Abstract
Despite their clinical benefits in cancer treatment, the deleterious effects on heart following chemo/radiotherapy are of increasing importance. Zingerone, a natural polyphenol, possesses multiple biological activities, such as antioxidant and anti-inflammatory. Thus, the current study was designed to assess the potential cardioprotective effects of zingerone against cisplatin or γ-radiation. Zingerone was given by intragastric intubation (25 mg/kg) daily for three successive weeks prior to the induction of cardiotoxicity using a single dose of cisplatin (20 mg/kg, i.p.) or a whole body γ-irradiation at a single dose of 6 Gy. Zingerone pre-treatment significantly reduced the abnormalities in heart histology and the increase in the cardiotoxicity indices, serum lactate dehydrogenase, and creatine kinase-MB activities, as well as plasma cardiac troponin T and B-natriuretic peptide, induced by cisplatin or γ-radiation. Further, zingerone, except for superoxide dismutase, notably ameliorated the state of oxidative stress as evidenced by a significant decrease in malondialdehyde level accompanied with a significant increase in the reduced glutathione content and catalase activity. Additionally, zingerone mitigated the increase in the inflammatory markers including serum level of tumor necrosis factor-alpha, cardiac myeloperoxidase activity, and cyclooxygenase-2 protein expression. Moreover, zingerone alleviated the elevation of caspase-3 gene expression and the prominent nuclear DNA fragmentation and attenuated the decrease in mitochondrial complexes’ activities. This study sheds the light on a probable protective role of zingerone as an antioxidant, anti-inflammatory, and antiapoptotic agent against cisplatin- or γ-radiation-induced cardiotoxicity and holds a potential in regard to therapeutic intervention for chemo/radiotherapy mediated cardiac damage.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ahmad B, Rehman MU, Amin I, Arif A, Rasool S, Bhat SA, Afzal I, Hussain I, Bilal S, Mir MR (2015) A review on pharmacological properties of zingerone (4-(4-Hydroxy-3-methoxyphenyl)-2-butanone). Sci World J 2015:816364–816366. https://doi.org/10.1155/2015/816364
Antunes LM, Darin JD, Bianchi ML (2000) Protective effects of vitamin C against cisplatin-induced nephrotoxicity and lipid peroxidation in adult rats: a dose-dependent study. Pharmacol Res 41:405–411. https://doi.org/10.1006/phrs.1999.0600
Ao X, Zhao L, Davis MA, Lubman DM, Lawrence TS, Kong FM (2009) Radiation produces differential changes in cytokine profiles in radiation lung fibrosis sensitive and resistant mice. J Hematol Oncol 2:6–17. https://doi.org/10.1186/1756-8722-2-6
Arany I, Safirstein RL (2003) Cisplatin nephrotoxicity. Semin Nephrol 23:460–464. https://doi.org/10.1016/S0270-9295(03)00089-5
Arany I, Kaushal GP, Portilla D, Megyesi J, Price PM, Safirstein RL (2008) Cellular mechanisms of nephrotoxicity. In: De Broe ME, Porter GA, Bennett WM, Deray G (eds) Clinical Nephrotoxins. Springer, New York, pp 155–170
Azimzadeh O, Scherthan H, Sarioglu H, Barjaktarovic Z, Conrad M, Vogt A, Calzada-Wack J, Neff F, Aubele M, Buske C, Atkinson MJ, Tapio S (2011) Rapid proteomic remodeling of cardiac tissue caused by total body ionizing radiation. Proteomics 11:3299–3311. https://doi.org/10.1002/pmic.201100178
Badary OA, Abdel-Maksoud S, Ahmed WA, Owieda GH (2004) Naringenin attenuates cisplatin nephrotoxicity in rats. Life Sci 76:2125–2135. https://doi.org/10.1016/j.lfs.2004.11.005
Beutler E, Duron O, Kelly B (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888
Chappel JB, Hansford RG (1972) Preparation of mitochondria from animal tissues and yeasts. In: Birnie GD (ed) Subcellular components: preparation and fractionation. Butterworths, London, pp 77–91
Cheong KO, Shin DS, Bak J, Lee C, Kim KW, Je NK, Chung HY, Yoon S, Moon JO (2016) Hepatoprotective effects of zingerone on carbon tetrachloride and dimethylnitrosamine-induced liver injuries in rats. Arch Pharm Res 39:279–291. https://doi.org/10.1007/s12272-015-0696-2
Chicco AJ, Sparagna GC (2007) Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol 292:33–44. https://doi.org/10.1152/ajpcell.00243.2006
Chittezhath M, Kuttan G (2006) Radioprotective activity of naturally occurring organosulfur compounds. Tumori 92:163–169
Conklin KA, Nicolson GL (2008) Molecular replacement in cancer therapy: reversing cancer metabolic and mitochondrial dysfunction, fatigue and the adverse effects of cancer therapy. Curr Cancer Ther Rev 4:66–76. https://doi.org/10.2174/157339408783565484
Connell BJ, Saleh MC, Khan BV, Saleh TM (2011) Apocynin may limit total cell death following cerebral ischemia and reperfusion by enhancing apoptosis. Food Chem Toxicol 49:3063–3069. https://doi.org/10.1016/j.fct.2011.09.010
Cromheecke M, Konings AW, Szabo BG, Hoekstra HJ (2000) Liver tissue tolerance for irradiation: experimental and clinical investigations. Hepato-Gastroenterology 47:1732–1740
Domitrović R, Jakovac H, Blagojević G (2011) Hepatoprotective activity of berberine is mediated by inhibition of TNF-α, COX-2, and iNOS expression in CCl4-intoxicated mice. Toxicology 280:33–43. https://doi.org/10.1016/j.tox.2010.11.005
El-Sawalhi MM, Ahmed LA (2014) Exploring the protective role of apocynin, a specific NADPH oxidase inhibitor, in cisplatin-induced cardiotoxicity in rats. Chem Biol Interact 207:58–66. https://doi.org/10.1016/j.cbi.2013.11.008
Fang Y, Yang S, Wu G (2002) Free radicals, antioxidants, and nutrition. Nutrition 18:879–887. https://doi.org/10.1016/S0899-9007(02)00916-4
Francescato HD, Costa RS, Scavone C, Coimbra TM (2007) Parthenolide reduces cisplatin-induced renal damage. Toxicology 230:64–75. https://doi.org/10.1016/j.tox.2006.10.025
Furnkranz A, Schober A, Bochkov VN, Bashtrykov P, Kronke G, Kadl A et al (2005) Oxidized phospholipids trigger atherogenic inflammation in murine arteries. Arterioscl Thromb Vasc Biol 25:633–663. https://doi.org/10.1161/01.ATV.0000153106.03644.a0
Halestrap AP, Clarke SJ, Khaliulin I (2007) The role of mitochondria in protection of the heart by preconditioning. Biochim Biophys Acta 1767:1007–1031. https://doi.org/10.1016/j.bbabio.2007.05.008
Hanigan MH, Devarajan P (2003) Cisplatin nephrotoxicity: molecular mechanisms. Cancer Ther 1:47–61
Heidenreich PA, Schnittger I, Strauss HW, Vagelos RH, Lee BK, Mariscal CS, Tate DJ, Horning SJ, Hoppe RT, Hancock SL (2007) Screening for coronary artery disease after mediastinal irradiation for Hodgkin’s disease. J Clin Oncol 25:43–49. https://doi.org/10.1200/JCO.2006.07.0805
Hemalatha KL, Prince PS (2015) Preventive effects of zingerone on altered lipid peroxides and nonenzymatic antioxidants in the circulation of isoproterenol-induced myocardial infarcted rats. J Biochem Mol Toxicol 29:63–69. https://doi.org/10.1002/jbt.21668
Hemalatha KL, Prince PS (2016) Preventive effects of zingerone on cardiac mitochondrial oxidative stress, calcium ion overload and adenosine triphosphate depletion in isoproterenol induced myocardial infarcted rats. RSC Adv 6:112332–112339. https://doi.org/10.1039/C6RA23330A
Horvath SE, Daum G (2013) Lipids of mitochondria. Prog Lipid Res 52:590–614. https://doi.org/10.1016/j.plipres.2013.07.002
Kang KP, Kim DH, Jung YJ, Lee AS, Lee S, Lee SY, Jang KY, Sung MJ, Park SK, Kim W (2009) Alpha-lipoic acid attenuates cisplatin-induced acute kidney injury in mice by suppressing renal inflammation. Nephrol Dial Transplant 24:3012–3020. https://doi.org/10.1093/ndt/gfp242
Kart A, Cigremi Y, Karaman M, Ozen H (2010) Caffeic acid phenethyl ester (CAPE) ameliorates cisplatin-induced hepatotoxicity in rabbit. Exp Toxicol Pathol 62:45–52. https://doi.org/10.1016/j.etp.2009.02.066
Kartalou M, Essigmann JM (2001) Mechanisms of resistance to cisplatin. Mutat Res 478:23–43. https://doi.org/10.1016/S0027-5107(01)00141-5
Kim MK, Chung SW, Kim DH, Kim JM, Lee EK, Kim JY, Ha YM, Kim YH, No JK, Chung HS, Park KY, Rhee SH, Choi JS, Yu BP, Yokozawa T, Kim YJ, Chung HY (2010) Modulation of age-related NF-휅B activation by dietary zingerone via MAPK pathway. Exp Gerontol 45:419–426. https://doi.org/10.1016/j.exger.2010.03.005
Kregel KC, Zhang HJ (2007) An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol 292:R18–R36. https://doi.org/10.1152/ajpregu.00327.2006
Krishna A, Kumar A (2005) Evaluation of radioprotective effect of Rajira (Amaranthus paniculatus) extract in Swiss albino mice. J Radiat Res 46:233–239. https://doi.org/10.1269/jrr.46.233
Kristal B, Shurtz-Swirski R, Chezar J, Manaster J, Levy R, Shapiro G et al (1998) Participation of peripheral polymorphonuclear leukocytes in the oxidative stress and inflammation in patients with essential hypertension. Am J Hypertens 11:921–928. https://doi.org/10.1016/S0895-7061(98)00099-5
Kruidering M, Van de Water B, de Heer E, Mulder GJ, Nagelkerke JF (1997) Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. J Pharmacol Exp Ther 280:638–649
Kumar L, Chhibber S, Harjai K (2013) Zingerone inhibit biofilm formation and improve antibiofilm efficacy of ciprofloxacin against Pseudomonas aeruginosa PAO1. Fitoterapia 90:73–78. https://doi.org/10.1016/j.fitote.2013.06.017
Kumar L, Chhibber S, Harjai K (2014) Hepatoprotective effect of zingerone (4-(4-hydroxy-3-methoxyphenyl) butan-2-one) in lipopolysaccharide induced liver injury mouse model through down regulation of inflammatory mediators. Int J Pharmacognosy Phytochem Res 6:308–314
Kvietys PR, Inauen W, Bacon BR, Grisham MB (1989) Xanthine oxidase-induced injury to endothelium: role of intracellular iron and hydroxyl radical. Am J Phys 257:H1640–H1646
Lee SY, Lee SJ, Han C, Patkar AA, Masand PS, Pae CU (2012) Oxidative/nitrosative stress and antidepressants: targets for novel antidepressants. Prog Neuro-Psychopharmacol Biol Psychiatry 46:224–235. https://doi.org/10.1016/j.pnpbp.2012.09.008
Livak K, Schmittgen T (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2 (−Delta Delta C(T)) method. Methods 25:402–408
Mani V, Arivalagan S, Siddique AI, Namasivayam N (2016) Antioxidant and anti-inflammatory role of zingerone in ethanol-induced hepatotoxicity. Mol Cell Biochem 421:169–181. https://doi.org/10.1007/s11010-016-2798-7
Mani V, Arivalagan S, Islam Siddique A, Namasivayam N (2017) Antihyperlipidemic and antiapoptotic potential of zingerone on alcohol induced hepatotoxicity in experimental rats. Chem Biol Interact 272:197–206. https://doi.org/10.1016/j.cbi.2017.04.019
Minakami S, Ringler RL, Singer TP (1962) Studies on the respiratory chain-linked dihydrodiphosphopyridine nucleotide dehydrogenase I. Assay of the enzyme in particulate and in soluble preparation. J Biol Chem 237:569–576
Oktem F, Arslan MK, Dundar B (2004) Renal effects and erythrocyte oxidative stress in long-term low-level lead-exposed adolescent workers in auto repair workshops. Arch Toxicol 78:681–687
Otto JC, Smith WI (1995) Prostaglandin endoperoxide synthase-1 and -2. J Lipid Mediat Cell Signal 12:139–156
Pearl W, Cascarano J, Zweifach BW (1963) Micro determination of cytochrome oxidase in rat tissues by the oxidation on N-phenyl-p-phenylene diamine or ascorbic acid. J Histochem Cytochem 11:102–104. https://doi.org/10.1177/11.1.102
Prise KM, Schettino G, Folkard M, Held KD (2005) New insights on cell death from radiation exposure. Lancet Oncol 6:520–528. https://doi.org/10.1016/S1470-2045(05)70246-1
Rajan I, Narayanan N, Rabindran R, Jayasree PR, Manish Kumar PR (2013) Zingerone protects against stannous chloride-induced and hydrogen peroxide-induced oxidative DNA damage in vitro. Biol Trace Elem Res 155:455–459. https://doi.org/10.1007/s12011-013-9801-x
Rao BN, Rao BS, Aithal BK, Sunil Kumar MR (2009) Radiomodifying and anticlastogenic effect of zingerone on Swiss albino mice exposed to whole body gamma radiation. Mutat Res 677:33–41. https://doi.org/10.1016/j.mrgentox.2009.05.004
Raschi E, Vasina V, Ursino MG, Boriani G, Martoni A, De Ponti F (2010) Anticancer drugs and cardiotoxicity: insights and perspectives in the era of targeted therapy. Pharmacol Ther 125:196–218. https://doi.org/10.1016/j.pharmthera.2009.10.002
Saleh OM, Soliman MM, Mansour AA, Abdel-Hamid OM (2013) Protective effects of propolis on gamma irradiated nigella sativa extract induced blood and immune changes in wistar rats. Am J Biochem Biotechnol 9:162–171. https://doi.org/10.3844/ajbbsp.2013.162.171
Satoh M, Kashihara N, Fujimoto S, Horike H, Tokura T, Namikoshi T, Sasaki T, Makino H (2003) A novel free radical scavenger, edarabone, protects against cisplatin-induced acute renal damage in vitro and in vivo. J Pharmacol Exp Ther 305:1183–1190. https://doi.org/10.1124/jpet.102.047522.oxygen.
Sawyer DB, Siwik DA, Xiao L, Pimentel DR, Singh K, Colucci WS (2002) Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol 34:379–388. https://doi.org/10.1006/jmcc.2002.1526
Sinha AK (1972) Colorimetric assay of catalase. Anal Biochem 47:389–394
Slater EC, Borner WD Jr (1952) The effect of fluoride on the succinic oxidase system. Biochem J 52:185–196
Spitz DR, Azzam EI, Li JJ, Gius D (2004) Metabolic oxidation reduction reaction and cellular responses to ionizing radiation: a unifying concept in stress response biology. Cancer Metastasis Rev. 23:311–322. https://doi.org/10.1023/B:CANC.0000031769.14728.bc
Surh Y (1999) Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat Res 428:305–327
Tsao R, Deng Z (2004) Separation procedures for naturally occurring antioxidant phytochemicals. J Chromatogr B Analyt Technol Biomed Life Sci 812:85–99
Umezawa K, Arigaand A, Matsumoto N (2000) Naturally occurring and synthetic inhibitors of NF-κB functions. Anticancer Drug Des 15:239–244
Vinothkumar R, Vinothkumar R, Sudha M, Nalini N (2014) Chemopreventive effect of zingerone against colon carcinogenesis induced by 1, 2-dimethylhydrazine in rats. Eur J Cancer Prev 23:361–371. https://doi.org/10.1097/CEJ.0b013e32836473ac
Vozenin-Brotons MC (2007) Tissue toxicity induced by ionizing radiation to the normal intestine: understanding the pathophysiological mechanisms to improve the medical management. World J Gastroenterol 13:3031–3032
Wang D, Lippard SJ (2005) Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 4:307–320. https://doi.org/10.1038/nrd1691
Weijl NI, Hopman GD, Wipkink-Bakker A, Lentjes EG, Berger HM, Cleton FJ, Osanto S (1998) Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients. Ann Oncol 9:1331–1337. https://doi.org/10.1023/A:1008407014084
Wozniak K, Czechowska A, Blasiak J (2004) Cisplatin-evoked DNA fragmentation in normal and cancer cells and its modulation by free radical scavengers and the tyrosine kinase inhibitor STI571. Chem Biol Interact 147:309–318. https://doi.org/10.1016/j.cbi.2004.03.001
Xia Y, Zweier JL (1997) Measurement of myeloperoxidase in leukocyte-containing tissues. Anal Biochem 245:93–96
Xie X, Sun S, Zhong W, Soromou LW, Zhou X, Wei M, Ren Y, Ding Y (2014) Zingerone attenuates lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol 19:103–109. https://doi.org/10.1016/j.intimp.2013.12.028
Yang Z, Schumaker LM, Egorin MJ, Zuhowski EG, Guo Z, Cullen KJ (2006) Cisplatin preferentially binds mitochondrial DNA and voltage-dependent anion channel protein in the mitochondrial membrane of head and neck squamous cell carcinoma: possible role in apoptosis. Clin Cancer Res 12:5817–5825. https://doi.org/10.1158/1078-0432.CCR-06-1037
Yoshioka T, Kawada K, Shimada T, Mori M (1979) Lipid peroxidation in maternal and cord blood and protective mechanism against activated-oxygen toxicity in the blood. Am J Obstet Gynecol 135:372–376. https://doi.org/10.1016/0002-9378(79)90708-7
Yousef MI, Saad AA, El-Shennawy LK (2009) Protective effect of grape seed proanthocyanidin extract against oxidative stress induced by cisplatin in rats. Food Chem Toxicol 47:1176–1183. https://doi.org/10.1016/j.fct.2009.02.007
Acknowledgements
We are indebted to Adel B. Kholoussy (PhD) at the Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Egypt for his assistance in examining and interpreting the histopathology aspects of this work.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Soliman, A.F., Anees, L.M. & Ibrahim, D.M. Cardioprotective effect of zingerone against oxidative stress, inflammation, and apoptosis induced by cisplatin or gamma radiation in rats. Naunyn-Schmiedeberg's Arch Pharmacol 391, 819–832 (2018). https://doi.org/10.1007/s00210-018-1506-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-018-1506-4