Sisplatin kardiyotoksisitesinde oksidatif ve nitrozatif stresin rolü

Yıl 2020, Cilt: 13 Sayı: 2, 218 - 226, 26.08.2020

Ertuğrul Emre Güntürk , Bilal Yücel Inayet Gunturk , Cevat Yazıcı , Kader Köse

Öz

Amaç: Sisplatin solid organ tümörlerinin tedavisinde yaygın olarak kullanılan, oldukça etkili bir kemoterapötik ajandır. Ancak klinik kullanımını sınırlayan yan etkileri mevcuttur ve bunların arasında kardiyotoksisite son yıllarda özellikle gündeme gelmiştir. Kardiyotoksisite gelişimine katkı sağlayan en önemli mekanizmaların da oksidatif ve nitrozatif stres olduğu öne sürülmektedir. Dolayısıyla kardiyotoksisitenin önüne geçilmesinde antioksidanların kullanımı ön plana çıkmaktadır. Klinikte farklı patolojilerde yaygın olarak kullanılan N-asetilsistein (NAC), doğrudan radikal yakalayıcı olarak ve/veya hücre içi redükte glutatyon düzeylerini artırarak etki gösteren güçlü bir antioksidandır. Bu çalışmada, NAC’ın ratlarda sisplatinle indüklenen kardiyotoksisite üzerine etkilerinin araştırılması amaçlanmıştır. Yöntem: Bu amaçla, her grupta sekiz hayvan olmak üzere, ratlar dört gruba ayrıldı: KONT, NAC-250, CP ve CP+NAC. Sisplatin uygulaması intraperitoneal (ip) tek doz, 10 mg/kg rat ağırlığı ve NAC uygulaması ip, ardışık üç gün, 250 mg/kg rat ağırlığı şeklinde yapıldı. Kan örneklerinde CK, CK-MB, İskemi Modifiye Albümin (İMA); doku örneklerinde 4-Hidroksinonenal (4-HNE) ve 3-Nitrotirozin (3-NT) seviyeleri ölçüldü. Bulgular: CP grubunda kontrole göre artan CK ve CK-MB düzeyleri ile kardiyotoksisite gelişimi gösterildi. Yine CP grubunda İMA, 4-HNE ve 3-NT seviyelerinin de arttığı ortaya konuldu. Bununla birlikte sisplatin ile birlikte NAC uygulaması ile tüm parametrelerde anlamlı azalma gösterildi. Sonuç: Sisplatin kardiyotoksisitesi gelişiminde oksidatif ve nitrozatif stresin rol oynadığı; bu toksik tabloyu önlemede, NAC’ın etkili bir kemoprotektan ajan olarak kullanılabileceği söylenebilir.

Anahtar Kelimeler

Rat , sisplatin , oksidatif stres , nitrozatif stres , N-asetilsistein

Proje Numarası

TTU-2015-6134

The role of oxidative and nitrozative stress in sisplatin cardiotoxicity

Öz

Objective: Cisplatin is a highly effective chemotherapeutic agent widely used in the treatment of solid organ tumors. However, there are side effects that limit its clinical use and among them, cardiotoxicity has been particularly on the agenda in recent years. It is suggested that the most important mechanisms that contribute to the development of cardiotoxicity are oxidative and nitrosative stress. Therefore, the use of antioxidants comes to the fore in preventing cardiotoxicity. N-acetylcysteine (NAC), widely used in different pathologies in the clinic, is a powerful antioxidant that acts as a direct radical trap and/or by increasing intracellular reduced glutathione levels. In the current study, it was aimed to investigate the effects of NAC on cisplatin-induced cardiotoxicity in rats. Methods: For this purpose, rats were divided into four groups, eight animals in each group: CONT, NAC-250, CP, and CP+NAC. Cisplatin administration was performed as intraperitoneal (IP) single dose, 10 mg/kg rat weight and NAC administration IP, 3 consecutive days, 250 mg/kg rat weight. In blood samples, CK, CK-MB, and Ischemia Modified Albumin (IMA) levels; in tissue samples, 4-Hydroxynonenal (4-HNE) and 3-Nitrotyrosine (3-NT) levels were measured. Results: in the CP group cardiotoxicity development was demonstrated with increased CK and CK-MB levels compared to the control. It was also demonstrated that IMA, 4-HNE and 3-NT levels increased in the CP group. However, NAC administration with cisplatin showed a significant decrease in all parameters. Conclusion: Oxidative and nitrosative stress played a role in the development of cisplatin cardiotoxicity; It can be said that NAC can be used as an effective chemoprotectant agent in preventing this toxic picture.

Anahtar Kelimeler

Rat , cisplatin , oxidative stress , nitrosative stress , N-acetylcysteine

Destekleyen Kurum

Erciyes Ünv. Bap Birimi

Proje Numarası

TTU-2015-6134

Kaynakça

• 1. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol 2014;740:364-378.
• 2. Perše M, Večerić-Haler Ž. Cisplatin-induced rodent model of kidney injury: characteristics and challenges. Biomed Res Int. 2018 Sep 12;2018:1462802. doi: 10.1155/2018/1462802. eCollection 2018.
• 3. Demkow U, Stelmaszczyk-Emmel A. Cardiotoxicity of cisplatin-based chemotherapy in advanced non-small cell lung cancer patients. Respir Physiol Neurobiol 2013;187(1):64-67.
• 4. Rosic G, Selakovic D, Joksimovic J, Srejovic I, Zivkovic V, Tatalović N, Orescanin-Dusic Z, Mitrovic S, Ilic M, Jakovljevic V. The effects of N-acetylcysteine on cisplatin-induced changes of cardiodynamic parameters within coronary autoregulation range in isolated rat hearts. Toxicol Lett 2016;242:34-46.
• 5. Patanè S. Cardiotoxicity: cisplatin and long-term cancer survivors. Int J Cardiol 2014;175(1):201-202.
• 6. Vincent DT, Ibrahim YF, Espey MG, Suzuki YJ. The role of antioxidants in the era of cardio-oncology. Cancer Chemother Pharmacol 2013;72(6):1157-1168.
• 7. O'Hare M, Sharma A, Murphy K, Mookadam F, Lee H. Cardio-oncology Part I: chemotherapy and cardiovascular toxicity. Expert Rev Cardiovasc Ther 2015;13(5):511-518.
• 8. Florea A-M, Büsselberg D. Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and ınduced side effects. Cancers 2011;3(1):1351-1371.
• 9. Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardiooncological prevention. J Natl Cancer Inst 2010;102(1):14-25.
• 10. Hussein A, Ahmed AA, Shouman SA, Sharawy S. Ameliorating effect of DL-α-lipoic acid against cisplatin-induced nephrotoxicity and cardiotoxicity in experimental animals. Drug Discov Ther 2012;6(3):147-156.
• 11. Luo J, Tsuji T, Yasuda H, Sun Y, Fujigaki Y, Hishida A. The molecular mechanisms of the attenuation of cisplatin-induced acute renal failure by N-acetylcysteine in rats. Nephrol Dial Transplant 2008;23(7):2198–2205.
• 12. Muldoon LL, Wu YJ, Pagel MA, Neuwelt EA. N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models. J Neurooncol 2015;121(3):433-440.
• 13. Lowry HO, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951;193(1):265–275.
• 14. Bar-Or D, Lau E, Winkler JV. A novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia-a preliminary report. J Emerg Med 2000;19(4):311-315.
• 15. Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol 2010;7(10):564-75.
• 16. El-Sawalhi MM, Ahmed LA. Exploring the protective role of apocynin, a specific NADPH oxidase inhibitor, in cisplatin-induced cardiotoxicity in rats. Chem Biol Interact 2014;207:58-66.
• 17. Xing JJ, Hou JG, Liu Y, Zhang RB, Jiang S, Ren S, Wang YP, Shen Q, Li W, Li XD, Wang Z. Supplementation of saponins from leaves of panax quinquefolius mitigates cisplatin-evoked cardiotoxicity via inhibiting oxidative stress-associated inflammation and apoptosis in mice. Antioxidants (Basel) 2019;8(9). pii: E347. doi: 10.3390/ antiox8090347.
• 18. Castro JP, Jung T, Grune T, Siems W. 4-Hydroxynonenal (HNE) modified proteins in metabolic diseases. Free Radic Biol Med 2017;111:309-315.
• 19. Sahin K, Tuzcu M, Gencoglu H, Dogukan A, Timurkan M, Sahin N, Aslan A, Kucuk O. Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. Life Sci 2010;87(7-8):240-245.
• 20. Razo-Rodríguez AC, Chirino YI, Sánchez-González DJ, Martínez-Martínez CM, Cruz C, Pedraza-Chaverri J. Garlic powder ameliorates cisplatin-induced nephrotoxicity and oxidative stress. J Med Food 2008;11(3):582-586.
• 21. Topal İ, Özbek Bilgin A, Keskin Çimen F, Kurt N, Süleyman Z, Bilgin Y, Özçiçek A, Altuner D. The effect of rutin on cisplatin-induced oxidative cardiac damage in rats. Anatol J Cardiol 2018;20(3):136-142.
• 22. Collinson PO, Gaze DC. Ischaemia-modified albumin: clinical utility and pitfalls in measurement. J Clin Pathol 2008;61(9):1025-1028.
• 23. Coverdale JPC, Katundu KGH, Sobczak AIS, Arya S, Blindauer CA, Stewart AJ. Ischemia-modified albumin: Crosstalk between fatty acid and cobalt binding. Prostaglandins Leukot Essent Fatty Acids 2018;135:147-157.
• 24. Yuluğ E, Türedi S, Yıldırım Ö, Yenilmez E, Aliyazıcıoğlu Y, Demir S, Özer-Yaman S, Menteşe A. Biochemical and morphological evaluation of the effects of propolis on cisplatin induced kidney damage in rats. Biotech Histochem 2019 ;94(3): 204-213.
• 25. Güneş S, Sahinturk V, Karasati P, Sahin IK, Ayhanci A. Cardioprotective effect of selenium against cyclophosphamide-induced cardiotoxicity in rats. Biol Trace Elem Res 2017;177(1):107-114.
• 26. Ahsan H. 3-Nitrotyrosine: A biomarker of nitrogen free radical species modified proteins in systemic autoimmunogenic conditions. Hum Immunol 2013;74(10):1392-1399.
• 27. Trujillo J, Molina-Jijón E, Medina-Campos ON, Rodríguez-Muñoz R, Reyes JL, Loredo ML, Tapia E, Sánchez-Lozada LG, Barrera-Oviedo D, Pedraza-Chaverri J. Renal tight junction proteins are decreased in cisplatin-induced nephrotoxicity in rats. Toxicol Mech Methods 2014;24(7):520-528.
• 28. Chirino YI, Pedraza-Chaverri J. Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp Toxicol Pathol 2009;61(3):223-242.
• 29. Samuni Y, Goldstein S, Dean OM, Berk M. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta 2013;1830:(8):4117-4129.
• 30. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 2007;7(4): 355-359.
• 31. Zafarullah M, Li WQ, Sylvester J. Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cellular and Molecular Life Sciences 2003;60(1):6-20.
• 32. Oun R, Moussa YE, Wheate NJ. The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans 2018;47(19):6645-6653.
• 33. Wu YJ, Muldoon LL, Neuwelt EA. The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J Pharmacol Exp Ther 2005;312(2):424–431.
• 34. Nematbakhsh M, Pezeshki Z. Sex-Related Difference in Nitric Oxide Metabolites Levels after Nephroprotectant Supplementation Administration against Cisplatin-Induced Nephrotoxicity in Wistar Rat Model: The Role of Vitamin E, Erythropoietin, or N-Acetylcysteine. ISRN Nephrol. 2013;2013:612675.
• 35. Huang S, You J, Wang K, Li Y, Zhang Y, Wei H, Liang X, Liu Y. N-Acetylcysteine attenuates cisplatin-induced acute kidney injury by inhibiting the C5a receptor. Biomed Res Int 2019;2019:4805853.