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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Review Article

Doxorubicin-induced Cardiotoxicity and Cardioprotective Agents: Classic and New Players in the Game

Author(s): Felipe dos Santos Arruda, Fernanda Dias Tomé, Marina Pacheco Miguel, Liliana Borges de Menezes, Patrícia Resende Alo Nagib, Erica Carolina Campos, Danilo Figueiredo Soave and Mara Rúbia Nunes Celes*

Volume 25, Issue 2, 2019

Page: [109 - 118] Pages: 10

DOI: 10.2174/1381612825666190312110836

Price: $65

Abstract

Doxorubicin (DOX) is a cytostatic antibiotic from the class of anthracyclines widely used in chemotherapeutic cancer treatments. Despite the efficiency against several types of cancer, the use of DOX remains limited due to the side effects, especially cardiotoxicity. Among the DOX administration strategies, there are the “classic players” such as nanoparticles and polymers, which are capable of DOX delivery directly to interesting neoplastic regions. On the other hand, the “new players” such as phytochemicals and probiotics emerged with the proposal to react with DOX free radicals, reducing the oxidative stress, inflammatory and apoptotic process. Thus, this review aims to report the studies involving these classics and new players along the years that focus on improved administration and reduction of DOX-induced cardiotoxicity.

Keywords: Doxorubicin, cardiotoxicity, nanotechnology, phytochemicals, probiotics, cardioprotective agents.

« Previous Next »
[1]
PW SW and C World Cancer Report 2014 Chapter 513.
[2]
November A, Medicines WHO. WHO Model List of Essential Medicines 2015.
[3]
Arcamone F, Cassinelli G, Fantini G, et al. Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol Bioeng 1969; 11(6): 1101-10.
[4]
Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 2004; 56(2): 185-229.
[5]
Damiani RM, Moura DJ, Viau CM, Caceres RA, Henriques JAP, Saffi J. Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone. Arch Toxicol 2016; 90(9): 2063-76.
[6]
Renu K. v G A, P B TP, Arunachalam S. Molecular mechanism of doxorubicin-induced cardiomyopathy - An update. Eur J Pharmacol 2018; 818(818): 241-53.
[7]
Reis-Mendes AF, Sousa E, de Lourdes Bastos M, Costa VM. The role of the metabolism of anticancer drugs in their induced-cardiotoxicity. Curr Drug Metab 2015; 17(1): 75-90.
[8]
de Almeida ALC, Silva VA, de Souza Filho AT, Rios VG, Lopes JRP, de Afonseca SO, et al. Subclinical ventricular dysfunction detected by speckle tracking two years after use of anthracycline. Arq Bras Cardiol 2014; 2(3): 206-7.
[9]
Pérez-Arnaiz C, Busto N, Leal JM, García B. New insights into the mechanism of the DNA/doxorubicin interaction. J Phys Chem B 2014; 118(5): 1288-95.
[10]
Mobaraki M, Faraji A, Zare M, Dolati P, Ataei M, Dehghan Manshadi HR. Molecular mechanisms of cardiotoxicity: A review on the major side-effects of doxorubicin. Indian J Pharm Sci 2017; 79(3): 335-44.
[11]
McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc Drugs Ther 2017; 31(1): 63-75.
[12]
Burgess DJ, Doles J, Zender L, et al. Topoisomerase levels determine chemotherapy response in vitro and in vivo. Proc Natl Acad Sci USA 2008; 105(26): 9053-8.
[13]
Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012; 18(11): 1639-42.
[14]
Green H, Stål O, Bachmeier K, et al. Pegylated liposomal doxorubicin as first-line monotherapy in elderly women with locally advanced or metastatic breast cancer: novel treatment predictive factors identified. Cancer Lett 2011; 313(2): 145-53.
[15]
Press MF, Sauter G, Buyse M, et al. Alteration of topoisomerase II-alpha gene in human breast cancer: Association with responsiveness to anthracycline-based chemotherapy. J Clin Oncol 2011; 29(7): 859-67.
[16]
Di Marco A, Gaetani M, Scarpinato B. Adriamycin (NSC-123,127): A new antibiotic with antitumor activity. Cancer Chemother Rep 1969; 53(1): 33-7.
[17]
Middleman E, Luce J, Frei E III. Clinical trials with adriamycin. Cancer 1971; 28(4): 844-50.
[18]
Laskin WB, Fetsch JF, Miettinen M. A Clinicopathologic Analysis of 104 Cases 2013; 1-12.
[19]
Qu Y, An F, Luo Y, et al. A nephron model for study of drug-induced acute kidney injury and assessment of drug-induced nephrotoxicity. Biomaterials 2018; 155: 41-53.
[20]
Ueda H, Fukuchi H, Tanaka C. Toxicity and efficacy of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma.(Review) Oncol Lett 2012; 3(2): 259-63.
[21]
Hydock DS, Lien C-Y, Jensen BT, Schneider CM, Hayward R. Characterization of the effect of in vivo doxorubicin treatment on skeletal muscle function in the rat. Anticancer Res 2011; 31(6): 2023-8.
[22]
Gouspillou G, Scheede-Bergdahl C, Spendiff S, et al. Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle. Sci Rep 2015; 5: 8717.
[23]
Zheng Z, Pavlidis P, Chua S, D’Agati VD, Gharavi AG. An ancestral haplotype defines susceptibility to doxorubicin nephropathy in the laboratory mouse. J Am Soc Nephrol 2006; 17(7): 1796-800.
[24]
Santos V, Loures TP, Hospital AF, Universit C, Santos V. Nephrotoxicity associated with chemotherapy for breast cancer 2017.
[25]
Jansen CE, Dodd MJ, Miaskowski CA, Dowling GA, Kramer J. Preliminary results of a longitudinal study of changes in cognitive function in breast cancer patients undergoing chemotherapy with doxorubicin and cyclophosphamide. Psychooncology 2008; 17(12): 1189-95.
[26]
Pugazhendhi A, Edison TNJI, Velmurugan BK, Jacob JA, Karuppusamy I. Toxicity of Doxorubicin (Dox) to different experimental organ systems. Life Sci 2018; 200: 26-30.
[27]
Yeh ETH, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 2009; 53(24): 2231-47.
[28]
Vejpongsa P, Yeh ETH. Prevention of anthracycline-induced cardiotoxicity: challenges and opportunities. J Am Coll Cardiol 2014; 64(9): 938-45.
[29]
Koleini N, Kardami E. Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Oncotarget 2017; 8(28): 46663-80.
[30]
Yoshida M, Shiojima I, Ikeda H, Komuro I. Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity. J Mol Cell Cardiol 2009; 47(5): 698-705.
[31]
Bartlett JJ, Trivedi PC, Pulinilkunnil T. Autophagic dysregulation in doxorubicin cardiomyopathy. J Mol Cell Cardiol 2017; 104: 1-8.
[32]
Wallace KB. Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis. Cardiovasc Toxicol 2007; 7(2): 101-7.
[33]
Mukhopadhyay P, Rajesh M, Batkai S, Kashiwaya Y, Hasko G, Liaudet L, et al. Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitroAJP: Heart and Circulatory Physiology 2009;296(5):H1466–83 Available from: http://ajpheart.physiology.org/cgi/doi/10.1152/ajpheart.00795.2008
[34]
Cheung KG, Cole LK, Xiang B, et al. Sirtuin-3 (SIRT3) protein attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes. J Biol Chem 2015; 290(17): 10981-93.
[35]
de Wolf FA. Binding of doxorubicin to cardiolipin as compared to other anionic phospholipids--an evaluation of electrostatic effects. Biosci Rep 1991; 11(5): 275-84.
[36]
Yi-Wei Z, Shi J, Li Y-J, Wei L. Cardiomyocyte death in doxorubicin-induced cardiotoxicity. NIH Public Access 2008; 29(10): 1883-9.
[37]
Solem LE, Heller LJ, Wallace KB, Wallace KB. Dose-dependent increase in sensitivity to calcium-induced mitochondrial dysfunction and cardiomyocyte cell injury by doxorubicin. J Mol Cell Cardiol 1996; 28(5): 1023-32.
[38]
Zhou S, Heller LJ, Wallace KB. Interference with calcium-dependent mitochondrial bioenergetics in cardiac myocytes isolated from doxorubicin-treated rats. Toxicol Appl Pharmacol 2001; 175(1): 60-7.
[39]
Berthiaume JM, Wallace KB. Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell Biol Toxicol 2007; 23(1): 15-25.
[40]
Arola OJ, Saraste A, Pulkki K, Kallajoki M, Parvinen M. Advances in Brief Acute Doxorubicin Cardiotoxicity Involves Cardiomyocyte Apoptosis 2000; 1: 1789-92.
[41]
Yancey DM, Guichard JL, Ahmed MI, et al. Cardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload. Am J Physiol Heart Circ Physiol 2015; 308(6): H651-63.
[42]
Yamaoka M, Yamaguchi S, Suzuki T, et al. Apoptosis in rat cardiac myocytes induced by Fas ligand: priming for Fas-mediated apoptosis with doxorubicin. J Mol Cell Cardiol 2000; 32(6): 881-9.
[43]
Dimitrakis P, Romay-Ogando MI, Timolati F, Suter TM, Zuppinger C. Effects of doxorubicin cancer therapy on autophagy and the ubiquitin-proteasome system in long-term cultured adult rat cardiomyocytes. Cell Tissue Res 2012; 350(2): 361-72.
[44]
O’Connell JL, Romano MMD, Campos Pulici EC, et al. Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes. Exp Toxicol Pathol 2017; 69(4): 213-9.
[45]
Carvalho C, Santos RX, Cardoso S, et al. Doxorubicin: The good, the bad and the ugly effect. Curr Med Chem 2009; 16(25): 3267-85.
[46]
Wallace KB. Doxorubicin-induced cardiac mitochondrionopathy. Pharmacol Toxicol 2003; 93(3): 105-15.
[47]
L’Ecuyer T, Sanjeev S, Thomas R, et al. DNA damage is an early event in doxorubicin-induced cardiac myocyte death. Am J Physiol Heart Circ Physiol 2006; 291(3): H1273-80.
[48]
Zhou S, Starkov A, Froberg MK, Leino RL, Wallace KB. Cumulative and Irreversible Cardiac Mitochondrial Dysfunction Induced by Doxorubicin Cumulative and Irreversible Cardiac Mitochondrial Dysfunction 2001; 771-.
[49]
Szalay CI, Erdélyi K, Kökény G, et al. Oxidative/nitrative stress and inflammation drive progression of doxorubicin-induced renal fibrosis in rats as revealed by comparing a normal and a fibrosis-resistant rat strain. PLoS One 2015; 10(6)e0127090
[50]
Dirks-Naylor AJ, Kouzi SA, Bero JD, et al. Doxorubicin alters the mitochondrial dynamics machinery and mitophagy in the liver of treated animals. Fundam Clin Pharmacol 2014; 28(6): 633-42.
[51]
Gharanei M, Hussain A, Janneh O, Maddock H. Attenuation of doxorubicin-induced cardiotoxicity by mdivi-1: A mitochondrial division/mitophagy inhibitor. PLoS One 2013; 8(10)e77713
[52]
Kobayashi S, Volden P, Timm D, Mao K, Xu X, Liang Q. Transcription factor GATA4 inhibits doxorubicin-induced autophagy and cardiomyocyte death. J Biol Chem 2010; 285(1): 793-804.
[53]
Kawaguchi T, Takemura G, Kanamori H, et al. Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes. Cardiovasc Res 2012; 96(3): 456-65.
[54]
Lai L, Chen J, Wang N, Zhu G, Duan X, Ling F. MiRNA-30e mediated cardioprotection of ACE2 in rats with Doxorubicin-induced heart failure through inhibiting cardiomyocytes autophagy. Life Sci 2017; 169: 69-75.
[55]
Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 2003; 97(11): 2869-79.
[56]
Navarro-Ulloa OD, Barranco-Camargo LA, Jurado-López SP, Zabala-Carballo CI, Giraldo-Peniche LE. Muerte súbita debida a cardiotoxicidad aguda inducida por antraciclinas 2017; 10(1): 22.
[57]
Kim BY, Rutka JT, Chan WCW. Nanomedicine. N Engl J Med 2011; 53(2–4): 401-20.
[58]
Chiannilkulchai N, Driouich Z, Benoit JP, Parodi AL, Couvreur P. [Nanoparticles of doxorubicin: colloidal vectors in the treatment of hepatic metastases in animals]. Bull Cancer 1989; 76(8): 845-8.
[59]
Carpignano R, Gasco MR, Morel S. Optimization of doxorubicine incorporation and of the yield of polybutylcyanacrylate nanoparticles. Pharm Acta Helv 1991; 66(1): 28-32.
[60]
Soma CE, Dubernet C, Barratt G, et al. Ability of doxorubicin-loaded nanoparticles to overcome multidrug resistance of tumor cells after their capture by macrophages. Pharm Res 1999; 16(11): 1710-6.
[61]
Gelperina SE, Khalansky AS, Skidan IN, et al. Toxicological studies of doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles in healthy rats and rats with intracranial glioblastoma. Toxicol Lett 2002; 126(2): 131-41.
[62]
Khaliq NU, Sandra FC, Park DY, et al. Doxorubicin/heparin composite nanoparticles for caspase-activated prodrug chemotherapy. Biomaterials 2016; 101: 131-42.
[63]
Moradzadeh Khiavi M, Rostami A, Hamishekar H, et al. Therapeutic efficacy of orally delivered doxorubicin nanoparticles in rat tongue cancer induced by 4-nitroquinoline 1-oxide. Adv Pharm Bull 2015; 5(2): 209-16.
[64]
Mansour HH, Eid M, El-Arnaouty MB. Effect of silver nanoparticles synthesized by gamma radiation on the cytotoxicity of doxorubicin in human cancer cell lines and experimental animals. Hum Exp Toxicol 2018; 37(1): 38-50.
[65]
Mao X, Si J, Huang Q, et al. Self-Assembling Doxorubicin Prodrug Forming Nanoparticles and Effectively Reversing Drug Resistance In Vitro and In Vivo. Adv Healthc Mater 2016; 5(19): 2517-27.
[66]
Kuruvilla SP, Tiruchinapally G, Crouch AC, ElSayed MEH, Greve JM. Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model. PLoS One 2017; 12(8)e0181944
[67]
Lewis W, Beckenstein K, Shapiro L, Puszkin S. Doxorubicin and covalently crosslinked doxorubicin derivatives binding to purified cardiac thin-filament proteins in vitro. Exp Mol Pathol 1985; 43(1): 64-73.
[68]
Zunino F, Pratesi G, Pezzoni G. Increased therapeutic efficacy and reduced toxicity of doxorubicin linked to pyran copolymer via the side chain of the drug. Cancer Treat Rep 1987; 71(4): 367-73.
[69]
Khaliq NU, Oh KS, Sandra FC, et al. Assembly of polymer micelles through the sol-gel transition for effective cancer therapy. J Control Release 2017; 255: 258-69.
[70]
Pawar S, Mahajan K, Vavia P. In Vivo Anticancer Efficacy and Toxicity Studies of a Novel Polymer Conjugate N-Acetyl Glucosamine (NAG)-PEG-Doxorubicin for Targeted Cancer Therapy. AAPS PharmSciTech 2017; 18(8): 3021-33.
[71]
Tang F, Zhou X, Wang L, et al. A novel compound DT-010 protects against doxorubicin-induced cardiotoxicity in zebrafish and H9c2 cells by inhibiting reactive oxygen species-mediated apoptotic and autophagic pathways. Eur J Pharmacol 2018; 820(820): 86-96.
[72]
Cui P-F, Zhuang W-R, Hu X, et al. A new strategy for hydrophobic drug delivery using a hydrophilic polymer equipped with stacking unitsChemical Communications 2018; Available from: http://xlink.rsc.org/?DOI=C8CC04363A
[73]
Scheggia ER. Valoración de esteroles en productos de molienda de trigos argentinos. Revista de la Facultad de Ciencias Quimicas (Quimica y Farmacia). La Plata Universidad Nacional Facultad de Quimica y Farmacia 1946; 19: 57-60.
[74]
Sager RW, Arrigoni L, Fischer L. A phytochemical study of Nereocystis luetkeana. Am J Pharm Sci Support Public Health 1946; 118: 156-63.
[75]
Scheindlin S, Dodge AA. A phytochemical study of Sansevieria zeylanica. Am J Pharm Sci Support Public Health 1947; 119(7): 232-53.
[76]
Knode KT, Levkoff AH. The treatment of familial hypercholesterolemia with a plant sterol. Pediatrics 1957; 19(1): 88-90.
[77]
Tygstrup N, Winkler K, Jorgensen K, Andersen B. [Sitosterol therapy of hypercholesterolemia]. Ugeskr Laeger 1957; 119(37): 1193-5.
[78]
Best MM, Duncan CH. Effects of sitosterol on the cholesterol concentration in serum and liver in hypothyroidism. Circulation 1956; 14(3): 344-8.
[79]
Sachs BA, Weston RE. Sitosterol administration in normal and hypercholesteremic subjects; the effect in man of sitosterol therapy on serum lipids and lipoproteins. AMA Arch Intern Med 1956; 97(6): 738-52.
[80]
Cloetens W. [Remote therapeutic results of the plant steroid: cafesterol in four cases of rheumatismal carditis]. Brux Med 1954; 34(15): 645-60.
[81]
Thiers H. The value of stigmasterol (R. Wulzen’s antistiffness factor essential for guinea pigs) in the therapy of rheumatic diseases. Revue du rhumatisme et des maladies osteo-articulaires 20(8–9): 636-43.
[82]
Grundy SM, Mok HY. Colestipol, clofibrate, and phytosterols in combined therapy of hyperlipidemia. J Lab Clin Med 1977; 89(2): 354-66.
[83]
Rocchietta S. [Current phytotherapeutic agents in the treatment of prostatic diseases]. Minerva Med 1977; 68(63): 4261-4.
[84]
Czerny K, Matysiak W, Chabros E. Experimental studies of the small intestine mucosa after an oral administration of Piasclédine (author’s transl). Ann Univ Mariae Curie Sklodowska Med 1978; 33: 327-32.
[85]
Neder AC, Garlipp OF, Ranali J, de Mattos Filho TR, Sahade W. [Unsaponifiable extract of Zea Mays L. Insadol in oral surgery]. Quintessencia 1978; 5(1): 129-31.
[86]
Abushouk AI, Ismail A, Salem AMA, Afifi AM, Abdel-Daim MM. Cardioprotective mechanisms of phytochemicals against doxorubicin-induced cardiotoxicity. Biomed Pharmacother 2017; 90: 935-46.
[87]
Bradamante S, Barenghi L, Villa A. Cardiovascular protective effects of resveratrol. Cardiovasc Drug Rev 2004; 22(3): 169-88.
[88]
Fiorentini D, Zambonin L, Dalla Sega FV, Hrelia S. Polyphenols as Modulators of Aquaporin Family in Health and Disease. Oxid Med Cell Longev 2015; 2015196914
[89]
Dutta D, Xu J, Dirain MLS, Leeuwenburgh C. Calorie restriction combined with resveratrol induces autophagy and protects 26-month-old rat hearts from doxorubicin-induced toxicity. Free Radic Biol Med 2014; 74: 252-62.
[90]
Gu J, Hu W, Zhang DD. Resveratrol, a polyphenol phytoalexin, protects against doxorubicin-induced cardiotoxicity. J Cell Mol Med 2015; 19(10): 2324-8.
[91]
Abdel-Daim MM, Kilany OE, Khalifa HA, Ahmed AAM. Allicin ameliorates doxorubicin-induced cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. Cancer Chemother Pharmacol 2017; 80(4): 745-53.
[92]
Dwivedi S, Chopra D. Revisiting Terminalia arjuna - An Ancient Cardiovascular Drug. J Tradit Complement Med 2014; 4(4): 224-31.
[93]
Bishop S, Liu SJ. Cardioprotective action of the aqueous extract of Terminalia arjuna bark against toxicity induced by doxorubicin. Phytomedicine 2017; 36: 210-6.
[94]
Zaletok SP, Gulua L, Wicker L, et al. Green tea, red wine and lemon extracts reduce experimental tumor growth and cancer drug toxicity. Exp Oncol 2015; 37(4): 262-71.
[95]
Mahbub AA, Le Maitre CL, Haywood-Small SL, Cross NA, Jordan-Mahy N. Polyphenols act synergistically with doxorubicin and etoposide in leukaemia cell lines. Cell Death Discov 2015; 1(9): 15043.
[96]
Amaretti A, di Nunzio M, Pompei A, Raimondi S, Rossi M, Bordoni A. Antioxidant properties of potentially probiotic bacteria: in vitro and in vivo activities. Appl Microbiol Biotechnol 2013; 97(2): 809-17.
[97]
Carr JS, King S, Dekaney CM. Depletion of enteric bacteria diminishes leukocyte infiltration following doxorubicin-induced small intestinal damage in mice. PLoS One 2017; 12(3)e0173429
[98]
Sadeghzadeh J, Vakili A, Sameni HR, Shadnoush M, Bandegi AR, Zahedi Khorasani M. The effect of oral consumption of probiotics in prevention of heart injury in a rat myocardial infarction model: A Histopathological, Hemodynamic and Biochemical Evaluation. Iran Biomed J 2017; 21(3): 174-81.
[99]
Abu-Elsaad NM, Abd Elhameed AG, El-Karef A, Ibrahim TM. Yogurt Containing the Probacteria Lactobacillus acidophilus Combined with Natural Antioxidants Mitigates Doxorubicin-Induced Cardiomyopathy in Rats. J Med Food 2015; 18(9): 950-9.
[100]
Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016; 37(36): 2768-801.
[101]
Henninger C, Huelsenbeck S, Wenzel P, et al. Chronic heart damage following doxorubicin treatment is alleviated by lovastatin. Pharmacol Res 2015; 91: 47-56.

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