Doxorubicin induced cardiotoxicity - mechanisms behind the toxicity and how to treat the same.

1. Doxorubicin-induced cardiotoxicity: An
update on the molecular mechanism and
novel therapeutic strategies for effective
management
Dr.Arun.S
First year Post Graduate
Dept of Pharmacology
GMC, Anantapuramu
A Journal review

2. SPECIFIC LEARNING OBJECTIVES
BY THE END OF THE SEMINAR, THE LEARNER
WILL BE ABLE TO DESCRIBE
• The basic pharmacology of doxorubucin
• Agents / drugs causing cardiotoxicity
• Major molecular mechanisms involved in
cardiotoxicity
• Therapeutic strategies to overcome the DOX induced
cardiotoxicity

3. WHAT IS DOXORUBICIN?
SOURCE OF DOXORUBICIN:
• Secondary metabolite of a mutated strain of Streptomyces
peucetius var. caesius.
• It is an anthracycline antibiotic.
• It is also called as “The Red devil” as it is available as I.V.
injection in a bright red solution.

4. STRUCTURE ACTIVITY RELATIONSHIP OF
DOXORUBICIN
Chemically, Doxorubicin is composed of naphthacenequinone nucleus joined via
glycosidic linkage to an amine sugar called daunosamine.

5. • Positions decreasing biological activity: 2, R2
• Positions increasing biological activity: 3,8
• Substitution at 1st and 7th position will have
negative impact on the biological activity of the
drug.

7. PHARMACOKINETICS OF DOX
• Dox has a multiphasic disposition after giving this drug via intravenously (IV).
• The dose range of 30–70 mg/m2 of Dox presented the dose-independent
pharmacokinetics profile in patients.
ABSORPTION:
• Unstable at gastric pH. Hence given i.v. Anthacycline part is lipophilic,
Aminisugar part is hydrophilic.
DISTRIBUTION:
• Initial distribution half life is 5 mins - due to fast tissue uptake of the drug.
• Terminal half-life distribution is slow to about 20–48 h, reflecting the slow
elimination from the tissue.
• 75% plasma protein bound.

8. DISTRIBUTION - contd..
• Conventional Dox is much distributed in the plasma and the tissues.
• Absorption occurs into the cell and attaches to the cellular components that further
bind to the nucleic acid in the cellular DNA.
• It does not cross the blood-brain barrier (BBB).
METABOLISM:
Doxorubicin --------------------------------> Doxorubicinol (active metabolite)
• Doxorubicinol provides the anti-neoplastic activity. The levels of active metabolite
in plasma reach 90% after 24hrs of administration.
EXCRETION:
• Dox and its metabolite -- Excreted in unchanged form in bile (95%) and urine (5%)
--- after 5 days of administration.
(NADPH dependent aldoreductase)
in liver, kidney and erythrocytes

9. PK OF DOX IN SPECIAL POPULATIONS
OBESE PATIENT:
• ↑ BMI -- ↑ body surface area - Clearance of Dox and its metabolite is reduced.
• ↓ in clearance leads to toxicity due to enhanced AUC levels in obese patients.
HEPATIC IMPAIRMENT:
• Clearance is reduced. Dose adjustment according to bilirubin levels.
• 2-3mg/dL - 50% reduction in usual dose
• 3-4mg/dL - 75% reduction in usual dose
• >5 mg/dL - stop Dox treatment.
CHILDREN:
• Age > 2 yrs --- ↑ CL rate.
• Age < 2 yrs --- ↓ CL rate.

10. PHARMACODYNAMICS OF DOX

14. THERAPEUTIC USES OF DOXORUBICIN
Major indications:
• Breast CA - 60-75mg/m2 - rapid infusion single dose - every 21 days
• AIDS related Kaposi sarcoma - 20mg/m2 - slow iv infusion over 60 minutes -
every 21 days
• Ovarian CA - 50 mg/m2 every 4 weeks.
• Multiple myeloma - 30-mg/m2 dose on day 4 of each 21-day cycle.
Other indications:
• Malignant lymphomas
• Pediatric and adult sarcomas, including osteogenic, Ewing, and soft-tissue
sarcomas

15. ADVERSE EFFECTS OF DOXORUBICIN
Short term toxicity:
• Myelosuppression - dose-limiting complication - maximal leukopenia usually
occurring during the second week of therapy and recovering by the fourth week;
thrombocytopenia and anemia follow a similar pattern but usually are less
pronounced.
• Stomatitis, mucositis, diarrhea, and alopecia are common but reversible.
• Erythematous streaking near the site of infusion (“flare”) is a benign local
allergic reaction and should not be confused with extravasation.
• Facial flushing, conjunctivitis, and lacrimation may occur rarely.
• The drug may produce severe local toxicity in irradiated tissues (e.g., the skin,
heart, lung, esophagus, and GI mucosa) even when the two therapies are not
administered concomitantly.

16. ADVERSE EFFECTS OF DOXORUBICIN - contd..
Long term toxicity:
• Cardiomyopathy - 3 forms
Acute form -
• Abnormal ECG changes, including ST- and T-wave alterations and arrhythmias -
short lasting, rarely serious.
• Acute reversible decrease in EF may occur 24hrs after administration.
• Troponin T may be raised.
• Acute pericarditis - myocarditis syndrome - severe disturbances in impulse
conduction and frank congestive heart failure, often associated with pericardial
effusion.

17. Chronic form:
• Dilated Cardiomyopathy, CCF.
• Cumulative, dose-related toxicity (usually total doses of ≥ 550 mg/m2) progressing
to congestive heart failure.
• Mortality rate in pts with CCF - 50%
• A total dose limit of 300 mg/m2 is advised for pediatric cases.
• In children treated with anthracyclines, there is a 3- to 10-fold elevated risk of
arrhythmias, congestive heart failure, and sudden death in adult life.
• Concomitant administration of dexrazoxane may reduce troponin T elevations and
avert later cardiotoxicity.
Delayed form:
Bone marrow suppression, Total alopecia, Radiation recall reaction.

18. CHEMOTHERAPEUTIC AGENTS CAUSING
CARDIOTOXICITY

19. DRUG CARDIOTOXIC
EFFECTS
MECHANISM OF
CARDIOTOXICITY
PREVALENCE OF
CARDIOTOXICITY
Traztuzumab Heart failure Damage to mitochondria 1-28%
Sunitinib,
Sorafenib
Heart failure, ACS,
Hypertension
Inhibit tyrosine kinase pathway 3-8%
Imatinib,
Desatinib,
Bevacizumab,
nilotinib
Heart failure inhibit ABL tyrosine kinase 1.7%
Hypertension Unknown 50%
CCF Unknown
5-Fluorouracil Dilated Cardiomyopathy Vasospasm 1.2 - 18%
Ventricular arrhythmias Autoimmune phenomenon
Sudden cardiac death Myocarditis
Anthracyclines Heart failure Production of free radicals 2%
Cisplatin Hypertension Generation of oxidative stress unknown
Heart failure - -
Taxanes
(Paclitaxel,
docetaxel)
Heart failure Direct cellular toxicity, lipid
peroxidation
2.3 - 8%
Cyclophosphamide Inflammation of cardiac Unknown 7-28%

20. MOLECULAR MECHANISMS BEHIND DOXORUBICIN
INDUCED CARDIOTOXICITY
1. OXIDATIVE STRESS
2. ROLE OF AMP - ACTIVATED PROTEIN KINASE
3. AUTOPHAGY
4. ROLE OF SIRTUINS
5. CREATINE KINASE
6. APOPTOSIS
7. ENDOTHELIN-1
8. FIBROSIS
9. PYROPTOSIS
10. NECROPTOSIS
11. ROLE OF EPIGENETICS

22. 1. OXIDATIVE STRESS
MECHANISM OF DAMAGE BY OXIDATIVE STRESS:
Aglycones and their iron complexes
↓
Increased ROS production and lipid peroxidation
↓
Cardiac cell damage

23. 1. NOS DEPENDENT INCREASED ROS PRODUCTION
• NOS - 3 types - eNOS, iNOS, nNOS
DOX binds to eNOS reductase enzyme
↓
Dox - semiquinone radical formed
↓
This complex reduces free O2 into superoxide (O2
-) radical
↓
Reduced levels of NO and increased levels of O2
-
↓
Caspase-3 activation - leads to apoptosis of cardiac myocyte

24. NOS DEPENDENT INCREASED ROS PRODUCTION
DOX administration - increases iNOS transcription
↓
formation of Nitrotyrosine (NT) with increased mitochondrial superoxide levels
↓
Potent radicals like carbonates and NO2 are formed
↓
Reduced levels of NO and increased levels of O2
-
↓
Caspase-3 activation - leads to apoptosis of cardiac myocyte

25. NOS DEPENDENT INCREASED ROS PRODUCTION
Cardiotoxicity was reduced when
• Dox was administered in eNOS knockout mice
• Dox was administered in iNOS knockout mice
• Administration of iNOS inhibitor like S,S˙-[1,3-phenylene-bis(1,2-ethanediyl)]bis-
isothiourea (1,3-PB-ITU)

26. 2. MITOCHONDRIAL DEPENDENT ROS
PRODUCTION
DOX administration
Reduces oxidation long chain fatty acids
DOX binds to cardiolipin in mitochondria ↓
↓ Increased glucose metabolism in cardiac muscle
DOX-cardiolipin complex ↓
↓ Increased anaerobic metabolism
Interferes with ETC functioning ↓
↓ Abnormal cardiac contractility
Generation of superoxides (ROS) ↓
↓ Heart failure
Cardiotoxicity

27. DOX affects expression of GATA-4 gene in mitochondria
↓
Supression of mitochondrial syntheis and metabolism
↓
Apoptosis
MITOCHONDRIAL DEPENDENT ROS PRODUCTION

28. 3. Role of HO-1 and CO
CO inhalation to mice at low concentration
↓
Stimulates mitochondrial synthesis and upregulates the nuclear-encoded heme
oxygenase (HO)-1
↓
HO-1 is an anti-oxidant which reduces cardiac apoptosis
↓
HO-1 / CO activates Akt and deactivates Glycogen synthase kinase 3β
↓
Nuclear translocation of Nuclear erythroid-2 related factor (Nrf-2)
↓
Activates GATA-4 gene
↓
Prevents apoptosis

30. 4. Fe-DOX COMPLEX

31. Dox inactivates Iron regulating proteins 1 & 2
↓
Inactive IRP -- modify iron response elements (IRE) in gene
↓
mRNA of Ferritin’s IRE is disrupted
↓
Increase in free intracellular iron pool
↓
Doxorubicin binds to Fe2+ --- ↑ in transferrin receptor transcription
↓
By Fenton’s redox reaction, Fe3+ is formed along with ROS
↓
Doxorubicin induces lipid peroxidation by inhibiting cytosolic and mitochondrial
GPX4 (Glutathione Peroxidase) resulting in ferroptosis
Fe-DOX COMPLEX

33. In Mitochondria,
• Upregulation of Hemeoxygenase - 1 by activation of nrf-2
• Downregulation of ABCB8 protein - essential for export of iron from
mitochondria
• Downregulation of Glutathione Peroxidase 4 (GPX4)

34. METHODS TO PREVENT FE-DOX INDUCED DAMAGE
• Anti-Tfr antibody
• Iron chelator dexrazoxane
• ferrostatin-1, a ferroptosis inhibitor
• MitoTempo - a mitochondrial antioxidant.

35. 5. NADPH DEPENDENT ROS

37. 6. INTRACELLULAR CALCIUM
DYSREGULATION
• Various mechanisms involved
DOXOL (Toxic metabolite of DOX)
↓
Inhibits Na-Ca exchanger channel in cardiac myocyte
↓
Alteration in Ryanodine receptor in SR
↓
Increased Ca efflux into the cytoplasm
↓
Activation of Calmodulin activated protein kinase 2 and Phospholamban
↓
Activation of caspases 3 and 9 --- Apoptosis.

38. contd..
Rise in intracellular Ca2+
↓
Activation of calpains (Calcium dependent proteases)
↓ ↓
Calpains cleave caspase-12 calpains degrade the titin that is the largest
protein and principal component of
↓ heart sarcomere
Apoptosis ↓
Destruction of cardiac muscle proteins

40. 2. ROLE OF AMPK SIGNALLING
AMPK - macromolecular protein with 3 subunits - α, β, γ - α1 present in
endothelium, α2 in heart.
DOX administration
↓
Inhibition of AMP-activated protein kinase (AMPK)
↓
Reduced levels of Acetyl Co-A carboxylase enzyme activity in heart
↓
Increased Genotoxic stress
↓
Activation of Akt and MAP signalling pathways
↓
DNA damage and Cardiac hypertrophy

42. 3. ROLE OF AUTOPHAGY
• Autophagy is a homeostatic process by which cellular components are degraded
and recycled under normal and stress conditions.
• Doxorubicin can trigger autophagy, but it is the deregulation of autophagy that
leads to excessive cardiomyocyte death.

44. 4. ROLE OF SIRTUINS
In the heart, sirtuins (SIRT) 1, 2, 3, and 6 activate the
• Autophagic process,
• Repress apoptosis and
• Protect the heart from various cardiovascular threats such as atherosclerosis,
ischemia-reperfusion injury, myocardial hypertrophy, diabetic cardiomyopathy,
and cardiac hypertrophy.

46. 5. ROLE OF CREATINE KINASE
Creatine kinase is a protein present in the number of tissues in the body and acts as
an energy reservoir. This enzyme aids in the preservation of the energy with the
conversion of creatine to phosphocreatine, which use ATP as a substrate.
Doxorubicin administered
↓
Oxidative stress generated
↓
Damages CK-MB in cardiac myocyte in presence of ferrous ions
↓
Generation of peroxynitrite free radical

47. 6. APOPTOTIC PATHWAYS
• Doxorubicin activates both extrinsic and intrinsic pathways of apoptosis
• Doxorubicin-induced upregulation of p53, Bax/Bak, and downregulation of
GATA4 and Bcl-XL, activating caspases 9, 3, and 7 resulting in apoptotic death.
• Mitochondrial calcium overload and activation of mitochondrial permeability
transition pore (mPTP) lead to
a) mitochondrial membrane potential loss,
b) mitochondrial swelling, and
c) outer membrane rupture allowing the release of endonuclease G (EndoG), cytochrome c and
activation of caspase 9.
• Doxorubicin induces the extrinsic apoptotic pathway via the upregulation of death
receptors and the activation of NFAT and NF-κΒ

49. 7. ROLE OF ENDOTHELIN-1
DOX treatment
↓
Increased levels of Endothelin-1
↓
Hypertrophic cardiomyopathy
Endothelin receptor antagonists (Eg. Bosentan) - exert cardioprotective action by
various modes
• Reduced TNF-α and Bax levels,
• Decreased lipid peroxidation
• Increase in GATA4

50. 8. ROLE OF FIBROSIS
DOX Rx inhibits mRNA synthesis of MMP
↓ ↓
MMP-1 affected MMP-2 and 9 affected
↓
activate the TGF-β and phosphor-SMAD3 signaling
↓
Decreased cancer cell mobility More collagen deposition on cardiac myocytes
↓
Cardiac fibrosis

51. 9. PYROPTOSIS
• Pyroptosis is characterized by increased inflammation and activation of caspases -
play a crucial role in pathology of cardiovascular diseases.
• Doxorubicin induces pyroptosis via the upregulation of TINCR, which recruits
IGF2BP and increases the expression of NLRP3 leading to activation of caspase-
1, the cleavage of GMDSD-N and the release of IL-1β, IL-18.
• Pyroptosis is also induced via BNIP3 activation in the mitochondria, which
activates caspase 3 and causes GSDME-dependent pyroptosis.
• Sirtuin 1 activation inhibits NLRP3 and protects cardiomyocytes from
doxorubicin-induced pyroptosis.

53. 10. NECROPTOSIS
• Necroptosis is a regulated form of necrosis that involves the release of death-
signaling cytokines.
• Doxorubicin causes upregulation of TNFα, activating TRADD and FADD, and
upon caspase 8 inhibition and activation of RIPK1, RIPK3, and MLKL induces
cell death via necroptosis.
• Doxorubicin can also activate necroptosis via the RIPK1 independent pathway,
where RIPK3 activates CAMKII and mitochondrial permeability transition pore
(mPTP) resulting in membrane potential and integrity loss.

55. 11. ROLE OF EPIGENETICS
• Epigenetics is a heritable phenotypic change in which there is no involvement in
altering DNA base-pair sequence (genotype).
• Epigenetic modifications cause alteration in the gene function. It is a natural
process in which alterations occur regularly with several factors like age,
environment, external, and disease state.
• Two main epigenetic modifications involved in many diseases and natural growth
include DNA methylation and histone protein modification.

56. 1. ALTERATION IN DNA METHYLATION
DNA methylation is a process in which there is the addition of methyl moieties to
the DNA molecule and this addition leads to a change in DNA activity without
disturbing the DNA base pair sequence.
DOX downregulates DNA methyl transferase-1
↓
Defective mitochondrial functioning
1. peroxisome proliferator-activated receptor-gamma coactivator alpha (PGC-1α),
2. Nuclear respiratory factor 1 (NRF-1)
3. Mitochondrial transcription factor A (TFAM)

57. 2. ALTERATION IN HISTONE MODIFICATION
Histones are highly basic proteins in nucleus that package and order the DNA into
structural units called nucleosomes. In the absence of histone proteins, unwound
DNA in chromosomes would be very long.
DOX administered
↓
Suppression of Histone deacetylase (HDAC)
↓
Apoptosis and hypertrophy

58. 3. ALTERATION IN NON CODING RNA
• Regulatory ncRNAs, including small interfering RNAs (siRNAs), microRNAs
(miRNAs), and long ncRNAs (lncRNAs) play significant roles in the regulation of
gene expression at several levels: transcription, mRNA degradation, splicing and
translation.
• miRNAs role in cardiac functioning like development, electrical signal conduction
and cardiac muscle constractions.
• Upregulated miRNAs:
miR-23a, miR-34a, miR-140, miR-146a, miR-532, miR-15
• Downregulated miRNAs:
miR-29b and miR-30

60. THERAPEUTIC STRATEGIES
Dexrazoxane
Metformin

61. 1. DEXRAZOXANE
• A cyclic derivative of EDTA, that quickly penetrates plasma membrane.
• MOA: Free radical scavenging, chelator action on iron-mediated oxygen free
radical activation as well as lipid peroxidation.

62. 2. STATINS
• Pitavastatin, Rosuvastatin, lovastatin - Cardioprotective action by activation of
AMPK signalling.

64. 3. BETA BLOCKERS AND ACEI
• Beta blockers like Carvedilol - has antioxidant action and it keeps the left
ventricular contraction constant - Cardioprotective.
• ACEI - prevent cardiac remodelling by anti-fibrotic and anti-apoptotic
mechanisms.

65. 4. PDE-5 INHIBITORS
Cardioprotective actions:
• Inhibition of cardiac muscle apoptosis
• Preserving the mitochondrial membrane potential
• Regulating myofibrillar integrity
• Prevention of ventricular dysfunction
• Protection from ST-interval prolongation
• Modulation of NO/cyclic GMP, mitochondrial K+ATP channel and oxidative
stress.

66. 5. ALPHA-1 AGONISTS
• Phenylephrine - generates anti-apoptotic factors (Bcl2) and maintains
mitochondrial functioning.
• It prevents DOX induced: apoptosis, interstitial fibrosis and cardiac muscle
impairment.

67. 6. METFORMIN
• Activates AMPK signalling - So more Acetyl Co-A is available for fatty acid
oxidation in cardiac mitochondria.
• Reduces levels of H2O2
• Maintains autophagy markers like LC3B-II and p62 in Dox-treated rats, thus
improving cardiac functioning.

68. 7. RESVERATROL
• Its a polyphenolic stilbene.
• Naturally occuraning agent having antioxidant and potential chemopreventive
activities.
• Produced from plants and is a constituent of Red wine
• Anti-oxidant effects are by enhancing levels like superoxide dismutase (SOD) and
catalase (CAT) activity.
• Cardioprotective action through the activation of AMPK.
• Pterostilbene, a natural analog of resveratrol, activates PGC-1α, reduces oxidative
stress via enhancing AMPK and SIRT1 cascades - Cardioprotective action.
• Other actions - Anti-inflammatory, inhibits cyclooxygenase and hydroperoxidase.

69. 8. VITAMIN E
• Four tocopherols and four tocotrienols are combined to make vitamin E, which is
fat-soluble.
• Anti-oxidant action is useful in acute DOX induced cardiotoxicity.
• Other anti-oxidants similar to Vitamin E useful in cardiotoxicity:
1. Vitamin C
2. Selenoorganic compound PZ51
3. Reduced glutathione,
4. Ambroxol,
5. Ursolic acid
6. Oleanolic acid

72. 9. PROBUCOL
• Probucol is an antihyperlipidemic agent.
• Also has an effective anti-oxidant action.
• Cardioprotective effect via a reduction in cardiac muscle injury and heart failure
without interrupting the antineoplastic effect of DOX.

73. 10. ALLICIN
• An active constituent of garlic and it is an organosulfur containing compound.
• Antimicrobial, antioxidant, anticarcinogenic, and antifungal effects.
• In acute DOX intoxication - efficiently reduces cardiac oxidative stress, reduces
inflammation, and reduces apoptosis.

74. 11. ADIPONECTIN AGONIST ADP355
• Adiponectin is a protein hormone responsible for the regulation of glucose and the
breakdown of fatty acids. It is mainly located in the adipose tissue and also in
muscles and brain
• Actions of ADP355:
1. Reduces serum creatine kinase level, lactate dehydrogenase and hydroxybutyrate
dehydrogenase level.
2. Anti-apoptotic action
3. Enhances anti-oxidant levels
4. Activates the sirtuin 2 signaling pathways

75. 12. ERYTHROPOEITIN
• It is a hormone generated from healthy kidney and a small amount by the liver.
• It is a glycoprotein cytokine mainly secreted from the kidney at the time of
cellular hypoxia.
• It is an antianemic agent which is used in anemia caused by chemotherapeutic
agents.
• Erythropoietin reduces apoptosis and cardiomyopathy when administered
prophylactically.

76. 13. MiR-181c
MiR-181c - one of the microRNAs that helps in the muscle cell survival via
PI3K/Akt signaling pathway
Treatment with Dox
↓
Downregulation in the MiR-181c
↓
Activation of the toxic markers like TNF-α, Fas and IL-6
↓
Cardiotoxicity
Treatment with MiR-181c inhibits apoptosis in the Dox treated cells

77. 14. 20(S)-ginsenoside Rh2
• Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides from Panax
ginseng - Chinese herb.
• Various pharmacological effects, including activating immune function, enhancing
cardiovascular health, increasing resistance to stress, improving memory and
learning, and developing social functioning and mental health in healthy
individuals and chemotherapy.
• Cardioprotective action: restores the lactate dehydrogenase, creatine kinase and
aspartate transaminase in the serum, increases the levels of antioxidants.

78. 15. CUCURMIN
• Curcumin is a natural compound derived from the plant Curcuma longa - active
constituent of turmeric.
• Actions:
1. Reduces Bax levels and prevents mitochondrial cell death.
2. Inhibits pyroptosis by modulating pro-pyroptosis markers like NLRP3, caspase1
and IL-18 and downregulates the inflammasome.
3. Reduces the levels of CK, LDH and AST.
4. Curcumin reduced autophagosome levels.
5. Curcumin upregulates the PI3K/Akt/mTOR pathway and shows
cardioprotection.
6. Curcumin also reduced pyroptosis and autophagy via activation of the
Akt/mTOR pathway.

79. 16. VISNAGIN
• Visnagin is a furochromone which is a derivative of chromone and furan.
• It is a major constituent of Ammi visnaga.
• In traditional medicine, visnagin has been used for kidney-associated problems.
• Cardioprotective action - inhibition of mitochondrial malate dehydrogenase
(MDH2).
• MDH2 is an important enzyme in the tricarboxylic acid (TCA) cycle.
• Dox has an affinity towards the MDH2 enzyme.

80. 17. SCHISANDRIN B (Sch B)
• Sch B the most abundant dibenzocyclooctadiene lignan present in Schisandra
chinensis.
• It has used in the treatment of cerebral ischemia and Alzheimer’s disorder.
• Cardioprotective actions:
1. Increases glutathione redox cycling - eliminates excessive ROS
2. Sch B partially relieves mTOR inhibition in muscle or adipose tissue under Dox
treatment and improves the body weight.

81. 18. MITOCHONDRIAL MODULATORS

82. 1. Mitochondrial division inhibitor (mdivi-1)
• Tried in heart failure and ischemia / reperfusion injury.
• Improves cardiac function and reduces the infarct size in ischemia/reperfusion
injury.

83. 2. LCZ696
Restoring the cardiac function,
mitochondrial morphology,
improves mitochondrial
respiration complex I activity
with increased adenosine
triphosphate content.

84. 3. LIENSININE
• It is a mitophagy inhibitor - inhibition of Drp1-mediated maladaptive
mitochondrial fission.
• Liensinine suppresses mitochondrial fragmentation, mitophagy, oxidative stress,
cytochrome C leakage, cardiomyocyte apoptosis and improved mitochondrial
function and cardiomyocyte contractile function in Dox-induced cardiac injury

85. 4. LUTEOLIN
• Luteolin is a phytochemical derived from vegetables and fruits having anti-
oxidative, anti-tumorigenic, and anti-inflammatory properties.
• Luteolin improves the Dox-induced alterations in defective mitochondrial
autophagy, mitochondrial dysfunction and cardiomyocyte injury and apoptosis via
stimulating autophagosome formation and improving lysosomal generation
through a Drp1/mTOR/TFEB-dependent mechanism

86. 5. MELATONIN
• Melatonin is a natural hormone produced by the pineal gland.
• CARDIOPROTECTIVE ACTION:
i. Free radical scavenger activity, modulates the autophagy, mitophagy,
mitochondrial bioenergetics, mitochondrial fission and fusion process and
apoptosis.
ii. Reduction of AMPKα2-dependent mitochondrial damage

87. 6. CHRYSOPHANOL
• Inhibition of cardiac apoptosis, mitochondrial damage and cellular PARylation
levels

88. 7. ECHINOCHROME A
• It is a naphthoquinoid pigment derived from sea urchins having antioxidant,
antimicrobial, anti-inflammatory and chelating abilities.
• Co-treatment of Echinochrome A with Dox improves the mitochondrial membrane
potential, reduces ROS level, preserve the function of mitochondrial oxidative
phosphorylation and adenosine triphosphate level.

89. 8. GHRELIN
• Cardioprotective action by modulation of TNF-alpha/NF-kappaB pathways and
increased the mitochondrial anti-apoptosis-related gene protein expression

90. 9. INTRAVENOUS MITOCHONDRIAL EXTRACT
• Administration of fresh mitochondria can be tried and could be a novel treatment
strategy for mitigating cardiac injury.
• However, there are no studies were reported with Dox-induced cardiotoxicity.
• It was given in mice with Parkinson’s disease.
• The administered exogenous mitochondria is well distributed in several tissues
such as brain, liver, kidney, muscle, and the heart, indicating beneficial effects in
multi-systemically mitochondrial diseases.

91. 19. OTHER RECENT STRATEGIES
• Proanthocyanidin: improves the anti-oxidant levels and inflammation. It
downregulates the expression of α-SMA, TGF-β1 and upregulates the CDK4 and
Rb protein expression with reduced expression of the NF-kB signaling pathway.
• Hydrogen sulfide: decreases the endoplasmic reticulum stress, autophagy and
upregulates the PI3K/AKT/mTOR protein expression resulting in reduced
myocardial fibrosis in Dox-treated rats.
• Tranilast (anti-allergy drug): suppressing chymase expression, reducing the
angiotensin II levels, and modulating the antioxidant level, thus preventing
apoptosis and fibrosis of cardiomyocytes.

92. Contd..
• Kirenol (diterpenoid): a phytochemical extracted from Herba Siegesbeckiae. It
has anti-inflammatory anti-rheumatic properties. Kirenol treatment decreases the
cardiac oxidative stress, cardiac remodeling, modulates the apoptosis process,
activates the IGF-IR-dependent p-PI3K/p-AKT and Nrf2 signaling, thereby
preventing the Dox-induced cardiac damage.
• Malva verticillata (Malvaceae): a medicinal plant with anti-inflammatory and
antioxidant activities. Improves the levels of cardiac-specific biochemical
parameters.
• Xinmailong - bioactive peptide extracted from American cockroaches - increases
antioxidant activity, upregulates HO-1 expression, restored lysosomal function and
improved autophagy flux.

93. Contd...
• Adeno-associated virus-mediated gene therapy: for the long-term expression of
telomerase - beneficial effects through the inhibition of apoptosis, which improves
cardiac function and mitochondrial morphology
• Other substances:
1. Methyl gallate
2. Alk A & B
3. Szeto-Schiller (SS)31
4. Quercetin
5. Calycosin-triblock copolymer nanomicelles
6. Compound DanShen Dripping Pill (CDDP)
7. Thymoquinone

97. CONCLUSION
• The anthracycline anticancer drug doxorubicin (DOX) is widely prescribed to treat
tumors such as breast, ovary, leukemia, lymphoma and other malignant tumors in both
adults and children.
• Dox administration leads to cardiac toxicity, resulting in increased mortality risks and
thus limiting its wide clinical applications among cancer patients.
• Multiple mechanisms are involved in Dox-induced cardiotoxicity, including oxidative
stress, impaired mitochondrial function, alterations in iron regulatory protein,
deregulation of Ca2+ homeostasis with impaired apoptosis.
• Therefore, targeting these alterations using allicin, metformin, enalapril, adiponectin,
visnagin and schisandrin B and other novel phytochemicals has shown protective effects
against Dox-induced cardiotoxicity and could reduce the mortality rate among cancer
patients.

99. REFERENCES
https://doi.org/10.3390/ijms23031912 - 2022
https://doi.org/10.1016/j.biopha.2021.111708 - MAY 2021
https://doi.org/10.1038/s41419-021-03614-x - 2021