Cardioprotective effect of vanillic acid against doxorubicin-induced cardiotoxicity in rat

Bahar Baniahmad , Leila Safaeian , Golnaz Vaseghi, Mohammad Rabbani, Behnoosh Mohammadi


Background and purpose: Doxorubicin (DOX) is an effective agent for the treatment of many neoplastic diseases. Cardiotoxicity is the major side effect of this drug and limits its use. Vanillic acid (VA) is                        a pharmaceutical compound from the phenolic acids family. The present study is an attempt to investigate the possible helpful effects of VA against DOX-induced cardiotoxicity in rats.

Experimental approach: For induction of cardiotoxicity, male Wistar rats received total of six doses of DOX (2.5 mg/kg i.p.) three times per week from days 14 to 28. Treatment groups received daily oral doses of VA (10, 20, and 40 mg/kg) two weeks before DOX injection and then plus DOX for 2 weeks. At the end of experiment, systolic blood pressure (SBP) and heart rate (HR) were detected using tail-cuff method. Lactate dehydrogenase (LDH), creatine phosphokinase-MB (CK-MB), serum glutamic oxaloacetic transaminase (SGOT), malondialdehyde (MDA), and ferric reducing antioxidant power (FRAP) were measured in serum samples. Troponin-I and toll-like receptor 4 (TLR4) were measured in cardiac tissue.               All the measurements processed spectrophotometrically using commercial ELISA kits. Cardiac tissue was also processed for histopathological examination.

Findings / Results: Treatment with VA significantly increased SBP compared to the DOX group and restored HR near to the normal level. Administration of VA at all of doses, decreased serum levels of LDH, SGOT, CK-MB, MDA, cardiac troponin-I, cardiac TLR4 and increased FRAP value.

Conclusion and implications: These results suggest that VA may exert cardioprotective effects against DOX-induced cardiotoxicity by decreasing oxidative stress and biomarkers of cardiotoxicity, suppression of TLR4 signaling and consequently inflammation pathway.




Antioxidant; Cardiotoxicity; Doxorubicin; TLR4; Vanillic acid.

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Zhou S, Palmeira CM, Wallace KB. Doxorubicin-induced persistent oxidative stress to cardiac myocytes. Toxicol Lett. 2001;121(3):151-157.

Gianny L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB. Anthracycline cardiotoxicity from bench to beside. J Clin Oncol. 2008;26(22):3777-3784.

Yagmurca M, Bas O, Mollaoglu H, Sahin O, Nacar A, Karaman O, et al. Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch Med Res. 2007;38(4):380-385.

Gorini S, De Angelis A, Berrino L, Malara N, Rosano G, Ferraro E. Chemotherapeutic drugs and mitochondrial dysfunction: focus on doxorubicin, trastuzumab, and sunitinib. Oxid Med Cell Longev. 2018;2018:1-15.

Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869-2879.

Chung WB, Youn HJ. Pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity. Korean J Intern Med. 2016;31(4):625-633.

Wold LE, Aberle NS, Ren J. Doxorubicin induced cardiomyocyte dysfunction via a p38 MAP kinase-dependent oxidative stress mechanism. Cancer Detect Prev. 2005;29(3):294-299.

Kim SY, Kim SJ, Kim BJ, Rah SY, Chung SM, Im MJ, et al. Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+ increase are reciprocally modulated in rat cardiomyocytes. Exp Mol Med. 2006;38(5):535-545.

Ahmed HH, Mannaa F, Elmegeed GA, Doss SH. Cardioprotective activity of melatonin and its novel synthesized derivatives on doxorubicin-induced cardiotoxicity. Bioorg Med Chem. 2005;13(5): 1847-1857.

Ma Y, Zhang X, Bao H, Mi S, Cai W, Yan H. et al. Toll-like receptor (TLR) 2 and TLR4 differentially regulate doxorubicin-induced cardiomyopathy in mice. PLoS One. 2012;7(7):1-10.

Nili-Ahmadabadi A, Ali-Heidar F, Ranjbar A, Mousavi L, Ahmadimoghaddam D, Larki-Harchegani A, et al. Protective effect of amlodipine on diazinon-induced changes on oxidative/antioxidant balance in rat hippocampus. Res Pharm Sci. 2018;13(4): 368-379.

Riad A, Bien S, Gratz M, Escher F, Westermann D, Heimesaat MM, et al. Toll‐like receptor‐4 deficiency attenuates doxorubicin‐induced cardiomyopathy in mice. Eur J Heart Fail. 2008;10(3):233-243.

Liu H, Wang H, Xiang D, Guo W. Pharmaceutical measures to prevent doxorubicin-induced cardiotoxicity. Mini-Rev Med Chem. 2017;17(1): 44-50.

Langer SW. Dexrazoxane for the treatment of chemotherapy-related side effects. Cancer Manag Res. 2014;6:357-363.

Marty M, Espié M, Llombart A, Monnier A, Rapoport BL, Stahalova V; et al. Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol. 2006;17(4):614-622.

Psotova J, Chlopcikova S, Miketova P, Hrbac J, Simanek V. Chemoprotective effect of plant phenolics against anthracycline‐induced toxicity on rat cardiomyocytes. Part III. Apigenin, baicalelin, kaempherol, luteolin and quercetin. Phytother Res. 2004;18(7):516-521.

Lirdprapamongkol K, Sakurai H, Kawasaki N, Choo MK, Saitoh Y, Aozuka Y, et al. Vanillin suppresses in vitro invasion and in vivo metastasis of mouse breast cancer cells. Eur J Pharm Sci. 2005;25(1):57-65.

Chou TH, Ding HY, Hung WJ, Liang CH. Antioxidative characteristics and inhibition of α‐melanocyte‐stimulating hormone‐stimulated melanogenesis of vanillin and VA from Origanum vulgare. Exp Dermatol. 2010;19(8):742-750.

Lirdprapamongkol K, Kramb JP, Suthiphongchai T, Surarit R, Srisomsap C, Dannhardt G, et al. Vanillic acid suppresses metastatic potential of human cancer cells through PI3K inhibition and decreases angiogenesis in vivo. ‏J Agric Food Chem. 2009;57(8):3055-3063.

Amin FU, Shah SA, Kim MO. Vanillic acid attenuates Aβ 1-42-induced oxidative stress and cognitive impairment in mice. ‏Sci Rep. 2017;18(1):1-15.

Dianat M, Hamzavi GR, Badavi M, Samarbaf-zadeh A. Effect of vanillic acid on ischemia-reperfusion of isolated rat heart: Hemodynamic parameters and infarct size assays. Indian J Exp Biol. 2015;53(1):641-646.

Krishnan DN, Prasanna N, Sabina EP, Rasool M. Hepatoprotective and antioxidant potential of ferulic acid against acetaminophen-induced liver damage in mice. Comp Clin Pathol. 2012;22(6):1177-1181.

Arunkumar P, Raju B, Vasantharaja R, Vijayaraghavan S, Preetham Kumar B, Jeganathan K, et al. Near infra-red laser mediated photothermal and antitumor efficacy of doxorubicin conjugated gold nanorods with reduced cardiotoxicity in swiss albino mice. Nanomed-Nanotechnol. 2015;11(6):1435-1444.

Adamcova M, Popelova‐Lencova O, Jirkovsky E, Simko F, Gersl V, Sterba M. Cardiac troponins-translational biomarkers in cardiology: Theory and practice of cardiac troponin high‐sensitivity assays. Biofactors. 2016;42(2):133-148.

Huang Z, Zhuang X, Xie C, Hu X, Dong X, Guo Y, et al. Exogenous hydrogen sulfide attenuates high glucose-induced cardiotoxicity by inhibiting NLRP3 inflammasome activation by suppressing TLR4/NF-κB pathway in H9c2 cells. Cell Physiol Biochem. 2016;40(6):1578-1590.

Taghiabadi E, Karimi G, Imenshahidi M, Sankian M, Mosafa F. The protective effect of silymarin on oxidative stress induced by acrolein in heart of mice. Res Pharm Sci. 2012;7(5):180.

Yarmohmmadi F, Rahimi N, Faghir-Ghanesefat H, Javadian N, Abdollahi A, Pasalar P, et al. Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat. Eur J Pharmacol. 2017;796(1):39-44.

Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol. 2012;52(6):1213-1225.

Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. ‏Pharmacol Rev. 2004;56(2):185-229.

Umlauf J, Horky M. Molecular biology of doxorubicin-induced cardiomyopathy. Exp Clin Cardiol. 2002;7(1):35-39.

Erboga M, Donmez YB, Sener U, Erboga ZF, Aktas C, Kanter M. Effect of Urtica Dioica against doxorubicin-induced cardiotoxicity in rats through suppression of histological damage, oxidative stress and lipid peroxidation. Eur J Intern Med. 2016;13(2):139-144.

Chularojmontri L, Wattanapitayakul SK, Herunsalee A, Charuchongkolwongse S, Niumsakul S, Srichairat. Cardioprotective effects of Phyllanthus urinaria L. on doxorubicin-induced cardiotoxicity. Biol Pharm Bull. 2005;28(7):1165-1171.

Khaper N, Bryan S, Dhingra S, Singal R, Bajaj A, Pathak CM, et al. Targeting the vicious inflammation-oxidative stress cycle for the management of heart failure. ‏Antioxid Redox Signal. 2010;13(7):1033-1049.

Liu L, Pang XL, Shang WJ, Xie HC, Wang JX, Feng GW. Over-expressed microRNA-181a reduces glomerular sclerosis and renal tubular epithelial injury in rats with chronic kidney disease via down-regulation of the TLR/NF-κB pathway by binding to CRY1. Mol Med. 2018;24(1):49-62.

Moure A, Cruz JM, Franco D, Dominguez JM, Sineiro J, Dominguez H, et al. Natural antioxidants from residual sources. Food Chem. 2001; 72(2):145-171.

Radmanesh E, Dianat M, Badavi M, Goudarzi G, Mard SA. The cardioprotective effect of vanillic acid on hemodynamic parameters, malondialdehyde, and infarct size in ischemia-reperfusion isolated rat heart exposed to PM10. Iran J Basic Med Sci. 2017;20(7):760-768.

Prince PS, Dhanasekar K, Rajakumar S. Preventive effects of vanillic acid on lipids, bax, bcl-2 and myocardial infarct size on isoproterenol-induced myocardial infarcted rats: a biochemical and in vitro study. Cardiovasc Toxicol. 2011;11(1):58-66.

Kim ME, Na JY, Park YD, Lee JS. Anti-neuroinflammatory effects of vanillin through the regulation of inflammatory factors and NF-κB signaling in LPS-stimulated microglia. Appl Biochem Biotechnol. 2019;187(3):884-893.

Aswar U, Mahajan U, Kandhare A, Aswar M. Ferulic acid ameliorates doxorubicin-induced cardiac toxicity in rats. Naunyn Schmiedebergs Arch Pharmacol. 2019;392(1):659-668.

Fadillioglu E, Oztas E, Erdogan H, Yagmurca M, Sogut S, Ucar M, et al. Protective effects of caffeic acid phenethyl ester on doxorubicin‐induced cardiotoxicity in rats. J Appl Toxicol. 2004;24(1):47-52.


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