation of oxidative stress-dependent heat shock factor such as HSF-1 which further activates
HSP25 and subsequently, p53 is equalized leading to the increased production of proapoptotic
proteins (Vedam et al., 2010). During doxorubicin treated condition, there is an accumulation of
accumulation changes the signalling pathway and elevates the apoptosis in cardiomyocytes by
either of the following two ways: mitochondrial L-carnitine and through the channel volume-
sensitive chloride ion. Doxorubicin activates MAPK, p38 and JNK (c-Jun-NH(2)-terminal
kinase) (Xie et al., 2009; Xu et al., 2005) which leads to apoptosis by impairing the Bcl2, Bax,
cleaved caspase-9 and cleaved caspase-3 (Chatterjee et al., 2010; Liu et al., 2004). Apoptosis is
due to the increased oxidative stress, calcium impairment, opening of the mitochondrial pore,
Doxorubicin elevates the expression of the death receptors (DR) such as tumour necrosis factor
receptor 1 (TNFR1), fas cell surface death receptor (Fas), DR4, and DR5 in cardiomyocyte. This
elevated expression contributes to activation of caspase cascade shepherd to apoptosis (Zhao and
Zhang, 2017).
5.2. Necrosis
The fundamental process of necrosis is swelling of cells which lead to the leakage of cells
and also cause the inflammation in the adjutant area. This necrosis occurs during acute
necrosis is still unclear the mitochondrial dysfunction, mitochondrial DNA damage and
alteration in ATP level all these are associated with the necrosis (L'Ecuyer et al., 2006; Solem et
5.3. Autophagy
Doxorubicin suppresses the AMPK and unc-51-like kinase 1 (Ulk1) pathway through which
there is diminished autophagy (Kawaguchi et al., 2012). In contrast, doxorubicin also causes a
down-regulation of GATA4 and Bcl-2. (Kobayashi et al., 2012). The depletion of GATA4 level
activates the S6 kinase beta-1 (S6K1) level and subsequently triggers autophagic genes leading
to induction of autophagy (Rubinstein and Kimchi, 2012). Some of the autophagy-related protein
(Atgs) genes such as Atg5, Atg12, Atg4, Atg4, and Bad are up-regulated during doxorubicin
treatment. (Smuder et al., 2013). The autophagy marker such as LC3B is up-regulated in
expression (Gu et al., 2012). Therefore we may conclude from comparing these studies in
doxorubicin cardiomyopathy, there is both the stimulation and depression of autophagy. Overall,
likely to avert or remit the doxorubicin cardiomyopathy (Bartlett et al., 2017). Curcumin protects
through the regulation c-Jun N-terminal kinases (JNK) mediated pathway (Katamura et al.,
2014). UV radiation resistance-associated gene protein (UVRAG) insufficiency increases
unbalanced fasting reduces impaired autophagy and rescues the pathological changes in
5.4. Fibrosis
al., 2014; Takemura and Fujiwara, 2007). Doxorubicin also increases the perivascular fibrosis.
There is an alteration in both the MMP-1 and MMP-2 in both the animal models and cell culture.
Doxorubicin inhibits the collagen transcription and translation in tumour cells (Goetzenich et al.,
2009; Octavia et al., 2012; Spallarossa et al., 2006; Tokarska-Schlattner et al., 2010).
though the increase in myofibroblast is evident the fate of endogenous stem cells remains elusive
6. Other mechanisms
The heart is considered as a terminally differentiated organ, but still, it has some capacity to
repair it after some injury by progenitor cells such as bone marrow progenitor cell(BMPCs) and
cardiac progenitor cells (CPCs). Doxorubicin has been shown to impair the viability of
clonogenic c-kit positive CPCs in vitro. Doxorubicin induces apoptosis of CPCS and prevents
differentiating into myocytes. Doxorubicin also reduces the endothelial cardiac repair and also in
case of cardiac lineage cells it reduced the proliferation and differentiation (Huang et al., 2010;
Yasuda et al., 2010). Doxorubicin decreases the expression of an insulin-like growth factor-1
cardiomyocyte progenitor cells (hCPCs) and pessimistic property continues with time moment
(Piegari et al., 2013). Doxorubicin not only interrupts the ability to differentiate but also
mediates cell death, senescence and apoptosis. Doxorubicin impedes with the growth factor
which regulates the cardiac repair and increases the condition of heart stress. Healthy hCPCs
treated with doxorubicin fails to recuperate the structure and functionality of heart. (De Angelis
et al., 2015). The infantile revelation of doxorubicin with the low dosage also mediates the
senescence and enduringly obstructs the quantity of inhabitant CPC, telomerase activity. The cell
cycle inhibitor p16INK4a and SA- β –gal are elevated. Doxorubicin elevates the expression of the
γH2AX, and phospho-P53 Ser15 further induce apoptosis (Piegari et al., 2013).
Doxorubicin treatment on endothelial progenitor cells (EPC) causes apoptosis at high dosage
and phenotype of early senescence at low dosage. Doxorubicin at sub-cytotoxic dosage elevates
the reactive oxygen specieslevel along with the changes in expression of the protein which
regulates cell cycle, cellular structural design and cytoskeletal adjustment (Maejima et al., 2008;
Spallarossa et al., 2010). The senescence and apoptotic regulators such as MAPKs38 and JNK
signalling pathway are elevated during sub-apoptotic dose exposure of doxorubicin (Wada et al.,
2008). The deregulation of TRF2 and activation of p16INK41 with impairment of telomere
function would supply senescence to EPC further it destroys the regenerative process of EPC (De
(G-CSF) are utilized for assessment of their movement competence in the neighbourhood of the
myocardium and their probable responsibility in hampering of the cardiac dysfunction (Tomita et
al., 2004). The toxic effect of doxorubicin on mesenchymal stem cells (MSC) impede with its
function and extra organ function (Oliveira et al., 2014; Yang et al., 2013).
proteasome both in-vitro and in-vivo in cardiomyocytes (Ranek and Wang, 2009). Briefly,
doxorubicin elevates E3 ligase which increases the structural protein i.e., myofibrillar, β-catenin
which is involved in UPS-mediated degradation and the release of survival factors like apoptosis
repressor with caspase recruitment domain (ARC ) and Bcl2 and p300 transcription factor. This
change leads to sarcomeric structure dysregulation (Shi et al., 2011). Administrating proteasome
inhibitors such as bortezomib which protects from toxicity so that we can administrate both
administration of proteasome inhibitor such as bortezomib along with doxorubicin has been
development and function. The reactive oxygen species-mediated NF-κB activates the miR-146a
the decreasing the ErbB4 signalling in a dose-dependent manner. (Horie et al., 2010).
Doxorubicin increases the level of ErbB2 ligand and activates downstream Akt signalling. There
is an increased level of the ErbB2 stabilizer and chaperone called HSP90 during doxorubicin
treatment (Gabrielson et al., 2007). The recombinant NRG1 signalling protects from cardiac
dysfunction by suppressing the proteasome-mediated degradation like troponin and also reduces
the ErbB2-PI3 –Akt signalling (Bian et al., 2009; Engelman et al., 2007; Liu et al., 2005; Sawyer
et al., 2002).
Natriuretic peptides are hormones which are produced by the cardiomyocyte. Natriuretic
peptides in plasma are increased during cardiac hypertrophy and left ventricular dysfunction.
During anthracycline cardiotoxicity, there is an increased level of the atrial natriuretic peptide
(ANP) and brain natriuretic peptide (BNP) in plasma. During doxorubicin treatment, there is no
significant increase compared to the control in the level of ANP produced by the atria. But BNP
which is secreted from the ventricles is elevated in the plasma which acts as a cardiac biomarker
during doxorubicin treatment (Troponin and BNP act as predictors) (Chen et al., 1999).
Doxorubicin intercalates with the two base pair of DNA helices and inhibits the synthesis of
DNA replication and RNA replication by affecting the topoisomerase II (Alexieva et al., 2014).
The intracellular damage of DNA stimulates the mitochondrial death pathway which is mediated
by p53 (Campisi, 2005) Doxorubicin also damages mtDNA which results in the mitochondrial
bio-energetic failure by changing the redox cycle (Alexieva et al., 2014). In general, doxorubicin
different concentrations and further protects from cardiotoxicity (Jean et al., 2015).
6.6. Role of β adrenergic receptors and adenylate cyclase
The cell membrane is made up of a polar bi-lipid layer with the larger amount of
phospholipid, it has a hydrophilic face and hydrophobic head, integral protein and glycoproteins
are present on the external surface. The cell membrane is responsible for many reactions include
enzymatic reactions, transport, and signalling. The β adrenergic receptor is the G protein-coupled
receptor. The β adrenergic receptor has an important role in the heart. During Doxorubicin
cardiotoxicity, the β adrenergic receptor is highly affected. Upon doxorubicin treatment, there
are changes in the physical properties of the membrane which also affects the β adrenergic
receptor. The relationship between alterations in the physical properties of the membrane and β
cardiac contractility with cirrhosis has a decreased membrane fluidity and β adrenergic receptor
and there is an increase in the density of β adrenergic receptor without any changes in affinity of
isoproterenol to β adrenergic receptor it decreases the density of (Xu et al., 2001). The chronic
administration in rabbit affects the whole adrenergic pathway and leads to the decrease in
Doxorubicin treatment increases the release of histamine in the peripheral tissues of dog.
Followed by the release of histamine there is an increased level of the catecholamine and
decreases the level of epinephrine and nor-epinephrine (Kawada et al., 2000). Chronic
Adriamycin treatment affects the β–adrenergic system. Adriamycin treatment affects entire β–
adrenergic pathway and a decrease in adrenergic cyclase in the heart (Calderone et al., 1991; Xu
et al., 2001).
The dysregulation of miRNAs found in a variety of pathological conditions of the heart. The
main enzyme for the formation of mature miRNAs is dicer. The altered expression of dicer in
cardiomyopathy leads to an abnormal profile of miRNAs (Asrih and Steffens, 2013). Under
7. Conclusion
Doxorubicin brings about a cure efficiently for a variety of cancer types, but its rigorous side
determined by oxidative stress. This oxidative stress is a disproportion between the oxidant and
but the outcome is cell death such as apoptosis, necrosis, fibrosis, and autophagy. Different
signalling pathways (Represented in figure 1 and table 1) are involved in doxorubicin treatment,
the target of signalling pathways with inhibitors may protect from doxorubicin-mediated
cardiomyopathy. Though there are different inhibitors are determined for treatment of
oncology treatment.
Acknowledgments
This study was financially supported by DST- SERB, Government of India, and Project file
number SB/LS/YS-99/2013.
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Figure legend
Fig. 2
Fig. 3
Fig. 4
time
1. Oxidative
stress
reactive species
reducing
Complex I of
ETC
production of mitochondrial
reactive iron
by proper
exporting
mitochondria
mitochondria
other cells
reactive species
oxygen species production by
NOX
of reactive intracellular
involved in
reactive
oxygen
species
production
oxidative increase
stress oxidative
stress
2.
Involvement
of sub-cellular
organelles
associated
oxidative
stress
genes in function
specific
subcellular
organelles
2.2.
Mitochondrial
bio-energetic
disruption in
myocardium
in heart glycolysis
pathway by
decreasing
PFK
uptake by
heart
metabolism,
ATP loss
due to
decreased
ATP
2.3. GRP78 and 5μM 6,12,24h Embryonic rat Increased ER (Wang et al.,
stress
2.3.1. RyR, SERCA2a, 24mg/kg 8 weeks Male Rabbits Changes in (Arai et al.,
systolic and
diastolic
changes
markers system
4. Cell death
4.1. Apoptosis TNFR1, Fas, 450μM 24h Human Augments the (Zhao et al.,
derived receptor
the condition
called
apoptosis
flux
5. Other
mechanisms
development
and its
function
Table 1: Effect of different concentration of a doxorubicin with exposure time and biological model system