Cardiotoxicity of Anticancer Drugs

An analysis of the literature for 2022 was carried out in order to study the latest data on the cardiotoxicity of antitumor drugs. The abundance of data on the pathogenesis of cardiotoxicity of even a single chemotherapeutic agent indicates the multifactorial effect and the characteristics of the individual sensitivity of each patient to a particular drug. Due to the multifactorial nature of the pathogenesis of cardiotoxicity, the clinical manifestations of this complication are also numerous. It should be taken into account that oncological patients could have suffered from various cardiovascular diseases even before tumor development, and that cancer progression even without therapeutic intervention, or before it, can cause cardiac side effects. To identify such processes, it is necessary to monitor cardio-oncological patients in dynamics. When conducting conservative cancer treatment and in the event of the development of side effects, the complete cancellation of treatment is impossible, as it is necessary to continue the therapy, as well as repeat its courses, often throughout the patient's life. In this regard, methods are needed to reduce the severity of the cardiotoxic effect, as well as suppress the adverse effects of anticancer drugs on the myocardium, and the search and development of effective methods for the prevention and treatment of cardiotoxicity of chemotherapy drugs are still relevant. Timely detection, and hence, prevention, as well as reduction of the degree of damaging effects of the beginning cardiotoxic effect when using cancer chemotherapy agents is possible only with close cooperation between oncologists and cardiologists.

1. Annabelle J. Que doit savoir un cardiologue sur le suivi et la prise en charge d'une femme atteinte de cancer du sein? [What should a cardiologist know about the follow-up and management of a woman with breast cancer?]. Ann Cardiol Angeiol (Paris). 2022: S0003- 3928(22)00115-9. French. doi: 10.1016/j.ancard.2022.07.007.

2. Elad B., Habib M., Caspi O. Cardio-Oncology Rehabilitation-Present and Future Perspectives. Life (Basel). 2022; 12 (7): 1006. doi: 10.3390/life12071006. PMID: 35888095; PMCID: PMC9320714.

3. Cicini M. P., Ferretti G., Morace N., Nisticò C., Cognetti F., Rulli F. Seconddegree type 2 atrioventricular block requiring permanent cardiac pacing in patients on CDK4/6 inhibitors: report of two cases. Breast Care (Basel). 2022;17(3):330-335. doi: 10.1159/000519728.

4. Khairnar S. I., Kulkarni Y. A., Singh K. Cardiotoxicity linked to anticancer agents and cardioprotective strategy. Arch Pharm Res. 2022; 45 (10): 704–730. doi: 10.1007/s12272-022-01411-4.

5. Chen Y., Shi S., Dai Y. Research progress of therapeutic drugs for doxorubicin-induced cardiomyopathy. Biomed Pharmacother. 2022; 156: 113903. doi: 10.1016/j.biopha.2022.113903.

6. Guler M. N., Tscheiller N. M., Sabater-Molina M., Gimeno J. R., Nebigil C. G. Evidence for reciprocal network interactions between injured hearts and cancer. Front Cardiovasc Med. 2022; 9: 929259. doi: 10.3389/fcvm.2022.929259.

7. de Wit S., Glen C., de Boer R. A., Lang N. N. Mechanisms shared between cancer, heart failure, and targeted anti-cancer therapies. Cardiovasc Res. 2022:cvac132. doi: 10.1093/cvr/cvac132.

8. Zhang X. Y., Wang Q., Yang K. L., Wei D., Liu X. N. Preventive strategies of cancer therapeutics-related cardiotoxicity in childhood cancer survivors: a protocol of systematic review. BMJ Open. 2022; 12 (9): e065776. doi: 10.1136/bmjopen-2022-065776.

9. Liu B., Wang Y., Lyu D., Ma F. Focus on anticancer therapy-induced cardiotoxicity from the perspective of oncologists. Chin Med J (Engl). 2022. doi: 10.1097/CM9.0000000000002133.

10. Porter C., Azam T. U., Mohananey D., Kumar R., Chu J., Lenihan D., Dent S., Ganatra S., Beasley G. S., Okwuosa T. Permissive cardiotoxicity: the clinical crucible of cardio-oncology. JACC CardioOncol. 2022; 4 (3): 302–312. doi: 10.1016/j.jaccao.2022.07.005.

11. Pantazi D., Tselepis A. D. Cardiovascular toxic effects of antitumor agents: Pathogenetic mechanisms. Thromb Res. 2022; 213 Suppl 1: S95–S102. doi: 10.1016/j.thromres.2021.12.017.

12. Chianca M., Fabiani I., Del Franco A., Grigoratos C., Aimo A., Panichella G., Giannoni A., Castiglione V., Gentile F., Passino C., Cipolla C. M., Cardinale D. M., Emdin M. Management and treatment of cardiotoxicity due to anticancer drugs: 10 questions and answers. Eur J Prev Cardiol. 2022; 29 (17): 2163–2172. doi: 10.1093/eurjpc/zwac170.

13. Bikomeye J. C., Terwoord J. D., Santos J. H., Beyer A. M. Emerging mitochondrial signaling mechanisms in cardio-oncology: beyond oxidative stress. Am J Physiol Heart Circ Physiol. 2022; 323 (4): H702–H720. doi: 10.1152/ajpheart.00231.2022.

14. Ishiguchi H., Uchida M., Okamura T., Kobayashi S., Yano M. Acute heart failure following the initiation of cabozantinib, a multikinase inhibitor: A case report. J Cardiol Cases. 2022; 26 (3): 217–220. doi: 10.1016/j.jccase.2022.04.012.

15. Brandão S. R., Carvalho F., Amado F., Ferreira R., Costa V. M. Insights on the molecular targets of cardiotoxicity induced by anticancer drugs: A systematic review based on proteomic findings. Metabolism. 2022; 134: 155250. doi: 10.1016/j.metabol.2022.155250.

16. Fox C. A., Romenskaia I., Dagda R. K., Ryan R. O. Cardiolipin nanodisks confer protection against doxorubicin-induced mitochondrial dysfunction. Biochim Biophys Acta Biomembr. 2022; 1864 (10): 183984. doi: 10.1016/j.bbamem.2022.183984.

17. Moro N., Dokshokova L., Perumal Vanaja I., Prando V., Cnudde S. J. A., Di Bona A., Bariani R., Schirone L., Bauce B., Angelini A., Sciarretta S., Ghigo A., Mongillo M., Zaglia T. Neurotoxic Effect of Doxorubicin Treatment on Cardiac Sympathetic Neurons. Int J Mol Sci. 2022; 23 (19): 11098. doi: 10.3390/ijms231911098.

18. Xie S., Yang Y., Luo Z., Li X, Liu J., Zhang B., Li W. Role of noncardiomyocytes in anticancer drug-induced cardiotoxicity: A systematic review. iScience. 2022; 25 (11): 105283. doi: 10.1016/j.isci.2022.105283.

19. Lérida-Viso A., Estepa-Fernández A., Morellá-Aucejo Á., Lozano-Torres B., Alfonso M., Blandez J. F., Bisbal V., Sepúlveda P., García-Fernández A., Orzáez M., Martínez-Máñez R. Pharmacological senolysis reduces doxorubicin-induced cardiotoxicity and improves cardiac function in mice. Pharmacol Res. 2022; 183: 106356. doi: 10.1016/j.phrs.2022.106356.

20. Kim S. W., Ahn B. Y., Tran T. T. V., Pyun J. H., Kang J. S., Leem Y. E. PRMT1 suppresses doxorubicin-induced cardiotoxicity by inhibiting endoplasmic reticulum stress. Cell Signal. 2022; 98: 110412. doi: 10.1016/j.cellsig.2022.110412.

21. Ebrahim N., Al Saihati H. A., Mostafa O., Hassouna A., Abdulsamea S., Abd El Aziz M El Gebaly E., Abo-Rayah N. H., Sabry D., El-Sherbiny M., Madboly A. G., Hussien N. I., Saadani R. E. H., Ebrahim H. A., Badr O. A. M., Elsherbiny N. M., Salim R. F. Prophylactic evidence of MSCs-derived exosomes in doxorubicin/trastuzumab-induced cardiotoxicity: beyond mechanistic target of NRG-1/Erb signaling pathway. Int J Mol Sci. 2022; 23 (11): 5967. doi: 10.3390/ijms23115967.

22. Li M. J., Sun W. S., Yuan Y., Zhang Y. K., Lu Q, Gao Y. Z., Ye T, Xing D. M. Breviscapine remodels myocardial glucose and lipid metabolism by regulating serotonin to alleviate doxorubicin-induced cardiotoxicity. Front Pharmacol. 2022; 13: 930835. doi: 10.3389/fphar.2022.930835.

23. Hosseini A., Safari M. K., Rajabian A., Boroumand-Noughabi S., Eid A. H., Al Dhaheri Y., Gumpricht E., Sahebkar A. Cardioprotective effect of rheum turkestanicum against doxorubicin-induced toxicity in rats. Front Pharmacol. 2022; 13: 909079. doi: 10.3389/fphar.2022.909079.

24. Liu X., Li D., Pi W., Wang B., Xu S, Yu L., Yao L., Sun Z., Jiang J., Mi Y. LCZ696 protects against doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via AKT/SIRT3/SOD2 signaling pathway activation. Int Immunopharmacol. 2022; 113 (Pt A): 109379. doi: 10.1016/j.intimp.2022.109379.

25. Yu W., Chen C., Xu C., Xie D., Wang Q., Liu W., Zhao H., He F., Chen B., Xi Y., Yan Y., Yu L., Cheng J. Activation of p62-NRF2 Axis protects against doxorubicin-induced ferroptosis in cardiomyocytes: a novel role and molecular mechanism of resveratrol. Am J Chin Med. 2022; 50 (8): 2103– 2123. doi: 10.1142/S0192415X22500902.

26. Tadokoro T., Ikeda M., Abe K., Ide T., Miyamoto H. D., Furusawa S., Ishimaru K., Watanabe M., Ishikita A., Matsushima S., Koumura T., Yamada K. I., Imai H., Tsutsui H. Ethoxyquin is a Competent Radical-Trapping Antioxidant for Preventing Ferroptosis in Doxorubicin Cardiotoxicity. J Cardiovasc Pharmacol. 2022; 80 (5): 690–699. doi: 10.1097/FJC.0000000 000001328.

27. Tang X. G., Lin K., Guo S. W., Rong Y., Chen D., Chen Z. S., Ping F. F., Wang J. Q. The Synergistic Effect of Ruthenium Complex -Ru1 and Doxorubicin in a Mouse Breast Cancer Model. Recent Pat Anticancer Drug Discov. 2022; 18 (2): 174–186. doi: 10.2174/1574892817666220629105543.

28. Zhang C., Dan Q., Lai S., Zhang Y., Gao E., Luo H., Yang L., Gao X., Lu C. Rab10 protects against DOX-induced cardiotoxicity by alleviating the oxidative stress and apoptosis of cardiomyocytes. Toxicol Lett. 2023; 373: 84–93. doi: 10.1016/j.toxlet.2022.10.005.

29. Liang F., Zhang K., Ma W, Zhan H., Sun Q., Xie L., Zhao Z. Impaired autophagy and mitochondrial dynamics are involved in Sorafenib-induced cardiomyocyte apoptosis. Toxicology. 2022; 481: 153348. doi: 10.1016/j.tox.2022.153348.

30. Chang W. T., Liu C. F., Feng Y. H., Liao C. T., Wang J. J., Chen Z. C., Lee H. C., Shih J. Y. An artificial intelligence approach for predicting cardiotoxicity in breast cancer patients receiving anthracycline. Arch Toxicol. 2022; 96 (10): 2731–2737. doi: 10.1007/s00204-022-03341-y.

31. Afrin H., Huda M. N., Islam T., Oropeza B. P., Alvidrez E., Abir M. I., Boland T., Turbay D., Nurunnabi M. Detection of Anticancer DrugInduced Cardiotoxicity Using V. C.AM1-Targeted Nanoprobes. ACS Appl Mater Interfaces. 2022; 14 (33): 37566–37576. doi: 10.1021/acsami.2c13019.

32. Al-Kuraishy H. M., Al-Hussaniy H. A., Al-Gareeb A. I., Negm W. A., ElKadem A. H., Batiha G. E., Welson N., Mostafa-Hedeab G., Qasem A. H., Conte-Junior C. A. Combination of Panax ginseng C. A. mey and febuxostat boasted cardioprotective effects against doxorubicin-induced acute cardiotoxicity in rats. Front Pharmacol. 2022; 13: 905828. doi: 10.3389/fphar.2022.905828.

33. Belen E., Canbolat I. P., Yigittürk G., Cetinarslan Ö., Akdeniz C. S., Karaca M., Sönmez M., Erbas O. Cardio-protective effect of dapagliflozin against doxorubicin induced cardiomyopathy in rats. Eur Rev Med Pharmacol Sci. 2022; 26 (12): 4403–4408. doi: 10.26355/eurrev_202206_29079.

34. Cheng Y., Wu X., Nie X., Wu Y., Zhang C., Lee S. M., Lv K., Leung G. P., Fu C., Zhang J., Li J. Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway. Phytomedicine. 2022; 106: 154407. doi: 10.1016/j.phymed.2022.154407.

35. Ding M., Shi R., Fu F., Li M., De D., Du Y., Li Z. Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. J Adv Res. 2023: 151–162. doi: 10.1016/j.jare.2022.07.002.

36. Dragojevic S., Ryu J. S., Hall M. E., Raucher D. Targeted Drug Delivery Biopolymers Effectively Inhibit Breast Tumor Growth and Prevent Doxorubicin-Induced Cardiotoxicity. Molecules. 2022; 27 (11): 3371. doi: 10.3390/molecules27113371.

37. Jones I. C., Dass C. R. Doxorubicin-induced cardiotoxicity: causative factors and possible interventions. J Pharm Pharmacol. 2022; 74 (12): 1677–1688. doi: 10.1093/jpp/rgac063. PMID: 35994421.

38. Liang Z., Chen Y., Wang Z., Wu X., Deng C., Wang C., Yang W., Tian Y., Zhang S., Lu C., Yang Y. Protective effects and mechanisms of psoralidin against adriamycin-induced cardiotoxicity. J Adv Res. 2022; 40: 249– 261. doi: 10.1016/j.jare.2021.12.007.

39. Lu D., Chatterjee S., Xiao K., Riedel I., Huang C. K., Costa A., Cushman S., Neufeldt D., Rode L., Schmidt A., Juchem M., Leonardy J., Büchler G., Blume J., Gern O. L., Kalinke U., Wen Tan W. L., Foo R., Vink A., van Laake L. W., van der Meer P., Bär C., Thum T. A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity. Eur Heart J. 2022; 43 (42): 4496–4511. doi: 10.1093/eurheartj/ehac337.

40. Maleki Dana P., Sadoughi F., Reiter R. J., Mohammadi S., Heidar Z., Mirzamoradi M., Asemi Z. Melatonin as an adjuvant treatment modality with doxorubicin. Biochimie. 2022; 49–55. doi: 10.1016/j.biochi.2022.06.007.

41. Nguyen N., Lienhard M., Herwig R., Kleinjans J., Jennen D. Epirubicin alters DNA methylation profiles related to cardiotoxicity. Front Biosci (Landmark Ed). 2022; 27 (6): 173. doi: 10.31083/j.fbl2706173.

42. Patil P. P., Khanal P., Patil V. S., Charla R., Harish D. R., Patil B. M., Roy S. Effect of Theobroma cacao L. on the efficacy and toxicity of doxorubicin in mice bearing ehrlich ascites carcinoma. Antioxidants (Basel). 2022; 11 (6): 1094. doi: 10.3390/antiox11061094.

43. Shetake N. G., Ali M., Kumar A., Bellare J., Pandey B. N. Theranostic magnetic nanoparticles enhance DNA damage and mitigate doxorubicin-induced cardio-toxicity for effective multi-modal tumor therapy. Biomater Adv. 2022; 142: 213147. doi: 10.1016/j.bioadv.2022.213147.

44. Sirangelo I., Liccardo M., Iannuzzi C. Hydroxytyrosol prevents doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes. Antioxidants (Basel). 2022; 11 (6): 1087. doi: 10.3390/antiox11061087.

45. Li J., Cheng Y., Li R., Wu X., Zheng C., Shiu P. H., Chan J. C., Rangsinth P., Liu C., Leung S. W., Lee S. M., Zhang C., Fu C., Zhang J., Cheung T. M., Leung G. P. Protective effects of Amauroderma rugosum on doxorubicin-induced cardiotoxicity through suppressing oxidative stress, mitochondrial dysfunction, apoptosis, and activating Akt/mTOR and Nrf2/HO- 1 signaling pathways. Oxid Med Cell Longev. 2022; 2022: 9266178. doi: 10.1155/2022/9266178.

46. Madanat L., Gupta R., Weber P., Kumar N., Chandra R., Ahaneku H., Bansal Y., Anderson J., Bilolikar A., Jaiyesimi I. Cardiotoxicity of biological therapies in cancer patients: an in-depth review. Curr Cardiol Rev. 2022. doi: 10.2174/1573403X18666220531094800.

47. Rosenkaimer S., Sieburg T., Winter L., Mavratzas A., Hofmann W. K., Hofheinz R. D., Akin I., Duerschmied D., Hohneck A. Adverse Cardiovascular effects of anti-tumor therapies in patients with breast cancer: a singlecenter cross-sectional analysis. Anticancer Res. 2022; 42 (6): 3075–3084. doi: 10.21873/anticanres.15795.

48. Serrao A., Malfona F., Assanto G. M., Orellana M. G. C., Santoro C., Chistolini A. Direct oral anticoagulants for the treatment of atrial fibrillation in patients with hematologic malignancies. J Thromb Thrombolysis. 202254 (4): 625–629. doi: 10.1007/s11239-022-02702-9.

49. Chen X., Wang H., Zhang Z., Xu Y., An X., Ai X., Li L. Case Report: Oxaliplatin-Induced Third-Degree Atrioventricular Block: First Discovery of an Important Side-Effect. Front Cardiovasc Med. 2022; 9: 900406. doi: 10.3389/fcvm.2022.900406.

50. Kwon S. S., Nam B. D., Lee M. Y., Lee M. H., Lee J., Park B. W., Bang D. W., Kwon S. H. Increased E. A. T volume after anthracycline chemotherapy is associated with a low risk of cardiotoxicity in breast cancer. Breast Cancer Res Treat. 2022; 196 (1): 111–119. doi: 10.1007/s10549-022-06696-z.

51. Duvillier P. Hypertension artérielle et cancer: les liaisons dangereuses [Hypertension and cancer: Dangerous Liaisons]. Ann Cardiol Angeiol (Paris). 2022 Sep 5; S0003–3928 (22) 00119–6. French. doi: 10.1016/j.ancard.2022.08.003.

52. Mędrek S., Szmit S. Echocardiography-assessed changes of left and right ventricular cardiac function may correlate with progression of advanced lung cancer-a generating hypothesis study. Cancers (Basel). 2022; 14 (19): 4770. doi: 10.3390/cancers14194770.

53. Gálvez L. C., Redondo E. A., Lorenzo C. C., Fernández T. L. Advanced echocardiographic techniques in cardio-oncology: the role for early detection of cardiotoxicity. Curr Cardiol Rep. 2022; 24 (9): 1109–1116. doi: 10.1007/s11886-022-01728-y.

54. Nenna A., Carpenito M., Chello C., Nappi P., Annibali O., Vincenzi B., Grigioni F., Chello M., Nappi F. Cardiotoxicity of chimeric antigen receptor T-cell (CAR-T) therapy: pathophysiology, clinical implications, and echocardiographic assessment. Int J Mol Sci. 2022; 23 (15): 8242. doi: 10.3390/ijms23158242.

55. Fan M., Li H., Shen D., Wang Z., Liu H., Zhu D., Wang Z., Li L., Popowski K. D., Ou C., Zhang K., Zhang J., Cheng K., Li Z. Decoy exosomes offer protection against chemotherapy-induced toxicity. Adv Sci (Weinh). 2022; 9 (32): e2203505. doi: 10.1002/advs.202203505.

56. Li X. R., Cheng X. H., Zhang G. N., Wang X. X., Huang J. M. Cardiac safety analysis of first-line chemotherapy drug pegylated liposomal doxorubicin in ovarian cancer. J Ovarian Res. 2022; 15 (1): 96. doi: 10.1186/s13048-022-01029-6.

57. Tang C., Yin D., Liu T., Gou R., Fu J., Tang Q., Wang Y., Zou L., Li H. Maleimide-functionalized liposomes: prolonged retention and enhanced efficacy of doxorubicin in breast cancer with low systemic toxicity. Molecules. 2022; 27 (14): 4632. doi: 10.3390/molecules27144632.

58. Zhao F., Qian Y., Li H., Yang Y., Wang J., Yu W., Li M., Cheng W., Shan L. Amentoflavone-loaded nanoparticles enhanced chemotherapy efficacy by inhibition of AKR1B10. Nanotechnology. 2022; 33 (38). doi: 10.1088/1361-6528/ac7810.

59. Yu B., Shen Y., Zhang X., Ding L., Meng Z., Wang X., Han M., Guo Y., Wang X. Poly(methacrylate citric acid) as a Dual Functional Carrier for Tumor Therapy. Pharmaceutics. 2022; 14 (9): 1765. doi: 10.3390/pharmaceutics14091765.

60. Al-Thani H. F., Shurbaji S., Zakaria Z. Z., Hasan M. H., Goracinova K., Korashy H. M., Yalcin H. C. Reduced cardiotoxicity of ponatinib-loaded PLGA-PEG-PLGA nanoparticles in zebrafish xenograft model. Materials (Basel). 2022; 15 (11): 3960. doi: 10.3390/ma15113960.

61. Das S., Janardhanan K. K., Thampi B. S. H. Bioactive extract of morel mushroom, morchella esculenta (ascomycota) attenuates doxorubicininduced oxidative stress leading to myocardial injury. Int J Med Mushrooms. 2022; 24 (8): 31–44. doi: 10.1615/IntJMedMushrooms.2022044516.