Isosorbide dinitrate improves doxorubicin-induced cardiotoxicity via diminishing proinflammatory mediators, oxidative stress, and apoptosis

Main Article Content

Hussein J. Al-Amir
Ali M. Janabi
Salim F. Kadhim
Rafid M.A. Wasfi


isosorbide dinitrate, doxorubicin-induced cardiotoxicity, inflammation, oxidative stress, and apoptosis


Cardiotoxicity is the presence of cardiac dysfunction resulting from electrical or muscle injury, which results in heart toxicity. The heart weakens and becomes less efficient in pumping blood. Cardiotoxicity is one of chemotherapy most serious side effects, with significantly increased morbidity and mortality. Isosorbide dinitrate is an antianginal agent used to treat chest pain in people with a certain heart condition (coronary artery disease). This medication belongs to the nitrate drug class. It works by relaxing and widening blood vessels, allowing more blood to flow to the heart. The role of isosorbide dinitrate in doxorubicin-induced cardiotoxicity reduction or prevention is briefly discussed in this work. The 28 male rats were randomly split into four groups (7 rats in each group). The control group of rats was provided with natural food and drink. For two weeks, rats in the normal saline group were fed 0.9% normal saline. For those in the doxorubicin-induced group, 2.5 mg/kg was administered thrice weekly to the rats for two weeks. ISDN group (treated with ISDN): ISDN was administered orally (10 mg/kg/d) for two weeks. Heart damage was a result of doxorubicin treatment. Cardiac tissues of doxorubicin-treated rats showed elevated tumor necrosis factor-alpha, interleukin-1beta, malondialdehyde, and caspase-3 levels (p<0.05), while total antioxidant capacity and Bcl-2 levels were considerably decreased (P<0.05). Inflammatory markers (TNF-α and IL-1β) are reduced after ISDN treatment, providing strong evidence that ISDN considerably mitigates doxorubicin-induced cardiotoxicity (P<0.05). In addition, total antioxidant capacity was considerably increased in the ISDN group compared to the doxorubicin-only group (P<0.05), whereas the oxidative marker malondialdehyde in cardiac tissue was decreased (P<0.05). ISDN dramatically mitigated doxorubicin-induced cardiotoxicity in rats by modulating oxidative stress, the inflammatory response, and the apoptotic pathway. This research aimed to see if ISDN may prevent doxorubicin-induced cardiotoxicity by limiting the effects of the medication on inflammation pathways, oxidative pathways, and apoptotic pathways.

Abstract 286 | pdf Downloads 199


1. Abd El-Hamid, E. S., Gamal-Eldeen, A. M., & Eldeen, A. M. S. (2019). Liposome-coated nano doxorubicin induces apoptosis on oral squamous cell carcinoma CAL-27 cells. Archives of Oral Biology, 103, 47–54.
2. Abdul-Rahman, T., Dunham, A., Huang, H., Bukhari, S. M. A., Mehta, A., Awuah, W. A., Ede-Imafidon, D., Cantu-Herrera, E., Talukder, S., & Joshi, A. (2023). Chemotherapy Induced Cardiotoxicity: A State of the Art Review on General Mechanisms, Prevention, Treatment and Recent Advances in Novel Therapeutics. Current Problems in Cardiology, 101591.
3. Alyasiry, E., Janabi, A., & Hadi, N. (2022). Dipyridamole ameliorates doxorubicin-induced cardiotoxicity. Journal of Medicine & Life, 15(9).
4. Aziz, M. M., Abd El Fattah, M. A., Ahmed, K. A., & Sayed, H. M. (2020). Protective effects of olmesartan and l-carnitine on doxorubicin-induced cardiotoxicity in rats. Canadian Journal of Physiology and Pharmacology, 98(4), 183–193.
5. Banerjee, I., Robinson, J., Annavarapu, A., & Gupta, R. K. (2021). An insight of medical student’s preference and opinions to Pharmacology textbooks. Journal of Biomedical Sciences, 8(1), 23–32.
6. Baniahmad, B., Safaeian, L., Vaseghi, G., Rabbani, M., & Mohammadi, B. (2020). Cardioprotective effect of vanillic acid against doxorubicin-induced cardiotoxicity in rat. Research in Pharmaceutical Sciences, 15(1), 87.
7. Calatayud, S., Barrachina, D., & Esplugues, J. V. (2001). Nitric oxide: relation to integrity, injury, and healing of the gastric mucosa. Microscopy Research and Technique, 53(5), 325–335.
8. Eid, B. G., El‐Shitany, N. A. E., & Neamatallah, T. (2021). Trimetazidine improved adriamycin‐induced cardiomyopathy by downregulating TNF‐α, BAX, and VEGF immunoexpression via an antioxidant mechanism. Environmental Toxicology, 36(6), 1217–1225.
9. Fouad, E. M., Elaidy, S. M., & Essawy, S. S. (2017). Anti-ulcerative, anti-oxidative, and anti-inflammatory effects of rosuvastatin and isosorbide dinitrate on cysteamine-induced chronic duodenal ulcer in rats. Egyptian Journal of Basic and Clinical Pharmacology, 7(1), 14–25.
10. Gonçalves, M. I. J. (2018). Nanotechnology approaches for the delivery of antitumor drugs: the case of doxorubicin.
11. Kitakata, H., Endo, J., Ikura, H., Moriyama, H., Shirakawa, K., Katsumata, Y., & Sano, M. (2022). Therapeutic targets for DOX-induced cardiomyopathy: role of apoptosis vs. ferroptosis. International Journal of Molecular Sciences, 23(3), 1414.
12. Kong, C.-Y., Guo, Z., Song, P., Zhang, X., Yuan, Y.-P., Teng, T., Yan, L., & Tang, Q.-Z. (2022). Underlying the Mechanisms of Doxorubicin-Induced Acute Cardiotoxicity: Oxidative Stress and Cell Death. International Journal of Biological Sciences, 18(2), 760.
13. Koutsoukis, A., Ntalianis, A., Repasos, E., Kastritis, E., Dimopoulos, M.-A., & Paraskevaidis, I. (2018). Cardio-oncology: a focus on cardiotoxicity. European Cardiology Review, 13(1), 64.
14. Ma, T., Kandhare, A. D., Mukherjee-Kandhare, A. A., & Bodhankar, S. L. (2019). Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: the decisive role of caspase-3, COX-II, cTn-I, iNOs and TNF-α. Molecular Biology Reports, 46(1), 105–118.
15. Mancilla, T. R., Iskra, B., & Aune, G. J. (2019). Doxorubicin-Induced Cardiomyopathy in Children. Comprehensive Physiology, 9(3), 905.
16. Mann, D. L. (2015). Innate immunity and the failing heart: the cytokine hypothesis revisited. Circulation Research, 116(7), 1254–1268.
17. Meeran, M. F. N., Al Taee, H., Azimullah, S., Tariq, S., Adeghate, E., & Ojha, S. (2019). β-Caryophyllene, a natural bicyclic sesquiterpene attenuates doxorubicin-induced chronic cardiotoxicity via activation of myocardial cannabinoid type-2 (CB2) receptors in rats. Chemico-Biological Interactions, 304, 158–167.
18. Mikhed, Y., Daiber, A., & Steven, S. (2015). Mitochondrial oxidative stress, mitochondrial DNA damage and their role in age-related vascular dysfunction. International Journal of Molecular Sciences, 16(7), 15918–15953.
19. Mo, X., Zhao, N., Du, X., Bai, L., & Liu, J. (2011). The protective effect of peony extract on acute myocardial infarction in rats. Phytomedicine, 18(6), 451–457.
20. Moutabian, H., Ghahramani-Asl, R., Mortezazadeh, T., Laripour, R., Narmani, A., Zamani, H., Ataei, G., Bagheri, H., Farhood, B., Sathyapalan, T., & Sahebkar, A. (2022). The cardioprotective effects of nano-curcumin against doxorubicin-induced cardiotoxicity: A systematic review. BioFactors, 48(3), 597–610.
21. Napoli, C., Bontempo, P., Palmieri, V., Coscioni, E., Maiello, C., Donatelli, F., & Benincasa, G. (2021). Epigenetic therapies for heart failure: current insights and future potential. Vascular Health and Risk Management, 247–254.
22. Nardin, S., Mora, E., Varughese, F. M., D’Avanzo, F., Vachanaram, A. R., Rossi, V., Saggia, C., Rubinelli, S., & Gennari, A. (2020). Breast cancer survivorship, quality of life, and late toxicities. Frontiers in Oncology, 10, 864.
23. Noguchi, S., Yatera, K., Wang, K.-Y., Oda, K., Akata, K., Yamasaki, K., Kawanami, T., Ishimoto, H., Toyohira, Y., & Shimokawa, H. (2014). Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice. Respiratory Research, 15(1), 1–12.
24. Norouzi, M., Yathindranath, V., Thliveris, J. A., Kopec, B. M., Siahaan, T. J., & Miller, D. W. (2020). Doxorubicin-loaded iron oxide nanoparticles for glioblastoma therapy: A combinational approach for enhanced delivery of nanoparticles. Scientific Reports, 10(1), 11292.
25. Nunes, J. P. S., Andrieux, P., Brochet, P., Almeida, R. R., Kitano, E., Honda, A. K., Iwai, L. K., Andrade-Silva, D., Goudenège, D., & Alcantara Silva, K. D. (2021). Co-exposure of cardiomyocytes to IFN-γ and TNF-α induces mitochondrial dysfunction and nitro-oxidative stress: implications for the pathogenesis of chronic chagas disease cardiomyopathy. Frontiers in Immunology, 4522.
26. Okpara, E. S., Adedara, I. A., Guo, X., Klos, M. L., Farombi, E. O., & Han, S. (2022). Molecular mechanisms associated with the chemoprotective role of protocatechuic acid and its potential benefits in the amelioration of doxorubicin-induced cardiotoxicity—A Review. Toxicology Reports.
27. Pérez-Herrero, E., & Fernández-Medarde, A. (2015). Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. European Journal of Pharmaceutics and Biopharmaceutics, 93, 52–79.
28. Perrotta, C., Bizzozero, L., Falcone, S., Rovere-Querini, P., Prinetti, A., Schuchman, E. H., Sonnino, S., Manfredi, A. A., & Clementi, E. (2007). Nitric oxide boosts chemoimmunotherapy via inhibition of acid sphingomyelinase in a mouse model of melanoma. Cancer Research, 67(16), 7559–7564.
29. Plotkine, M., Allix, M., Guillou, J., & Boulu, R. (1992). [Experimental antithrombotic activity of oral isosorbide dinitrate]. Archives Des Maladies Du Coeur et Des Vaisseaux, 85 Spec No 1(SPEC. ISS. I), 57–60.
30. Quagliariello, V., De Laurentiis, M., Rea, D., Barbieri, A., Monti, M. G., Carbone, A., Paccone, A., Altucci, L., Conte, M., Canale, M. L., Botti, G., & Maurea, N. (2021). The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin. Cardiovascular Diabetology, 20(1), 1–20.
31. Rawat, P. S., Jaiswal, A., Khurana, A., Bhatti, J. S., & Navik, U. (2021). Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomedicine and Pharmacotherapy, 139.
32. Renu, K., Pureti, L. P., Vellingiri, B., & Valsala Gopalakrishnan, A. (2022). Toxic effects and molecular mechanism of doxorubicin on different organs–an update. Toxin Reviews, 41(2), 650–674.
33. Rusul Nadheer Albakaa* , Fadhil A. Rizij, R. M. A. H. (2022). Potential Role of Selenium to Ameliorate Doxorubicin Induced Cardiotoxicity in Male Rats. Journal of Medicinal and Chemical Sciences, 6(2023), 1498–1505.
34. Sakr, H. F., Abbas, A. M., & Elsamanoudy, A. Z. (2016). Effect of valsartan on cardiac senescence and apoptosis in a rat model of cardiotoxicity. Canadian Journal of Physiology and Pharmacology, 94(6), 588–598.
35. Shaker, R. A., Abboud, S. H., Assad, H. C., & Hadi, N. (2018). Enoxaparin attenuates doxorubicin induced cardiotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. BMC Pharmacology and Toxicology, 19(1), 1–10.
36. Sheta, A., Elsakkar, M., Hamza, M., & Solaiman, A. (2016). Effect of metformin and sitagliptin on doxorubicin-induced cardiotoxicity in adult male albino rats. Human & Experimental Toxicology, 35(11), 1227–1239.
37. Singh, R., Letai, A., & Sarosiek, K. (2019). Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nature Reviews Molecular Cell Biology, 20(3), 175–193.
38. Singla, S., Kumar, N. R., & Kaur, J. (2014). In vivo studies on the protective effect of propolis on doxorubicin-induced toxicity in liver of male rats. Toxicology International, 21(2), 191.
39. Songbo, M., Lang, H., Xinyong, C., Bin, X., Ping, Z., & Liang, S. (2019). Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicology Letters, 307, 41–48.
40. Sun, Z., Yan, B., Yu, W. Y., Yao, X., Ma, X., Sheng, G., & Ma, Q. (2016). Vitexin attenuates acute doxorubicin cardiotoxicity in rats via the suppression of oxidative stress, inflammation and apoptosis and the activation of FOXO3a. Experimental and Therapeutic Medicine, 12(3), 1879–1884.
41. Thadani, U., & Opie, L. H. (2012). Nitrates updated: current use in angina, ischemia, infarction and failure. Springer Science & Business Media.
42. Vo, T. T. T., Vo, Q. C., Tuan, V. P., Wee, Y., Cheng, H.-C., & Lee, I.-T. (2021). The potentials of carbon monoxide-releasing molecules in cancer treatment: An outlook from ROS biology and medicine. Redox Biology, 46, 102124.
43. Wang, P. G., Cai, T. B., & Taniguchi, N. (2005). Nitric oxide donors: for pharmaceutical and biological applications. John Wiley & Sons.
44. Wenningmann, N., Knapp, M., Ande, A., Vaidya, T. R., & Ait-Oudhia, S. (2019). Insights into Doxorubicin-induced Cardiotoxicity: Molecular Mechanisms, Preventive Strategies, and Early Monitoring. Molecular Pharmacology, 96(2), 219–232.
45. Yay, A., Onses, M. S., Sahmetlioglu, E., Ceyhan, A., Pekdemir, S., Onder, G. O., Sezer, G., Sarica, Z. S., & Aydin, F. (2020). Raman spectroscopy: A novel experimental approach to evaluating cisplatin induced tissue damage. Talanta, 207, 120343.
46. Zhang, Q.-L., Yang, J.-J., & Zhang, H.-S. (2019). Carvedilol (CAR) combined with carnosic acid (CAA) attenuates doxorubicin-induced cardiotoxicity by suppressing excessive oxidative stress, inflammation, apoptosis and autophagy. Biomedicine & Pharmacotherapy, 109, 71–83.