Pristimerin Protects Against Doxorubicin-induced Cardiotoxicity and Fibrosis Through Modulation of Nrf2 and MAPK/NF-kB Signaling Pathways

Overview

Journal Cancer Manag Res

Publisher Dove Medical Press

Specialty Oncology

Date 2018 Dec 28

PMID 30588110

Citations 50

Authors

Dina S El-Agamy

Khaled M El-Harbi

Saad Khoshhal

Nishat Ahmed

Mohamed A Elkablawy

Ahmed A Shaaban

Hany M Abo-Haded

Affiliations

Soon will be listed here.

Abstract

Background/purpose: Pristimerin (Pris) is triterpenoid compound with many biological effects. Until now, nothing is known about its effect on doxorubicin (DOX)-induced cardiotoxicity. Hence, this study investigated the impact of Pris on DOX-induced cardiotoxic effects.

Materials And Methods: Rats were treated with Pris 1 week before and 2 weeks contaminant with repeated DOX injection. Afterwards, electrocardiography (ECG), biochemical, histopathological, PCR, and Western blot assessments were performed.

Results: Pris effectively alleviated DOX-induced deleterious cardiac damage. It inhibited DOX-induced ECG abnormities as well as DOX-induced elevation of serum indices of cardiotoxicity. The histopathological cardiac lesions and fibrosis were remarkably improved in Pris-treated animals. Pris reduced hydroxyproline content and attenuated the mRNA and protein expression of the pro-fibrogenic genes. The antioxidant activity of Pris was prominent through the amelioration of oxidative stress parameters and enhancement of antioxidants. Furthermore, Pris enhanced the activation of nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway as it increased the mRNA and protein expression of Nrf2 and Nrf2-dependent antioxidant genes (GCL, NQO1, HO-1). Additionally, the anti-inflammatory effect of Pris was obvious through the inhibition of mitogen activated protein kinase (MAPK)/nuclear factor kappa-B (NF-kB) signaling and subsequent inhibition of inflammatory mediators.

Conclusion: This study provides evidence of the cardioprotective activity of Pris which is related to the modulation of Nrf2 and MAPK/NF-kB signaling pathways.

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References

Spinale F, Coker M, Bond B, Zellner J . Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target. Cardiovasc Res. 2000; 46(2):225-38. DOI: 10.1016/s0008-6363(99)00431-9. View

Johnson G, Lapadat R . Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002; 298(5600):1911-2. DOI: 10.1126/science.1072682. View

Mukherjee S, Banerjee S, Maulik M, Dinda A, Talwar K, Maulik S . Protection against acute adriamycin-induced cardiotoxicity by garlic: role of endogenous antioxidants and inhibition of TNF-alpha expression. BMC Pharmacol. 2003; 3:16. PMC: 324401. DOI: 10.1186/1471-2210-3-16. View

Nozaki N, Shishido T, Takeishi Y, Kubota I . Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2-knockout mice. Circulation. 2004; 110(18):2869-74. DOI: 10.1161/01.CIR.0000146889.46519.27. View

Guerra J, de Jesus A, Santiago-Borrero P, Roman-Franco A, Rodriguez E, Crespo M . Plasma nitric oxide levels used as an indicator of doxorubicin-induced cardiotoxicity in rats. Hematol J. 2005; 5(7):584-8. DOI: 10.1038/sj.thj.6200573. View

Morrow D, Cannon C, Jesse R, Newby L, Ravkilde J, Storrow A . National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical characteristics and utilization of biochemical markers in acute coronary syndromes. Circulation. 2007; 115(13):e356-75. DOI: 10.1161/CIRCULATIONAHA.107.182882. View

Zhang J, An J . Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007; 45(2):27-37. PMC: 2785020. DOI: 10.1097/AIA.0b013e318034194e. View

Marcal da Costa P, Ferreira P, da Silva Bolzani V, Furlan M, Dos Santos V, Corsino J . Antiproliferative activity of pristimerin isolated from Maytenus ilicifolia (Celastraceae) in human HL-60 cells. Toxicol In Vitro. 2008; 22(4):854-63. DOI: 10.1016/j.tiv.2008.01.003. View

Zhao W, Zhao T, Chen Y, Ahokas R, Sun Y . Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats. Mol Cell Biochem. 2008; 317(1-2):43-50. DOI: 10.1007/s11010-008-9803-8. View

10.

Mukhopadhyay P, Rajesh M, Batkai S, Kashiwaya Y, Hasko G, Liaudet L . Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am J Physiol Heart Circ Physiol. 2009; 296(5):H1466-83. PMC: 2685360. DOI: 10.1152/ajpheart.00795.2008. View

11.

Deng S, Kruger A, Schmidt A, Metzger A, Yan T, Godtel-Armbrust U . Differential roles of nitric oxide synthase isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice. Naunyn Schmiedebergs Arch Pharmacol. 2009; 380(1):25-34. PMC: 3085792. DOI: 10.1007/s00210-009-0407-y. View

12.

Thorn C, Oshiro C, Marsh S, Hernandez-Boussard T, Mcleod H, Klein T . Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2010; 21(7):440-6. PMC: 3116111. DOI: 10.1097/FPC.0b013e32833ffb56. View

13.

Morgan M, Liu Z . Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2010; 21(1):103-15. PMC: 3193400. DOI: 10.1038/cr.2010.178. View

14.

Das J, Ghosh J, Manna P, Sil P . Taurine suppresses doxorubicin-triggered oxidative stress and cardiac apoptosis in rat via up-regulation of PI3-K/Akt and inhibition of p53, p38-JNK. Biochem Pharmacol. 2011; 81(7):891-909. DOI: 10.1016/j.bcp.2011.01.008. View

15.

Ghosh J, Das J, Manna P, Sil P . The protective role of arjunolic acid against doxorubicin induced intracellular ROS dependent JNK-p38 and p53-mediated cardiac apoptosis. Biomaterials. 2011; 32(21):4857-66. DOI: 10.1016/j.biomaterials.2011.03.048. View

16.

Shi Y, Moon M, Dawood S, McManus B, Liu P . Mechanisms and management of doxorubicin cardiotoxicity. Herz. 2011; 36(4):296-305. DOI: 10.1007/s00059-011-3470-3. View

17.

Xiao J, Sun G, Sun B, Wu Y, He L, Wang X . Kaempferol protects against doxorubicin-induced cardiotoxicity in vivo and in vitro. Toxicology. 2011; 292(1):53-62. DOI: 10.1016/j.tox.2011.11.018. View

18.

Ivanova M, Dovinova I, Okruhlicova L, Tribulova N, Simoncikova P, Bartekova M . Chronic cardiotoxicity of doxorubicin involves activation of myocardial and circulating matrix metalloproteinases in rats. Acta Pharmacol Sin. 2012; 33(4):459-69. PMC: 4003364. DOI: 10.1038/aps.2011.194. View

19.

Octavia Y, Tocchetti C, Gabrielson K, Janssens S, Crijns H, Moens A . Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol. 2012; 52(6):1213-25. DOI: 10.1016/j.yjmcc.2012.03.006. View

20.

Sterba M, Popelova O, Vavrova A, Jirkovsky E, Kovarikova P, Gersl V . Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid Redox Signal. 2012; 18(8):899-929. PMC: 3557437. DOI: 10.1089/ars.2012.4795. View