Journal of Forensic Medicine, Volume. 41, Issue 2, 120(2025)
Research on Doxorubicin-Induced Cardiotoxicity Mechanism and Its Forensic Application
[1] [1] USMAN R M, RAZZAQ F, AKBAR A, et al. Role and mechanism of autophagy-regulating factors in tumorigenesis and drug resistance[J]. Asia Pac J Clin Oncol, 2021, 17(3): 193−208. doi: 10.1111/ajco.13449.
[2] [2] WALLACE K B, SARDO V A, OLIVEIRA P J. Mitochondrial determinants of doxorubicin-induced cardiomyopathy[J]. Circ Res, 2020, 126(7): 926−941. doi: 10.1161/circresaha.119.314681.
[3] [3] CHRISTIDI E, BRUNHAM L R. Regulated cell death pathways in doxorubicin-induced cardiotoxicity[J]. Cell Death Dis, 2021, 12(4): 339. doi: 10.1038/s41419-021-03614-x.
[4] [4] CARVALHO F S, BURGEIRO A, GARCIA R, et al. Doxorubicin-induced cardiotoxicity: From bioenergetic failure and cell death to cardiomyopathy[J]. Med Res Rev, 2014, 34(1): 106−135. doi: 10.1002/med.21280.
[5] [5] SANGWENI N F, GABUZA K, HUISAMEN B, et al. Molecular insights into the pathophysiology of doxorubicin-induced cardiotoxicity: A graphical representation[J]. Arch Toxicol, 2022, 96(6): 1541−1550. doi: 10.1007/s00204-022-03262-w.
[6] [6] ARMSTRONG J, DASS C R. Doxorubicin action on mitochondria: Relevance to osteosarcoma therapy?[J]. Curr Drug Targets, 2018, 19(5): 432−438. doi: 10.2174/1389450116666150416115852.
[7] [7] DENG Y, NGO D T M, HOLIEN J K, et al. Mitochondrial dynamin-related protein Drp1: A new player in cardio-oncology[J]. Curr Oncol Rep, 2022, 24(12): 1751−1763. doi: 10.1007/s11912-022-01333-w.
[8] [8] DING M, SHI R, FU F, et al. Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKC-Stat3 pathway[J]. J Adv Res, 2023, 47: 151−162. doi: 10.1016/j.jare.2022.07.002.
[9] [9] MITRY M A, EDWARDS J G. Doxorubicin induced heart failure: Phenotype and molecular mechanisms[J]. Int J Cardiol Heart Vasc, 2016, 10: 17−24. doi: 10.1016/j.ijcha.2015.11.004.
[10] [10] JONES R L, SWANTON C, EWER M S. Anthracycline cardiotoxicity[J]. Expert Opin Drug Saf, 2006, 5(6): 791−809. doi: 10.1517/14740338.5.6.791.
[12] [12] CONROY B, GUTHRIE W. Endocardial fibroelastosis associated with fatal adriamycin (doxorubicin) cardiomyopathy during treatment of Ewing’s sarcoma[J]. Scott Med J, 1983, 28(3): 295−299. doi: 10.1177/003693308302800317.
[15] [15] ZHANG P, LU H, WU Y, et al. COX5A alleviates doxorubicin-induced cardiotoxicity by suppressing oxidative stress, mitochondrial dysfunction and cardiomyocyte apoptosis[J]. Int J Mol Sci, 2023, 24(12): 10400. doi: 10.3390/ijms241210400.
[16] [16] DIRKS-NAYLOR A J. The role of autophagy in doxorubicin-induced cardiotoxicity[J]. Life Sci, 2013, 93(24): 913−916. doi: 10.1016/j.lfs.2013.10.013.
[17] [17] FERRANS V J, CLARK J R, ZHANG J, et al. Pathogenesis and prevention of doxorubicin cardiomyopathy[J]. Tsitologiia, 1997, 39(10): 928−937.
[18] [18] ABDULLAH C S, ALAM S, AISHWARYA R, et al. Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration[J]. Sci Rep, 2019, 9(1): 2002. doi: 10.1038/s41598-018-37862-3.
[19] [19] KONG C Y, GUO Z, SONG P, et al. Underlying the mechanisms of doxorubicin-induced acute cardiotoxicity: Oxidative stress and cell death[J]. Int J Biol Sci, 2022, 18(2): 760−770. doi: 10.7150/ijbs.65258.
[20] [20] MOSTAFA A M, NAGI M N, AL RIKABI A C, et al. Protective effect of aminoguanidine against cardiovascular toxicity of chronic doxorubicin treatment in rats[J]. Res Commun Mol Pathol Pharmacol, 1999, 106(3): 193−202.
[21] [21] DE OLIVEIRA B L, NIEDERER S. A biophysical systems approach to identifying the pathways of acute and chronic doxorubicin mitochondrial cardiotoxicity[J]. PLoS Comput Biol, 2016, 12(11): e1005214. doi: 10.1371/journal.pcbi.1005214.
[22] [22] YI X, BEKEREDJIAN R, DEFILIPPIS N J, et al. Transcriptional analysis of doxorubicin-induced cardiotoxicity[J]. Am J Physiol Heart Circ Physiol, 2006, 290(3): H1098−H1102. doi: 10.1152/ajpheart.00832.2005.
[23] [23] AVERSANO R C, BOOR P J. Histochemical alterations of acute and chronic doxorubicin cardiotoxicity[J]. J Mol Cell Cardiol, 1983, 15(8): 543−553. doi: 10.1016/0022-2828(83)90330-9.
[24] [24] ZHANG L, JIANG Q, WANG X, et al. Boesenbergia rotunda displayed anti-inflammatory, antioxidant and anti-apoptotic efficacy in doxorubicin-induced cardiotoxicity in rats[J]. Sci Rep, 2023, 13(1): 11398. doi: 10.1038/s41598-023-38560-5.
[25] [25] ZHANG W, FAN Z, WANG F, et al. Tubeimoside I ameliorates doxorubicin-induced cardiotoxicity by upregulating SIRT3[J]. Oxid Med Cell Longev, 2023, 2023: 9966355. doi: 10.1155/2023/9966355.
[26] [26] WANG Y, ZAN Y, HUANG Y, et al. NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress[J]. Cell Death Discov, 2023, 9(1): 43. doi: 10.1038/s41420-022-01294-w.
[28] [28] ZHANG H, PAN J, HUANG S, et al. Hydrogen sulfide protects cardiomyocytes from doxorubicin-induced ferroptosis through the SLC7A11/GSH/GPx4 pathway by Keap1 S-sulfhydration and Nrf2 activation[J]. Redox Biol, 2024, 70: 103066. doi: 10.1016/j.redox.2024.103066.
[29] [29] XIAO Z, YU Z, CHEN C, et al. GAS-STING signaling plays an essential pathogenetic role in doxorubicin-induced cardiotoxicity[J]. BMC Pharmacol Toxicol, 2023, 24(1): 19. doi: 10.1186/s40360-022-00631-0.
[30] [30] SUN X, MENG H, XIAO J, et al. Pretreatment of 3-MA prevents doxorubicin-induced cardiotoxicity through inhibition of autophagy initiation[J]. Toxicology, 2023, 490: 153512. doi: 10.1016/j.tox.2023.153512.
[31] [31] LI D, LIU X, PI W, et al. Fisetin attenuates doxorubicin-induced cardiomyopathyin vivoandin vitroby inhibiting ferroptosis through SIRT1/Nrf2 signaling pathway activation[J]. Front Pharmacol, 2021, 12: 808480. doi: 10.3389/fphar.2021.808480.
[32] [32] THAM Y K, BERNARDO B C, OOI J Y, et al. Pathophysiology of cardiac hypertrophy and heart failure: Signaling pathways and novel therapeutic targets[J]. Arch Toxicol, 2015, 89(9): 1401−1438. doi: 10.1007/s00204-015-1477-x.
[33] [33] WALLACE K B. Doxorubicin-induced cardiac mitochondrionopathy[J]. Pharmacol Toxicol, 2003, 93(3): 105−115. doi: 10.1034/j.1600-0773.2003.930301.x.
[34] [34] MUKHOPADHYAY P, RAJESH M, BTKAI S, et al. Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell deathin vivoandin vitro[J]. Am J Physiol Heart Circ Physiol, 2009, 296(5): H1466−H1483. doi: 10.1152/ajpheart.00795.2008.
[35] [35] MALISZA K L, HASINOFF B B. Production of hydroxyl radical by iron (Ⅲ)-anthraquinone complexes through self-reduction and through reductive activation by the xanthine oxidase/hypoxanthine system[J]. Arch Biochem Biophys, 1995, 321(1): 51−60. doi: 10.1006/abbi.1995.1367.
[36] [36] MAY P M, WILLIAMS G K, WILLIAMS D R. Solution chemistry studies of adriamycin-iron complexes presentin vivo[J]. Eur J Cancer (1965), 1980, 16(9): 1275−1276. doi: 10.1016/0014-2964(80)90189-9.
[37] [37] ZHANG Y Y, YI M, HUANG Y P. Oxymatrine ameliorates doxorubicin-induced cardiotoxicity in rats[J]. Cell Physiol Biochem, 2017, 43(2): 626−635. doi: 10.1159/000480471.
[38] [38] YIN J, GUO J, ZHANG Q, et al. Doxorubicin-induced mitophagy and mitochondrial damage is associated with dysregulation of the PINK1/parkin pathway[J]. Toxicol In Vitro, 2018, 51: 1−10. doi: 10.1016/j.tiv.2018.05.001.
[39] [39] PARKER M A, KING V, HOWARD K P. Nuclear magnetic resonance study of doxorubicin binding to cardiolipin containing magnetically oriented phospholipid bilayers[J]. Biochim Biophys Acta, 2001, 1514(2): 206−216. doi: 10.1016/S0005-2736(01)00371-6.
[40] [40] RENU K, ABILASH V G, TIRUPATHI PICHIAH P B, et al. Molecular mechanism of doxorubicin-induced cardiomyopathy — An update[J]. Eur J Pharmacol, 2018, 818: 241−253. doi: 10.1016/j.ejphar.2017.10.043.
[41] [41] ASHLEY N, POULTON J. Mitochondrial DNA is a direct target of anti-cancer anthracycline drugs[J]. Biochem Biophys Res Commun, 2009, 378(3): 450−455. doi: 10.1016/j.bbrc.2008.11.059.
[42] [42] SONGBO M, LANG H, XINYONG C, et al. Oxidative stress injury in doxorubicin-induced cardiotoxicity[J]. Toxicol Lett, 2019, 307: 41−48. doi: 10.1016/j.toxlet.2019.02.013.
[43] [43] AWAD H H, EL-DERANY M O, MANTAWY E M, et al. Comparative study on beneficial effects of vitamins B and D in attenuating doxorubicin induced cardiotoxicity in rats: Emphasis on calcium homeostasis[J]. Biomed Pharmacother, 2021, 140: 111679. doi: 10.1016/j.biopha.2021.111679.
[44] [44] KIM S Y, KIM S J, KIM B J, et al. Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+ increase are reciprocally modulated in rat cardiomyocytes[J]. Exp Mol Med, 2006, 38(5): 535−545. doi: 10.1038/emm.2006.63.
[45] [45] BARTLETT J J, TRIVEDI P C, PULINILKUNNIL T. Autophagic dysregulation in doxorubicin cardiomyopathy[J]. J Mol Cell Cardiol, 2017, 104: 1−8. doi: 10.1016/j.yjmcc.2017.01.007.
[46] [46] JOHNSON R, SHABALALA S, LOUW J, et al. Aspalathin reverts doxorubicin-induced cardiotoxicity through increased autophagy and decreased expression of p53/mTOR/p62 signaling[J]. Molecules, 2017, 22(10): 1589. doi: 10.3390/molecules22101589.
[47] [47] MANCILLA T R, DAVIS L R, AUNE G J. Doxorubicin-induced p53 interferes with mitophagy in cardiac fibroblasts[J]. PLoS One, 2020, 15(9): e0238856. doi: 10.1371/journal.pone.0238856.
[48] [48] MCSWEENEY K M, BOZZA W P, ALTEROVITZ W L, et al. Transcriptomic profiling reveals p53 as a key regulator of doxorubicin-induced cardiotoxicity[J]. Cell Death Discov, 2019, 5: 102. doi: 10.1038/s41420-019-0182-6.
[49] [49] LI D L, WANG Z V, DING G, et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification[J]. Circulation, 2016, 133(17): 1668−1687. doi: 10.1161/CIRCULATIONAHA.115.017443.
[50] [50] KONG L, ZHANG Y, NING J, et al. CaMKII orchestrates endoplasmic reticulum stress and apoptosis in doxorubicin-induced cardiotoxicity by regulating the IRE1/XBP1s pathway[J]. J Cell Mol Med, 2022, 26(20): 5303−5314. doi: 10.1111/jcmm.17560.
[51] [51] GUPTA V, KUMAR SINGH S, AGRAWAL V, et al. Role of ACE inhibitors in anthracycline-induced cardiotoxicity: A randomized, double-blind, placebo-controlled trial[J]. Pediatr Blood Cancer, 2018, 65(11): e27308. doi: 10.1002/pbc.27308.
[52] [52] UPSHAW J N, RUTHAZER R, MILLER K D, et al. Personalized decision making in early stage breast cancer: Applying clinical prediction models for anthracycline cardiotoxicity and breast cancer mortality demonstrates substantial heterogeneity of benefit-harm trade-off[J]. Clin Breast Cancer, 2019, 19(4): 259−267.e1. doi: 10.1016/j.clbc.2019.04.012.
[53] [53] LI X, LIANG J, QU L, et al. Exploring the role of ferroptosis in the doxorubicin-induced chronic cardiotoxicity using a murine model[J]. Chem Biol Interact, 2022, 363: 110008. doi: 10.1016/j.cbi.2022.110008.
[54] [54] ROMO P V M, PALOZI R A C, GUARNIER L P, et al. Cardioprotective effects ofPlinia cauliflora(Mart.) Kausel in a rabbit model of doxorubicin-induced heart failure[J]. J Ethnopharmacol, 2019, 242: 112042. doi: 10.1016/j.jep.2019.112042.
[56] [56] KUNO A, HOSODA R, TSUKAMOTO M, et al. SIRT1 in the cardiomyocyte counteracts doxorubicin-induced cardiotoxicity via regulating histone H2AX[J]. Cardiovasc Res, 2023, 118(17): 3360−3373. doi: 10.1093/cvr/cvac026.
[57] [57] CHEN X, ZHANG Y, ZHU Z, et al. Protective effect of berberine on doxorubicin-induced acute hepatorenal toxicity in rats[J]. Mol Med Rep, 2016, 13(5): 3953−3960. doi: 10.3892/mmr.2016.5017.
[58] [58] QIAN H, QIAN Y, LIU Y, et al. Identification of novel biomarkers involved in doxorubicin-induced acute and chronic cardiotoxicity, respectively, by integrated bioinformatics[J]. Front Cardiovasc Med, 2022, 9: 996809. doi: 10.3389/fcvm.2022.996809.
[59] [59] PECORARO M, DEL PIZZO M, MARZOCCO S, et al. Inflammatory mediators in a short-time mouse model of doxorubicin-induced cardiotoxicity[J]. Toxicol Appl Pharmacol, 2016, 293: 44−52. doi: 10.1016/j.taap.2016.01.006.
[63] [63] NERI B, CINI-NERI G, BANDINELLI M, et al. Doxorubicin and epirubicin cardiotoxicity: Experimental and clinical aspects[J]. Int J Clin Pharmacol Ther Toxicol, 1989, 27(5): 217−221.
[64] [64] LI Y, TIAN C, HUANG S, et al. Potential biomarker of acute anthracycline-induced cardiotoxicity among children with acute lymphoblastic leukemia: Cardiac adriamycin-responsive protein[J]. J Cardiovasc Pharmacol, 2023, 82(6): 489−495. doi: 10.1097/fjc.0000000000001479.
[65] [65] PONGPROT Y, SITTIWANGKUL R, CHAROENKWAN P, et al. Use of cardiac markers for monitoring of doxorubixin-induced cardiotoxicity in children with cancer[J]. J Pediatr Hematol Oncol, 2012, 34(8): 589−595. doi: 10.1097/MPH.0b013e31826faf44.
[66] [66] LIANG S, BRUNDAGE R C, JACOBSON P A, et al. Pharmacokinetic-pharmacodynamic modelling of acute N-terminal pro B-type natriuretic peptide after doxorubicin infusion in breast cancer[J]. Br J Clin Pharmacol, 2016, 82(3): 773−783. doi: 10.1111/bcp.12989.
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ZHANG Shuai, XU Hong-fei, ZHANG Zhi-xiang, WANG Ying, ZHU Shao-hua. Research on Doxorubicin-Induced Cardiotoxicity Mechanism and Its Forensic Application[J]. Journal of Forensic Medicine, 2025, 41(2): 120
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Received: Apr. 12, 2024
Accepted: Aug. 25, 2025
Published Online: Aug. 25, 2025
The Author Email: ZHU Shao-hua (zhushaohua@suda.edu.cn)