A Review of the Pathophysiological Mechanisms of Doxorubicin-induced Cardiotoxicity and Aging

Overview

Journal NPJ Aging

Publisher Springer Nature

Specialty Geriatrics

Date 2024 Jan 23

PMID 38263284

Authors

Annet Nicole Linders

Itamar Braga Dias

Teresa Lopez Fernandez

Carlo Gabriele Tocchetti

Nils Bomer

Peter van der Meer

Affiliations

Soon will be listed here.

Abstract

The population of cancer survivors is rapidly increasing due to improving healthcare. However, cancer therapies often have long-term side effects. One example is cancer therapy-related cardiac dysfunction (CTRCD) caused by doxorubicin: up to 9% of the cancer patients treated with this drug develop heart failure at a later stage. In recent years, doxorubicin-induced cardiotoxicity has been associated with an accelerated aging phenotype and cellular senescence in the heart. In this review we explain the evidence of an accelerated aging phenotype in the doxorubicin-treated heart by comparing it to healthy aged hearts, and shed light on treatment strategies that are proposed in pre-clinical settings. We will discuss the accelerated aging phenotype and the impact it could have in the clinic and future research.

Citing Articles

Anti-Proliferative Activity of Ethylenediurea Derivatives with Alkyl and Oxygen-Containing Groups as Substituents.

Oshchepkov M, Kovalenko L, Kalistratova A, Sherstyanykh G, Gorbacheva E, Antonov A Biomedicines. 2025; 13(2).

PMID: 40002729 PMC: 11852481. DOI: 10.3390/biomedicines13020316.

Small Extracellular Vesicles from Breast Cancer Cells Induce Cardiotoxicity.

Osorio-Mendez J, Gomez-Grosso L, Montoya-Ortiz G, Novoa-Herran S, Dominguez-Romero Y Int J Mol Sci. 2025; 26(3).

PMID: 39940718 PMC: 11816698. DOI: 10.3390/ijms26030945.

FNDC5/irisin mitigates the cardiotoxic impacts of cancer chemotherapeutics by modulating ROS-dependent and -independent mechanisms.

Kumar M, Sengar A, Lye A, Kumar P, Mukherjee S, Kumar D Redox Biol. 2025; 80:103527.

PMID: 39923397 PMC: 11850786. DOI: 10.1016/j.redox.2025.103527.

Doxorubicin treatment has a biphasic effect over time on dopamine release and impulsive behavior in Wistar rats.

Garcia K, Theismann J, Schneider T, LeComte R, Jarmolowicz D, Johnson M Naunyn Schmiedebergs Arch Pharmacol. 2025; .

PMID: 39820646 DOI: 10.1007/s00210-024-03766-5.

Titanium nanostructure mitigating doxorubicin-induced testicular toxicity in rats via regulating major autophagy signaling pathways.

Abdel-Megeed R, Abdel-Hamid A, Kadry M Toxicol Rep. 2025; 14():101869.

PMID: 39811821 PMC: 11731616. DOI: 10.1016/j.toxrep.2024.101869.

References

Tang X, Li P, Chen H . Cardiomyocyte Senescence and Cellular Communications Within Myocardial Microenvironments. Front Endocrinol (Lausanne). 2020; 11:280. PMC: 7253644. DOI: 10.3389/fendo.2020.00280. View

De Angelis A, Piegari E, Cappetta D, Russo R, Esposito G, Ciuffreda L . SIRT1 activation rescues doxorubicin-induced loss of functional competence of human cardiac progenitor cells. Int J Cardiol. 2015; 189:30-44. DOI: 10.1016/j.ijcard.2015.03.438. View

Bordoni A, Biagi P, Hrelia S . The impairment of essential fatty acid metabolism as a key factor in doxorubicin-induced damage in cultured rat cardiomyocytes. Biochim Biophys Acta. 1999; 1440(1):100-6. DOI: 10.1016/s1388-1981(99)00113-4. View

Pommier Y, Leo E, Zhang H, Marchand C . DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol. 2010; 17(5):421-33. PMC: 7316379. DOI: 10.1016/j.chembiol.2010.04.012. View

Ruan Y, Dong C, Patel J, Duan C, Wang X, Wu X . SIRT1 suppresses doxorubicin-induced cardiotoxicity by regulating the oxidative stress and p38MAPK pathways. Cell Physiol Biochem. 2015; 35(3):1116-24. DOI: 10.1159/000373937. View

Sturgeon K, Schadler K, Muthukumaran G, Ding D, Bajulaiye A, Thomas N . Concomitant low-dose doxorubicin treatment and exercise. Am J Physiol Regul Integr Comp Physiol. 2014; 307(6):R685-92. PMC: 4166763. DOI: 10.1152/ajpregu.00082.2014. View

Hua Y, Zhang Y, Ceylan-Isik A, Wold L, Nunn J, Ren J . Chronic Akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy. Basic Res Cardiol. 2011; 106(6):1173-91. DOI: 10.1007/s00395-011-0222-8. View

Spallarossa P, Altieri P, Aloi C, Garibaldi S, Barisione C, Ghigliotti G . Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2. Am J Physiol Heart Circ Physiol. 2009; 297(6):H2169-81. DOI: 10.1152/ajpheart.00068.2009. View

Rabkin S, Cheng X, Thompson D . Detailed analysis of the impact of age on the QT interval. J Geriatr Cardiol. 2016; 13(9):740-748. PMC: 5122499. DOI: 10.11909/j.issn.1671-5411.2016.09.013. View

10.

Maillet A, Tan K, Chai X, Sadananda S, Mehta A, Ooi J . Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes. Sci Rep. 2016; 6:25333. PMC: 4855185. DOI: 10.1038/srep25333. View

11.

Zhang Y, Chen Y, Zhang M, Tang Y, Xie Y, Huang X . Doxorubicin induces sarcoplasmic reticulum calcium regulation dysfunction via the decrease of SERCA2 and phospholamban expressions in rats. Cell Biochem Biophys. 2014; 70(3):1791-8. DOI: 10.1007/s12013-014-0130-2. View

12.

Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni C, Veglia F . Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015; 131(22):1981-8. DOI: 10.1161/CIRCULATIONAHA.114.013777. View

13.

Cakouros D, Gronthos S . Epigenetic Regulation of Bone Marrow Stem Cell Aging: Revealing Epigenetic Signatures associated with Hematopoietic and Mesenchymal Stem Cell Aging. Aging Dis. 2019; 10(1):174-189. PMC: 6345334. DOI: 10.14336/AD.2017.1213. View

14.

Gunven P, Theve N, Peterson C . Serum and tissue concentrations of doxorubicin after IV administration of doxorubicin or doxorubicin-DNA complex to patients with gastrointestinal cancer. Cancer Chemother Pharmacol. 1986; 17(2):153-6. DOI: 10.1007/BF00306745. View

15.

Martin-Fernandez B, Gredilla R . Mitochondria and oxidative stress in heart aging. Age (Dordr). 2016; 38(4):225-238. PMC: 5061683. DOI: 10.1007/s11357-016-9933-y. View

16.

Hees P, Fleg J, Lakatta E, Shapiro E . Left ventricular remodeling with age in normal men versus women: novel insights using three-dimensional magnetic resonance imaging. Am J Cardiol. 2002; 90(11):1231-6. DOI: 10.1016/s0002-9149(02)02840-0. View

17.

Lefrak E, Pitha J, ROSENHEIM S, Gottlieb J . A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973; 32(2):302-14. DOI: 10.1002/1097-0142(197308)32:2<302::aid-cncr2820320205>3.0.co;2-2. View

18.

Du Q, Zhu B, Zhai Q, Yu B . Sirt3 attenuates doxorubicin-induced cardiac hypertrophy and mitochondrial dysfunction via suppression of Bnip3. Am J Transl Res. 2017; 9(7):3360-3373. PMC: 5553885. View

19.

Lotrionte M, Biondi-Zoccai G, Abbate A, Lanzetta G, DAscenzo F, Malavasi V . Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am J Cardiol. 2013; 112(12):1980-4. DOI: 10.1016/j.amjcard.2013.08.026. View

20.

Nattel S . Aging and Protein Kinase Activation: Is It the Missing Link Between Age and Atrial Fibrillation?. Circ Res. 2018; 122(6):799-801. DOI: 10.1161/CIRCRESAHA.118.312786. View