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Cisplatin and cisplatin analogues perfusion through isolated rat heart: the effects of acute application on oxidative stress biomarkers

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Abstract

Drug-induced oxidative stress can occur in numerous tissues and organ systems (liver, kidney, ear, nervous system, and cardiovascular system). Cancer therapy with cisplatin is associated with side effects to which oxidative stress may contribute. We have compared the influences of cisplatin (reference compound) and its’ analogues (dichloro(1,2-diaminocyclohexane)platinum(II) and chloro(2,2′:6′,2″-terpyridine)platinum(II)) in a model of isolated rat heart using the Langendorff technique. The production of oxidative stress biomarkers, antioxidant enzymes, myocardial damage, and expression of Bax, OH-1, and SODs were studied. Cisplatin and the analogues were perfused at concentration of 10−6 and 10−5 M during 30 min. The results of this study showed that examined platinum complexes had different ability to induce oxidative stress of isolated perfused rat heart. Varying the carrier ligands, such as 1,2-diaminocyclohexane and 2,2′:6′,2″-terpyridine, related to amino ligands (cisplatin) directly influenced the strength to induce production of oxidative stress biomarkers. Introducing 2,2′:6′,2″-terpyridine ligands provoked the smallest changes in antioxidant enzymes activity, lipid peroxidation, and expression of heme oxygenase-1, that undoubtedly indicated that this complex had the lowest impact on redox status in heart tissue. These findings may be useful in synthesis of novel platinum analogues with lower potential for oxidative stress induction. However, the fact that platinum complexes could induce toxic effects in the heart by other mechanisms should be taken into the consideration.

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References

  1. Kart A, Cigremis Y, Karaman M, Ozen H (2010) Caffeic acid phenethyl ester (CAPE) ameliorates cisplatin-induced hepatotoxicity in rabbit. Exp Toxicol Pathol 62:45–52. doi:10.1016/j.etp.2009.02.066

    Article  CAS  PubMed  Google Scholar 

  2. 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. doi:10.1016/j.fct.2009.02.007

    Article  CAS  PubMed  Google Scholar 

  3. Paolicchi A, Sotiropuolou M, Perego P, Daubeuf S, Visvikis A, Lorenzini E, Franzini M, Romiti N, Chieli E, Leone R, Apostoli P, Colangelo D, Zunino F, Pompella A (2003) Gamma-glutamyl transpeptidase catalyses the extracellular detoxification of cisplatin in a human cell line derived from the proximal convoluted tubule of the kidney. Eur J Cancer 39:996–1003

    Article  CAS  PubMed  Google Scholar 

  4. Townsend DM, Tew KD, He L, King JB, Hanigan MH (2009) Role of glutathione S-transferase Pi in cisplatin-induced nephrotoxicity. Biomed Pharmacother 63:79–85. doi:10.1016/j.biopha.2008.08.004

    Article  CAS  PubMed  Google Scholar 

  5. 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. doi:10.1158/1078-0432.CCR-06-1037

    Article  CAS  PubMed  Google Scholar 

  6. Dzagnidze A, Katsarava Z, Makhalova J, Liedert B, Yoon MS, Kaube H, Limmroth V, Thomale J (2007) Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy. J Neurosci 27:9451–9457. doi:10.1523/JNEUROSCI.0523-07.2007

    Article  CAS  PubMed  Google Scholar 

  7. Kintzel PE (2001) Anticancer drug-induced kidney disorders. Drug Saf 24:19–38

    Article  CAS  PubMed  Google Scholar 

  8. Rabik CA, Dolan ME (2007) Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 33:9–23. doi:10.1016/j.ctrv.2006.09.006

    Article  CAS  PubMed  Google Scholar 

  9. Raja W, Mir MH, Dar I, Banday MA, Ahmad I (2013) Cisplatin induced paroxysmal supraventricular tachycardia. Indian J Med Paediatr Oncol 34:330–332. doi:10.4103/0971-5851.125262

    Article  PubMed  PubMed Central  Google Scholar 

  10. Guglin M, Aljayeh M, Saiyad S, Ali R, Curtis AB (2009) Introducing a new entity: chemotherapy-induced arrhythmia. Europace 11:1579–1586. doi:10.1093/europace/eup300

    Article  PubMed  Google Scholar 

  11. Dolci A, Dominici R, Cardinale D, Sandri MT, Panteghini M (2008) Biochemical markers for prediction of chemotherapy-induced cardiotoxicity: systematic review of the literature and recommendations for use. Am J Clin Pathol 130:688–695. doi:10.1309/AJCPB66LRIIVMQDR

    Article  CAS  PubMed  Google Scholar 

  12. Khan S, Chen CL, Brady MS, Parameswaran R, Moore R, Hassoun H, Carvajal RD (2012) Unstable angina associated with cisplatin and carboplatin in a patient with advanced melanoma. J Clin Oncol 30:e163–e164. doi:10.1200/JCO.2011.38.7852

    Article  CAS  PubMed  Google Scholar 

  13. Ryberg M (2012) Recent advances in cardiotoxicity of anticancer therapies. Am Soc Clin Oncol Educ Book 2012:555–559. doi:10.14694/EdBook_AM.2012.32.555

    Google Scholar 

  14. Dugbartey GJ, Peppone LJ, de Graaf IA (2016) An integrative view of cisplatin-induced renal and cardiac toxicities: molecular mechanisms, current treatment challenges and potential protective measures. Toxicology 371:58–66. doi:10.1016/j.tox.2016.10.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. El-Awady ESE, Moustafa YM, Abo-Elmatty DM, Radwan A (2011) Cisplatin-induced cardiotoxicity: mechanisms and cardioprotective strategies. Eur J Pharmacol 650:335–341. doi:10.1016/j.ejphar.2010.09.085

    Article  CAS  Google Scholar 

  16. Ma H, Jones KR, Guo R, Xu P, Shen Y, Ren J (2010) Cisplatin compromises myocardial contractile function and mitochondrial ultrastructure: role of endoplasmic reticulum stress. Clin Exp Pharmacol Physiol 37:460–465. doi:10.1111/j.1440-1681.2009.05323.x

    Article  CAS  PubMed  Google Scholar 

  17. Chirino YI, Pedraza-Chaverri J (2009) Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp Toxicol Pathol 61:223–242. doi:10.1016/j.etp.2008.09.003

    Article  CAS  PubMed  Google Scholar 

  18. Baek SM, Kwon CH, Kim JH, Woo JS, Jung JS, Kim YK (2003) Differential roles of hydrogen peroxide and hydroxyl radical in cisplatin-induced cell death in renal proximal tubular epithelial cells. J Lab Clin Med 142:178–186. doi:10.1016/S0022-2143(03)00111-2

    Article  CAS  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. Rosic G, Selakovic D, Joksimovic J, Srejovic I, Zivkovic V, Tatalović N, Orescanin-Dusic Z, Mitrovic S, Ilic M, Jakovljevic V (2016) The effects of N-acetylcysteine on cisplatin-induced changes of cardiodynamic parameters within coronary autoregulation range in isolated rat hearts. Toxicol Lett 242:34–46. doi:10.1016/j.toxlet.2015.11.028

    Article  CAS  PubMed  Google Scholar 

  21. Chowdhury S, Sinha K, Banerjee S, Sil PC (2016) Taurine protects cisplatin induced cardiotoxicity by modulating inflammatory and endoplasmic reticulum stress responses. BioFactors 42:647–664. doi:10.1002/biof.1301

    Article  CAS  PubMed  Google Scholar 

  22. Najam R, Bano N, Mirza T, Hassan S (2014) Adverse effects on cardiovascular status and lipid levels of albino Wistar rats treated with cisplatin and oxaliplatin in combination with 5 Fluorouracil. Pak J Pharm Sci. 27(5):1409–1418

    CAS  PubMed  Google Scholar 

  23. Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378. doi:10.1016/j.ejphar.2014.07.025

    Article  CAS  PubMed  Google Scholar 

  24. Rixe O, Ortuzar W, Alvarez M, Parker R, Reed E, Paull K, Fojo T (1996) Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute’s Anticancer Drug Screen panel. Biochem Pharmacol 52:1855–1865

    Article  CAS  PubMed  Google Scholar 

  25. Zhang CX, Lippard SJ (2003) New metal complexes as potential therapeutics. Curr Opin Chem Biol 7:481–489

    Article  CAS  PubMed  Google Scholar 

  26. Bugarčić ŽD, Bogojeski J, Petrović B, Hochreuther S, van Eldik R (2012) Mechanistic studies on the reactions of platinum(II) complexes with nitrogen- and sulfur-donor biomolecules. Dalton Trans 41:12329–12345. doi:10.1039/c2dt31045g

    Article  PubMed  Google Scholar 

  27. Bugarcic ZD, Heinemann FW, van Eldik R (2004) Substitution reactions of [Pt(terpy)X]2+ with some biologically relevant ligands. Synthesis and crystal structure of [Pt(terpy)(cyst-S)](ClO4)2.0.5H2O and [Pt(terpy)(guo-N7)](ClO4)2.0.5guo.1.5H2O. Dalton Trans 21:279–286. doi:10.1039/b311056g

    Article  Google Scholar 

  28. Pouna P, Bonoron-Adèl S, Gouverneur G, Tariosse L, Besse P, Robert J (1995) Evaluation of anthracycline cardiotoxicity with the model of isolated, perfused rat heart: comparison of new analogues versus doxorubicin. Cancer Chemother Pharmacol 35:257–261

    Article  CAS  PubMed  Google Scholar 

  29. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  PubMed  Google Scholar 

  30. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite and [15 N] nitrate in biological fluids. Anal Biochem 126:131–138

    Article  CAS  PubMed  Google Scholar 

  31. Auclair C, Voisin E (1985) Nitroblue tetrazolium reduction. In: Ra Greenvvald (ed) Handbook of methods for oxygen radical research. CRC Press Une, Boca Raton, pp 123–132

    Google Scholar 

  32. Pick E, Keisari Y (1980) A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture. J Immunol Methods 38:161–170

    Article  CAS  PubMed  Google Scholar 

  33. Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888

    CAS  PubMed  Google Scholar 

  34. Aebi H (1984) Catalase in vitro. Methods Enzymol 105(121–126):25

    Google Scholar 

  35. Beutler E (1984) Superoxide dismutase. In: Beutler E (ed) Red cell metabolism a manual of biochemical methods. Grune & Stratton, Philadelphia, pp 83–85

    Google Scholar 

  36. Saksida T, Nikolic I, Vujicic M, Nilsson UJ, Leffler H, Lukic ML et al (2013) Galectin-3 deficiency protects pancreatic islet cells from cytokine-triggered apoptosis in vitro. J Cell Physiol 228:1568–1576

    Article  CAS  PubMed  Google Scholar 

  37. Galanski M, Keppler BK (1995) Synthesis and characterization of new ethylenediamine platinum(IV) complexes containing lipophilic carboxylate ligands. Metal Drugs 2:57–63

    Article  CAS  Google Scholar 

  38. Demkow U, Biatas-Chromiec B, Stelmaszczyk-Emmel A, Radzikowska E, Wiatr E, Radwan-Rohrenschef P, Szturmowicz M (2011) The cardiac markers and oxidative stress parameters in advanced non-small cell lung cancer patients receiving cisplatin-based chemotherapy. EJIFCC 22:6–15

    PubMed  PubMed Central  Google Scholar 

  39. Mythili Y, Sudharsan PT, Selvakumar E, Varalakshmi P (2004) Protective effect of dl-alpha-lipoic acid on cyclophosphamide induced oxidative cardiac injury. Chem Biol Interact 151:13–19. doi:10.1016/j.cbi.2004.10.004

    Article  CAS  PubMed  Google Scholar 

  40. 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. doi:10.1016/j.cbi.2013.11.008

    Article  CAS  PubMed  Google Scholar 

  41. Saleh RM, Awadin WF, El-Shafei RA, Elseady YY, Wehaish FE, Elshal MF (2015) Cardioprotective role of tadalafil against cisplatin-induced cardiovascular damage in rats. Eur J Pharmacol 765:574–581. doi:10.1016/j.ejphar.2015.09.015

    Article  CAS  PubMed  Google Scholar 

  42. Lushchak VI (2012) Glutathione homeostasis and functions: potential targets for medical interventions. J Amino Acid 2012:736837. doi:10.1155/2012/736837

    Google Scholar 

  43. Abdellatief SA, Galal AA, Farouk SM, Abdel-Daim MM (2017) Ameliorative effect of parsley oil on cisplatin-induced hepato-cardiotoxicity: a biochemical, histopathological, and immunohistochemical study. Biomed Pharmacother 86:482–491. doi:10.1016/j.biopha.2016.12.038

    Article  CAS  PubMed  Google Scholar 

  44. Hussein A, Ahmed AA, Shouman SA, Sharawy S (2012) Ameliorating effect of dl-α-lipoic acid against cisplatin-induced nephrotoxicity and cardiotoxicity in experimental animals. Drug Discov Ther 6:147–156

    CAS  PubMed  Google Scholar 

  45. Warner BB, Stuart L, Gebb S, Wispé JR (1996) Redox regulation of manganese superoxide dismutase. Am J Physiol 271(1 Pt 1):L150–L158

    CAS  PubMed  Google Scholar 

  46. Kim JW, Sahm H, You J, Wang M (2010) Knock-down of superoxide dismutase 1 sensitizes cisplatin-resistant human ovarian cancer cells. Anticancer Res 30(7):2577–2581

    CAS  PubMed  Google Scholar 

  47. Fridovich I (1995) Superoxide radical and superoxide dismutases. Annu Rev Biochem 64:97–112

    Article  CAS  PubMed  Google Scholar 

  48. Valdivia A, Pérez-Alvarez S, Aroca-Aguilar JD, Ikuta I, Jordán J (2009) Superoxide dismutases: a physiopharmacological update. J Physiol Biochem. 65(2):195–208

    Article  CAS  PubMed  Google Scholar 

  49. Landriscina M, Maddalena F, Laudiero G, Esposito F (2009) Adaptation to oxidative stress, chemoresistance, and cell survival. Antioxid Redox Signal 11(11):2701–2716. doi:10.1089/ars.2009.2692

    Article  CAS  PubMed  Google Scholar 

  50. Stohs SJ, Bagchi D (1995) Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 18:321–336

    Article  CAS  PubMed  Google Scholar 

  51. Gardner CR, Laskin JD, Dambach DM, Sacco M, Durham SK, Bruno MK, Cohen SD, Gordon MK, Gerecke DR, Zhou P, Laskin DL (2002) Reduced hepatotoxicity of acetaminophen in mice lacking inducible nitric oxide synthase: potential role of tumor necrosis factor-alpha and interleukin-10. Toxicol Appl Pharmacol 184:27–36

    Article  CAS  PubMed  Google Scholar 

  52. Harstad EB, Klaassen CD (2002) iNOS-null mice are not resistant to cadmium chloride-induced hepatotoxicity. Toxicology 175:83–90

    Article  CAS  PubMed  Google Scholar 

  53. Nishikawa M, Nagatomi H, Nishijima M, Ohira G, Chang BJ, Sato E, Inoue M (2001) Targeting superoxide dismutase to renal proximal tubule cells inhibits nephrotoxicity of cisplatin and increases the survival of cancer-bearing mice. Cancer Lett 171:133–138

    Article  CAS  PubMed  Google Scholar 

  54. Davis CA, Nick HS, Agarwal A (2001) Manganese superoxide dismutase attenuates Cisplatin-induced renal injury: importance of superoxide. J Am Soc Nephrol 12:2683–2690

    CAS  PubMed  Google Scholar 

  55. Pecorelli A, Bocci V, Acquaviva A, Belmonte G, Gardi C, Virgili F, Ciccoli L, Valacchi G (2013) NRF2 activation is involved in ozonated human serum upregulation of HO-1 in endothelial cells. Toxicol Appl Pharmacol 267(1):30–40

    Article  CAS  PubMed  Google Scholar 

  56. Surh YJ, Kundu JK, Na HK (2008) Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 74(13):1526–1539

    Article  CAS  PubMed  Google Scholar 

  57. Liu Q, Si T, Xu X, Liang F, Wang L, Pan S (2015) Electromagnetic radiation at 900 MHz induces sperm apoptosis through bcl-2, bax and caspase-3 signaling pathways in rats. Reprod Health 12:65. doi:10.1186/s12978-015-0062-3

    Article  PubMed  PubMed Central  Google Scholar 

  58. Liu Q, Hu S, He Y, Zhang J, Zeng X, Gong F, Liang L (2017) The protective effects of Zhen-Wu-Tang against cisplatin-induced acute kidney injury in rats. PLoS ONE 12(6):e0179137. doi:10.1371/journal.pone.0179137

    Article  PubMed  PubMed Central  Google Scholar 

  59. Howe-Grant ME, Lippard SJ (1980) Aqueous platinum(II) chemistry: binding to biological macromolecules. In: Siegel H (ed) Metal ions in biological systems, 11th edn. Marcel Dekker, New York, pp 63–125

    Google Scholar 

  60. Summa N, Schiessl W, Puchta R, van Eikema Hommes N, van Eldik R (2006) Thermodynamic and kinetic studies on reactions of Pt(II) complexes with biologically relevant nucleophiles. Inorg Chem 45:2948–2959. doi:10.1021/ic051955r

    Article  CAS  PubMed  Google Scholar 

  61. Bogojeski J, Bugarčić ŽD, Puchta R, Eldik R (2010) Kinetic studies on the reactions of different bifunctional platinum(II) complexes with selected nucleophiles. Eur JIC 2010:5439–5445

    Google Scholar 

  62. Hofmann A, Jaganyi D, Munro OQ, Liehr G, van Eldik R (2003) Electronic tuning of the lability of Pt(II) complexes through pi-acceptor effects. Correlations between thermodynamic, kinetic, and theoretical parameters. Inorg Chem 42:1688–1700

    Article  CAS  PubMed  Google Scholar 

  63. Hofmann A, Dahlenburg L, van Eldik R (2003) Cyclometalated analogues of platinum terpyridine complexes: kinetic study of the strong sigma-donor cis and trans effects of carbon in the presence of a pi-acceptor ligand backbone. Inorg Chem 42:6528–6538

    Article  CAS  PubMed  Google Scholar 

  64. Petrovic BV, Djuran MI, Bugarcic ZD (1999) Binding of platinum(II) to some biologically important thiols. Met Based Drugs 6:355–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jaganyi D, Hofmann A, van Eldik R (2001) Controlling the lability of square-planar Pt(II) complexes through electronic communication between π-acceptor ligands. Angew Chem Int Ed Engl 40:1680–1683

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac, 34000, Serbia

    Isidora M. Stojic, Tamara R. Nikolic, Nevena S. Jeremic, Jovana N. Jeremic, Katarina G. Radonjic & Slobodan S. Novokmet

  2. Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac, 34000, Serbia

    Vladimir I. Zivkovic, Ivan M. Srejovic & Vladimir L. J. Jakovljevic

  3. Institute of Medical Physiology “Richard Burian” Faculty of Medicine, University of Belgrade, Visegradska 26/II, Belgrade, 11000, Serbia

    Dragan M. Djuric

  4. Department of Histology and Embriology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac, 34000, Serbia

    Nemanja Jovicic

  5. Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovica 12, Kragujevac, 34000, Serbia

    Zivadin D. Bugarcic

  6. Department of Human Pathology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

    Vladimir L. J. Jakovljevic

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  1. Isidora M. Stojic
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  2. Vladimir I. Zivkovic
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Correspondence to Vladimir L. J. Jakovljevic.

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Stojic, I.M., Zivkovic, V.I., Srejovic, I.M. et al. Cisplatin and cisplatin analogues perfusion through isolated rat heart: the effects of acute application on oxidative stress biomarkers. Mol Cell Biochem 439, 19–33 (2018). https://doi.org/10.1007/s11010-017-3132-8

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