Document Type : Original articles


1 Ph.D. candidate. University of Al-Qadisiyah

2 Department of Biochemistry, College of Medicine, University of Al-Qadisiyah, Diwaniyah, Iraq


Background: Doxorubicin-induced cardiotoxicity (DIC) is a major complication of cancer chemotherapy. Thus, developing effective myocardial protection strategies during doxorubicin (Dox) therapy is a medical necessity.
Objectives: To evaluate and compare the cardioprotective effectiveness of free berberine (Ber) and berberine loaded in micelles (mBer) against DIC.
Materials and Methods: The study, which was conducted in 2023, employed the H9c2 cell line, derived from embryonic cardiomyocytes, as a model. The study included a control group and six experimental groups: the Ber-treated group, the mBer-treated group, the Dox-treated group, the Ber-Dox combination-treated group, and the mBer-Dox combination-treated group, as well as the void micelles-treated group. The study evaluated the alterations in several cardiotoxicity markers with triplicate measurements: [lactate dehydrogenase (LDH), creatine kinase myocardial band (CK-MB), and cardiac troponin I (cTn-1)], lipid peroxidation indicator (malondialdehyde (MDA), oxidative stress markers [Reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD), inflammatory cytokines (interleukin-1β (IL-1β) and interleukin-6 (IL-6)], and the activity of the apoptosis proteins caspases 3/7.
Results: The DOX group demonstrated significant increases in cardiotoxicity enzyme indices, lipid peroxidation, generation of free radicals, inflammatory cytokines, and caspase 3/7 activity relative to the control group. When Ber, or mBer, was co-delivered with Dox, the levels of LDH, CK-MB, cTn-1, and MDA significantly decreased. Whereas the activities of SOD and CAT were significantly improved when Ber, or mBer, was co-delivered with Dox. They reduced the elevation in both IL- β and IL-6 levels as well as the activities of caspases 3 and 7 induced by Dox. Importantly, the utilization of the micellar formulation of Ber in conjunction with Dox significantly enhanced the cardioprotective efficacy of Ber against DIC in H9c2 cells.
Conclusion: Our results suggest that mBer offers a novel Ber delivery approach and prospective therapeutic strategy for the treatment of DIC.


Main Subjects

[1]      T. Attachaipanich, S. C. Chattipakorn, and N. Chattipakorn, “Potential Roles of Melatonin in Doxorubicin-Induced Cardiotoxicity: From Cellular Mechanisms to Clinical Application,” Pharmaceutics, vol. 15, no. 3, p. 785, 2023.
[2]      P. S. Rawat, A. Jaiswal, A. Khurana, J. S. Bhatti, and U. Navik, “Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management,” Biomed. Pharmacother., vol. 139, p. 111708, 2021.
[3]      J. Herrmann, “Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia,” Nat. Rev. Cardiol., vol. 17, no. 8, pp. 474–502, 2020.
[4]      B. B. Hasinoff and E. H. Herman, “Dexrazoxane: How it works in cardiac and tumor cells. Is it a prodrug or is it a drug?,” in Cardiovascular Toxicology, vol. 7, no. 2, pp. 140–144, 2007.
[5]      D. S. Monahan, E. Flaherty, A. Hameed, and G. P. Duffy, “Resveratrol significantly improves cell survival in comparison to dexrazoxane and carvedilol in a h9c2 model of doxorubicin induced cardiotoxicity,” Biomed. Pharmacother., vol. 140, p. 111702, 2021.
[6]      J. A. Smith et al., “Is it equivalent? Evaluation of the clinical activity of single agent Lipodox® compared to single agent Doxil® in ovarian cancer treatment,” J. Oncol. Pharm. Pract., vol. 22, no. 4, pp. 599–604, 2016.
[7]      S. Sritharan and N. Sivalingam, “A comprehensive review on time-tested anticancer drug doxorubicin,” Life Sci., vol. 278, p. 119527, 2021.
[8]      S. Ojha et al., “Cardioprotective potentials of plant-derived small molecules against doxorubicin associated cardiotoxicity,” Oxid. Med. Cell. Longev., vol. 2016, 2016.
[9]      I. P. Singh and S. Mahajan, “Berberine and its derivatives: a patent review (2009–2012),” Expert Opin. Ther. Pat., vol. 23, no. 2, pp. 215–231, 2013.
[10]    Y. Cai et al., “A new therapeutic candidate for cardiovascular diseases: Berberine,” Front. Pharmacol., vol. 12, p. 631100, 2021.
[11]    C. S. Liu, Y. R. Zheng, Y. F. Zhang, and X. Y. Long, “Research progress on berberine with a special focus on its oral bioavailability,” Fitoterapia, vol. 109, pp. 274–282, 2016.
[12]    J. Niu et al., “Berberine-loaded thiolated pluronic f127 polymeric micelles for improving skin permeation and retention,” Int. J. Nanomedicine, vol. 15, pp. 9987–10005, 2020.
[13]    V. Kuete, O. Karaosmanoğlu, and H. Sivas, “Anticancer Activities of African Medicinal Spices and Vegetables,” in Medicinal Spices and Vegetables from Africa: Therapeutic Potential Against Metabolic, Inflammatory, Infectious and Systemic Diseases, Elsevier, 2017, pp. 271–297.
[14]    C. Siebel, C. Lanvers-Kaminsky, G. Würthwein, G. Hempel, and J. Boos, “Bioanalysis of doxorubicin aglycone metabolites in human plasma samples–implications for doxorubicin drug monitoring,” Sci. Rep., vol. 10, no. 1, pp. 1–7, 2020.
[15]    Y. J. Wu, L. F. Li, and J. H. Meng, “Study on the Pharmacokinetics of Berberine,” J. Math. Med., vol. 21, pp. 217–219, 2008.
[16]    M. Ghezzi et al., “Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions,” J. Control. Release, vol. 332, pp. 312–336, 2021.
[17]    Z. Wang, P. Chen, M. Guo, X. Yang, W. Song, and F. Huang, “Physicochemical Characterization of Berberine-loaded Pluronic F127 Polymeric Micelles and In Vivo Evaluation of Hypoglycemic Effect,” J. Pharm. Innov., pp. 1–10, 2022.
[18]    M. H. Shahid, I. Anjum, M. N. Mushtaq, and S. Riaz, “Cardioprotective effect of boswellic acids against doxorubicin induced myocardial infarction in rats.,” Pak. J. Pharm. Sci., vol. 34, 2021.
[19]    G. C Pereira, A. M Silva, C. V Diogo, F. S Carvalho, P. Monteiro, and P. J Oliveira, “Drug-induced cardiac mitochondrial toxicity and protection: from doxorubicin to carvedilol,” Curr. Pharm. Des., vol. 17, no. 20, pp. 2113–2129, 2011.
[20]    Y. Z. Wu, L. Zhang, Z. X. Wu, T. T. Shan, and C. Xiong, “Berberine Ameliorates Doxorubicin-Induced Cardiotoxicity via a SIRT1/p66Shc-Mediated Pathway,” Oxid. Med. Cell. Longev., vol. 2019, 2019.
[21]    F. Gholampour and S. Keikha, “Berberine protects the liver and kidney against functional disorders and histological damages induced by ferrous sulfate,” Iran. J. Basic Med. Sci., vol. 21, no. 5, p. 476, 2018.
[22]    J.-S. Moon et al., “NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages,” Nat. Med., vol. 22, no. 9, pp. 1002–1012, 2016.
[23]    A. Riad et al., “Toll‐like receptor‐4 deficiency attenuates doxorubicin‐induced cardiomyopathy in mice,” Eur. J. Heart Fail., vol. 10, no. 3, pp. 233–243, 2008.
[24]    Y.-P. Yuan et al., “CTRP3 protected against doxorubicin-induced cardiac dysfunction, inflammation and cell death via activation of Sirt1,” J. Mol. Cell. Cardiol., vol. 114, pp. 38–47, 2018.
[25]    Z. Qin-Wei and L. I. Yong-Guang, “Berberine attenuates myocardial ischemia reperfusion injury by suppressing the activation of PI3K/AKT signaling,” Exp. Ther. Med., vol. 11, no. 3, pp. 978–984, 2016.
[26]    M. Olsson and B. Zhivotovsky, “Caspases and cancer,” Cell Death Differ., vol. 18, no. 9, pp. 1441–1449, 2011.
[27]    L. J. Carlson, B. Cote, A. W. G. Alani, and D. A. Rao, “Polymeric micellar co-delivery of resveratrol and curcumin to mitigate in vitro doxorubicin-induced cardiotoxicity,” J. Pharm. Sci., vol. 103, no. 8, pp. 2315–2322, 2014.
[28]    A. Abdulredha, M. Abosaooda, F. Al-Amran, and N. R. Hadi, “Berberine protests the heart from ischemic reperfusion injury via interference with oxidative and inflammatory pathways,” Med. Arch., vol. 75, no. 3, p. 174, 2021.