Doxorubicin-Induced Cardiomyopathy: From the Cardiotoxic Mechanisms to Management

doi:10.1016/j.pcad.2006.10.002

Progress in Cardiovascular Diseases

Volume 49, Issue 5, March–April 2007, Pages 330-352

https://doi.org/10.1016/j.pcad.2006.10.002 Get rights and content

First isolated in the early 1960s, doxorubicin (DOX) remains among the most effective anticancer drug ever developed. However, this drug has proven to be a double-edged sword because it also causes a cardiomyopathy that leads to a form of congestive heart failure that is usually refractory to common medications. It is hoped that a better understanding of the mechanisms underlying DOX's cardiotoxicity will enable development of therapies with which to prevent and/or treat the heart failure it causes. Suggested contributors to DOX-induced cardiomyopathy include formation of reactive oxygen species, apoptosis, inhibited expression of cardiomyocyte-specific genes, and altered molecular signaling. And taking these various contributors into consideration, a variety of approaches aimed at preventing or mitigating the cardiotoxicity of DOX have been tried, but so far, the ability of these treatments to protect the heart from damage has been limited. That said, one recent approach that shows promise is adjuvant therapy with a combination of hematopoietic cytokines, including erythropoietin, granulocyte colony-stimulating factor, and thrombopoietin. We suggest this approach to preventing DOX-induced cardiomyopathy is worthy of serious consideration for clinical use.

Section snippets

Morphological Aspects of DOX-Induced Cardiomyopathy

As with other forms of dilated cardiomyopathy, hearts affected by DOX's cardiotoxicity are enlarged with dilation of all chambers, and mural thrombi are seen frequently in both ventricles. At the light microscope level, there are multifocal areas of patchy and interstitial fibrosis and scattered cardiomyocytes with vacuolation (Fig 2). Vacuolated cardiomyocytes are occasionally observed adjacent to areas of fibrosis (Adria cells). Fibrotic foci generally predominate, whereas areas of acute

Pathogenic Mechanisms of DOX-Induced Cardiomyopathy

The mechanism responsible for DOX-induced cardiomyopathy remains unclear, but it seems very different from that underlying DOX's antitumor activity. This has raised hopes that treatment protocols can be designed that protect the heart without diminishing the drug's antitumor activity.

Although numerous mechanisms have been proposed (Table 1), most studies support the view that an increase in oxidative stress, evidenced increases in the levels of ROS,36, 37, 38 and lipid peroxidation,20, 36, 39

Epidemiology and Clinical Features

Doxorubicin exerts both acute and chronic effects on the cardiovascular system. Its acute effects include arrhythmias (eg, supraventricular tachycardia, ventricular premature beats), hypotension, and various electrocardiographic changes (eg, nonspecific ST-T change, left axial deviation, low voltage).2, 121, 122 These effects occur in approximately 11% of patients during or soon after (within a couple of days) DOX administration and are generally reversible and clinically manageable.² Acute

Monitoring of Patients and Diagnostic Procedures

The monitoring of patients receiving DOX includes (1) assessment of baseline cardiac performance before DOX therapy begins (to exclude contraindicated patients), (2) regular assessments during treatment (to prevent overdosage or to determine when DOX should be terminated), and (3) follow-up after therapy has been completed (to watch for insidious progression of cardiomyopathy). Various diagnostic procedures are listed in Table 6.

Management: Prevention of DOX-induced cardiomyopathy

Limiting the cumulative dose of DOX to less than 450 mg/m² is the first line of defense against cardiotoxicity.¹⁵² To minimize the total amount of DOX used, it is administered concurrently with other antitumor drugs such as vincristine, procarbazine, cisplatin and cyclophosphamide.127, 152 Additional strategies that have been used in an attempt to prevent DOX-induced cardiomyopathy include the use of DOX analogues, alternative drug-delivery methods, antioxidants, and the iron chelator

Management: Treatment of DOX-induced cardiomyopathy

At present, there is no specific treatment for DOX cardiomyopathy. Typically, DOX cardiomyopathy and heart failure are refractory to conventional therapy.¹⁷⁹β-Blockers (eg, metoprolol) and angiotensin-converting enzyme inhibitors (eg, enalapril and captopril) may be useful in patients with congestive heart failure.180, 181 Malignant arrhythmias may also require treatment. Cardiac transplantation remains a vital option for patients with end-stage heart failure due to DOX cardiomyopathy.181, 182,

Conclusions

Anthracyclines, including DOX, rank among the most effective anticancer drugs ever developed, despite their dose-dependent cardiotoxic effects.1, 185 Contributors to DOX-induced cardiomyopathy include free radical formation, apoptosis, inhibited expression of cardiomyocyte-specific genes, and altered molecular signaling pathways.¹⁸⁶ A variety of approaches to preventing this cardiotoxicity have be tried, but so far, the ability of these treatments to protect the heart from DOX-induced damage

References (186)

M.R. Bristow et al.
Early anthracycline cardiotoxicity
Am. J. Med.
(1978)
D.A. Gewirtz
A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin
Biochem. Pharmacol.
(1999)
B.K. Sinha et al.
Adriamycin-stimulated hydroxyl radical formation in human breast tumor cells
Biochem. Pharmacol.
(1987)
M. Potmesil et al.
Two mechanisms of adriamycin-DNA interaction in L1210 cells
Biochem. Pharmacol.
(1984)
J.R. Muindi et al.
Hydroxyl radical production and DNA damage induced by anthracycline-iron complex
FEBS Lett.
(1984)
A.P. Breen et al.
Reactions of oxyl radicals with DNA
Free Radic. Biol. Med.
(1995)
P.K. Singal et al.
Combination therapy with probucol prevents adriamycin-induced cardiomyopathy
J. Mol. Cell. Cardiol.
(1995)
K. Shimpo et al.
Ascorbic acid and adriamycin toxicity
Am. J. Clin. Nutr.
(1991)
A. Cervantes et al.
The role of oxygen-derived free radicals in the cytotoxicity of doxorubicin in multidrug resistant and sensitive human ovarian cancer cells
Cancer Lett.
(1988)
B.K. Sinha et al.
Binding mode of chemically activated semiquinone free radicals from quinone anticancer agents to DNA
Chem. Biol. Interact.
(1979)

G. Capranico et al.

Formation, resealing and persistence of DNA breaks produced by 4-demethoxydaunorubicin in P388 leukemia cells

Chem. Biol. Interact.

(1989)

A. Skladanowski et al.

Adriamycin and daunomycin induce programmed cell death (apoptosis) in tumour cells

Biochem. Pharmacol.

(1993)

S. Anand et al.

Induction of apoptosis in chronic myelogenous leukemia lymphocytes by hydroxyurea and adriamycin

Cancer Lett.

(1995)

J. Zhang et al.

Doxorubicin-induced apoptosis in spontaneously hypertensive rats: Differential effects in heart, kidney and intestine, and inhibition by ICRF-187

J. Mol. Cell. Cardiol.

(1996)

P.K. Singal et al.

Subcellular effects of adriamycin in the heart: A concise review

J. Mol. Cell. Cardiol.

(1987)

B. Kalyanaraman et al.

Spin-trapping and direct electron spin resonance investigations of the redox metabolism of quinone anticancer drugs

Biochim. Biophys. Acta.

(1980)

A.L. Odom et al.

Biochemical determinants of Adriamycin toxicity in mouse liver, heart and intestine

Biochem. Pharmacol.

(1992)

S. Kotamraju et al.

Doxorubicin-induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. Role of reactive oxygen and nitrogen species

J. Biol. Chem.

(2000)

A. Elsasser et al.

Unresolved issues regarding the role of apoptosis in the pathogenesis of ischemic injury and heart failure

J. Mol. Cell. Cardiol.

(2000)

E.A. Konorev et al.

Cell-permeable superoxide dismutase and glutathione peroxidase mimetics afford superior protection against doxorubicin-induced cardiotoxicity: The role of reactive oxygen and nitrogen intermediates

Arch. Biochem. Biophys.

(1999)

K.J. Davies et al.

Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase

J. Biol. Chem.

(1986)

V. Berlin et al.

Reduction of adriamycin to a semiquinone-free radical by NADPH cytochrome P-450 reductase produces DNA cleavage in a reaction mediated by molecular oxygen

J. Biol. Chem.

(1981)

P.J. Thornalley et al.

Free radical production from normal and adriamycin-treated rat cardiac sarcosomes

Biochem. Pharmacol.

(1985)

L. Costa et al.

Direct detection of paramagnetic species in adriamycin perfused rat hearts

Biochem. Biophys. Res. Commun.

(1988)

S.V. Kalivendi et al.

Doxorubicin-induced apoptosis is associated with increased transcription of endothelial nitric-oxide synthase. Effect of antiapoptotic antioxidants and calcium

J. Biol. Chem.

(2001)

C.F. Curran et al.

Toxicity profile of dexrazoxane (Zinecard, ICRF-187, ADR-529, NSC-169780), a modulator of doxorubicin cardiotoxicity

Cancer Treat. Rev.

(1991)

R.D. Klausner et al.

Regulating the fate of mRNA: The control of cellular iron metabolism

Cell

(1993)

E.A. Martins et al.

Oxidative stress induces activation of a cytosolic protein responsible for control of iron uptake

Arch. Biochem. Biophys.

(1995)

K. Pantopoulos et al.

Differences in the regulation of iron regulatory protein-1 (IRP-1) by extra- and intracellular oxidative stress

J. Biol. Chem.

(1997)

N.H. Gehring et al.

Inactivation of both RNA binding and aconitase activities of iron regulatory protein-1 by quinone-induced oxidative stress

J. Biol. Chem.

(1999)

T.A. Rouault et al.

Iron-sulfur clusters as biosensors of oxidants and iron

Trends Biochem. Sci.

(1996)

J.J. Cohen

Programmed cell death in the immune system

Adv. Immunol.

(1991)

D.A. Carson et al.

Apoptosis and disease

Lancet

(1993)

R.B. Weiss

The anthracyclines: Will we ever find a better doxorubicin?

Semin. Oncol.

(1992)

E.A. Lefrak et al.

A clinicopathologic analysis of adriamycin cardiotoxicity

Cancer

(1973)

A.C. Gilladoga et al.

The cardiotoxicity of adriamycin and daunomycin in children

Cancer

(1976)

D.D. Von Hoff et al.

Risk factors for doxorubicin-induced congestive heart failure

Ann. Intern. Med.

(1979)

G. Minotti et al.

Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity

Pharmacol. Rev.

(2004)

N.R. Bachur et al.

Nuclear catalyzed antibiotic free radical formation

Cancer Res.

(1982)

B.K. Sinha et al.

Differential formation of hydroxyl radicals by adriamycin in sensitive and resistant MCF-7 human breast tumor cells: Implications for the mechanism of action

Biochemistry

(1987)

J. Muindi et al.

Thiol-dependent DNA damage produced by anthracycline-iron complexes. The structure-activity relationships and molecular mechanisms

Mol. Pharmacol.

(1985)

H. Eliot et al.

Oxidative destruction of DNA by the adriamycin-iron complex

Biochemistry

(1984)

C.E. Myers et al.

Adriamycin: The role of lipid peroxidation in cardiac toxicity and tumor response

Science

(1977)

C. Myers et al.

A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine

Semin. Oncol.

(1983)

Y. Yoda et al.

Prevention of doxorubicin myocardial toxicity in mice by reduced glutathione

Cancer Res.

(1986)

N. Siveski-Iliskovic et al.

Probucol protects against adriamycin cardiomyopathy without interfering with its antitumor effect

Circulation

(1995)

D.E. Graves et al.

Adriamycin and daunorubicin bind in a cooperative manner to deoxyribonucleic acid

Biochemistry

(1983)

C. Holm et al.

DNA topoisomerase II must act at mitosis to prevent nondisjunction and chromosome breakage

Mol. Cell. Biol.

(1989)

R. Cece et al.

Apoptosis of hair follicle cells during doxorubicin-induced alopecia in rats

Lab. Invest.

(1996)

M.E. Billingham et al.

Anthracycline cardiomyopathy monitored by morphologic changes

Cancer. Treat. Rep.

(1978)

Cited by (702)

Cellular and molecular mechanisms of oroxylin A in cancer therapy: Recent advances
2024, European Journal of Pharmacology
Seeking an effective and safe scheme is the common goal of clinical treatment of tumor patients. In recent years, traditional Chinese medicine has attracted more and more attention in order to discover new drugs with good anti-tumor effects. Oroxylin A (OA) is a compound found in natural Oroxylum indicum and Scutellaria baicalensis Georgi plants and has been used in the treatment of various cancers. Studies have shown that OA has a wide range of powerful biological activities and plays an important role in neuroprotection, anti-inflammation, anti-virus, anti-allergy, anti-tumor and so on. OA shows high efficacy in tumor treatment. Therefore, it has attracted great attention of researchers all over the world. This review aims to discuss the anti-tumor effects of OA from the aspects of cell cycle arrest, induction of cell proliferation and apoptosis, induction of autophagy, anti-inflammation, inhibition of glycolysis, angiogenesis, invasion, metastasis and reversal of drug resistance. In addition, the safety and toxicity of the compound were also discussed. As a next step, to clarify the benefits and adverse effects of Oroxylin A in cancer patients further experiments, especially clinical trials, are needed.
AKT2 deficiency alleviates doxorubicin-induced cardiac injury via alleviating oxidative stress in cardiomyocytes
2024, International Journal of Biochemistry and Cell Biology
Doxorubicin (DOX), a widely used chemotherapy agent in cancer treatment, encounters limitations in clinical efficacy due to associated cardiotoxicity. This study aims to explore the role of AKT serine/threonine kinase 2 (AKT2) in mitigating DOX-induced oxidative stress within the heart through both intracellular and extracellular signaling pathways. Utilizing Akt2 knockout (KO) and Nrf2 KO murine models, alongside neonatal rat cardiomyocytes (NRCMs), we systematically investigate the impact of AKT2 deficiency on DOX-induced cardiac injury. Our findings reveal that DOX administration induces significant oxidative stress, a primary contributor to cardiac injury. Importantly, Akt2 deficiency exhibits a protective effect by alleviating DOX-induced oxidative stress. Mechanistically, Akt2 deficiency facilitates nuclear translocation of NRF2, thereby suppressing intracellular oxidative stress by promoting the expression of antioxidant genes. Furthermore, We also observed that AKT2 inhibition facilitates superoxide dismutase 2 (SOD2) expression both inside macrophages and SOD2 secretion to the extracellular matrix, which is involved in lowering oxidative stress in cardiomyocytes upon DOX stimulation. The present study underscores the important role of AKT2 in mitigating DOX-induced oxidative stress through both intracellular and extracellular signaling pathways. Additionally, our findings propose promising therapeutic strategies for addressing DOX-induced cardiomyopathy in clinic.
Protective effect of misoprostol against paclitaxel-induced cardiac damage in rats
2024, Prostaglandins and Other Lipid Mediators
One of the most critical reasons for limiting cancer treatment is the toxic effects of anti-cancer drugs on healthy tissues and organs. This study aims to investigate the possible protective effects of misoprostol (MS) against the damage that arises from paclitaxel (PT), an anti-cancer pharmacological agent, in the rat heart using histopathological and biochemical analyses.
In this study, four groups, each containing seven animals, were formed by random selection from 28 Sprague Dawley female rats. Control group rats were administered 1 ml of normal saline orally and intraperitoneally (i.p.) for six days. While the PT group rats were administered PT at a dose of 2 mg/kg intraperitoneally (i.p.) on days 0, 2, 4, and 6, the MS group was administered MS at a dose of 0.2 mg/kg in 1 ml normal saline by oral gavage for six days. PT and MS were administered to the PT + MS group rats in the same dose and route as the previous groups.
Administration of PT increased serum lactate dehydrogenase (LDH), cardiac troponin I (cTn-I), creatine kinase isoenzyme MB (CK-MB), and brain natriuretic peptide (BNP) levels. PT administration also decreased the levels of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in the heart tissue while increasing the level of malondialdehyde (MDA) (p < 0.05). In histopathological examinations, pathological changes, such as edema, congestion, hemorrhage, apoptosis, and degeneration, occurred in the heart tissue of PT-treated rats. The negative changes in histopathological and biochemical parameters that occurred in the PT group were almost not observed in the PT + MS group (p < 0.005).
When the findings were evaluated, it was concluded that MS protects the heart tissue from the harmful effects of PT, probably due to its antioxidant, anti-apoptotic and TNF-alpha suppressive effects.
TBC1D15 deficiency protects against doxorubicin cardiotoxicity via inhibiting DNA-PKcs cytosolic retention and DNA damage
2023, Acta Pharmaceutica Sinica B
Clinical application of doxorubicin (DOX) is heavily hindered by DOX cardiotoxicity. Several theories were postulated for DOX cardiotoxicity including DNA damage and DNA damage response (DDR), although the mechanism(s) involved remains to be elucidated. This study evaluated the potential role of TBC domain family member 15 (TBC1D15) in DOX cardiotoxicity. Tamoxifen-induced cardiac-specific Tbc1d15 knockout (Tbc1d15^CKO) or Tbc1d15 knockin (Tbc1d15^CKI) male mice were challenged with a single dose of DOX prior to cardiac assessment 1 week or 4 weeks following DOX challenge. Adenoviruses encoding TBC1D15 or containing shRNA targeting Tbc1d15 were used for Tbc1d15 overexpression or knockdown in isolated primary mouse cardiomyocytes. Our results revealed that DOX evoked upregulation of TBC1D15 with compromised myocardial function and overt mortality, the effects of which were ameliorated and accentuated by Tbc1d15 deletion and Tbc1d15 overexpression, respectively. DOX overtly evoked apoptotic cell death, the effect of which was alleviated and exacerbated by Tbc1d15 knockout and overexpression, respectively. Meanwhile, DOX provoked mitochondrial membrane potential collapse, oxidative stress and DNA damage, the effects of which were mitigated and exacerbated by Tbc1d15 knockdown and overexpression, respectively. Further scrutiny revealed that TBC1D15 fostered cytosolic accumulation of the cardinal DDR element DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Liquid chromatography–tandem mass spectrometry and co-immunoprecipitation denoted an interaction between TBC1D15 and DNA-PKcs at the segment 594–624 of TBC1D15. Moreover, overexpression of TBC1D15 mutant (∆594–624, deletion of segment 594–624) failed to elicit accentuation of DOX-induced cytosolic retention of DNA-PKcs, DNA damage and cardiomyocyte apoptosis by TBC1D15 wild type. However, Tbc1d15 deletion ameliorated DOX-induced cardiomyocyte contractile anomalies, apoptosis, mitochondrial anomalies, DNA damage and cytosolic DNA-PKcs accumulation, which were canceled off by DNA-PKcs inhibition or ATM activation. Taken together, our findings denoted a pivotal role for TBC1D15 in DOX-induced DNA damage, mitochondrial injury, and apoptosis possibly through binding with DNA-PKcs and thus gate-keeping its cytosolic retention, a route to accentuation of cardiac contractile dysfunction in DOX-induced cardiotoxicity.
Gemini nanoparticles-based quadruple therapy (GNQT) achieved effective tumor immunotherapy by comprehensive regulation of tumor microenvironment
2023, Nano Today
Even though immune checkpoint blockade (ICB) therapy has advanced cancer immunotherapy greatly due to its quick development, and scientists have also tried a variety of combination therapies to further amplify the therapeutic impact, the therapeutic outcome is still limited because of the complex immunosuppressive microenvironment of tumor tissue. To improve the antitumor effect of immunotherapy, developing more comprehensive and effective tumor microenvironment regulation strategy is necessary. In this work, we prepared Gemini NPs composed of drug-loaded nanoparticles DI NPs (Doxorubicin and Ibrutinib were simultaneously encapsulated by PLG-g-mPEG) and gene-loaded nanoparticles PPD NPs (pSpam1 and pshPD-L1 were simultaneously encapsulated by PEI1.8k-RT), and proposed a Gemini nanoparticles-based quadruple therapy (GNQT). Compared with triple therapy and four-drug combination therapy, GNQT demonstrated comprehensive modulation of the tumor microenvironment and had exceptional anticancer ability in melanoma model without obvious toxicity. In addition, by establishing a persistent immunological memory effect, GNQT could also successfully prevent tumor lung metastasis in mice. The GNQT proposed here provided new insights into tumor immunotherapy and had important implications for the research of preclinical antitumor immunotherapy.
Cardiac Morbidity and Mortality in Patients with Sarcoma: A Population-Based Study
2024, Clinical Medicine Insights: Oncology

View all citing articles on Scopus

View full text

Doxorubicin-Induced Cardiomyopathy: From the Cardiotoxic Mechanisms to Management

Section snippets

Morphological Aspects of DOX-Induced Cardiomyopathy

Pathogenic Mechanisms of DOX-Induced Cardiomyopathy

Epidemiology and Clinical Features

Monitoring of Patients and Diagnostic Procedures

Management: Prevention of DOX-induced cardiomyopathy

Management: Treatment of DOX-induced cardiomyopathy

Conclusions

Am. J. Med.

Biochem. Pharmacol.

Biochem. Pharmacol.

Biochem. Pharmacol.

FEBS Lett.

Free Radic. Biol. Med.

J. Mol. Cell. Cardiol.

Am. J. Clin. Nutr.

Cancer Lett.

Chem. Biol. Interact.

Chem. Biol. Interact.

Biochem. Pharmacol.

Cancer Lett.

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

Biochim. Biophys. Acta.

Biochem. Pharmacol.

J. Biol. Chem.

J. Mol. Cell. Cardiol.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Cancer Treat. Rev.

Cell

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

Trends Biochem. Sci.

Adv. Immunol.

Lancet

The anthracyclines: Will we ever find a better doxorubicin?

Semin. Oncol.

A clinicopathologic analysis of adriamycin cardiotoxicity

Cancer

The cardiotoxicity of adriamycin and daunomycin in children

Cancer

Risk factors for doxorubicin-induced congestive heart failure

Ann. Intern. Med.

Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity

Pharmacol. Rev.

Nuclear catalyzed antibiotic free radical formation

Cancer Res.

Differential formation of hydroxyl radicals by adriamycin in sensitive and resistant MCF-7 human breast tumor cells: Implications for the mechanism of action

Biochemistry

Thiol-dependent DNA damage produced by anthracycline-iron complexes. The structure-activity relationships and molecular mechanisms

Mol. Pharmacol.

Oxidative destruction of DNA by the adriamycin-iron complex

Biochemistry

Adriamycin: The role of lipid peroxidation in cardiac toxicity and tumor response

Science

A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine

Semin. Oncol.

Prevention of doxorubicin myocardial toxicity in mice by reduced glutathione

Cancer Res.

Probucol protects against adriamycin cardiomyopathy without interfering with its antitumor effect

Circulation

Adriamycin and daunorubicin bind in a cooperative manner to deoxyribonucleic acid

Biochemistry

DNA topoisomerase II must act at mitosis to prevent nondisjunction and chromosome breakage

Mol. Cell. Biol.

Apoptosis of hair follicle cells during doxorubicin-induced alopecia in rats

Lab. Invest.

Anthracycline cardiomyopathy monitored by morphologic changes

Cancer. Treat. Rep.