Effect of N-acetylcysteine on cisplatin induced apoptosis in rat kidney

Year 2022, Volume: 47 Issue: 2, 519 - 525, 30.06.2022

Inayet Gunturk , Gönül Şeyda Seydel , Fatma Dağlı , Arzu Yay , Cevat Yazıcı , Kader Köse

Abstract

Purpose: Cisplatin is one of the most potent and widely used chemotherapeutic agents for the treatment of a wide variety of solid organ cancers. However, due to various side-effects such as nephrotoxicity, its therapeutic applications are limited. In the current study, it was aimed to investigate the effects of N-acetylcysteine (NAC), which is an effective antioxidant and anti-inflammatory agent, on cisplatin-induced apoptosis in rat kidneys.
Materials and Methods: Twentyfour male Wistar rats were separated into 4 equal groups: Control, NAC-250, cisplatin (CP), and CP+NAC groups. Rats in the experimental groups were treated with intraperitoneally (i.p.) single-dose cisplatin (10 mg/kg) and NAC (i.p., 250 mg/kg) for 3 days.
Results: At the end of the experiment, nephrotoxicity was confirmed by blood urea nitrogen and creatinine levels, and the apoptotic changes were demonstrated by TdT-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and caspase-3 levels in rat kidneys. The number of TUNEL-positive cells and caspase-3 levels were significantly increased by cisplatin. Treating the rats with NAC significantly decreased TUNEL-positive cells and caspase-3 levels.
Conclusion: These data suggest that apoptotic cell death is involved in the pathogenesis of cisplatin-induced nephrotoxicity, and that the inhibition of apoptosis plays a central role in the beneficial effects of NAC.

Keywords

Cisplatin, N-acetylcysteine, Apoptosis

Project Number

TDK-2014-5056

N-asetilsisteinin rat böbreklerinde sisplatin ile indüklenen apoptoz üzerine etkisi

Abstract

için en güçlü ve yaygın olarak kullanılan kemoterapötik ajanlardan biridirAncak nefrotoksisite gibi çeşitli yan etkileri nedeniyle terapötik uygulamaları sınırlıdır. Bu çalışmada, etkili bir antioksidan ve antienflamatuar ajan olan N-asetilsistein (NAC)’in rat böbreklerinde sisplatin kaynaklı apoptoz üzerindeki etkilerinin araştırılması amaçlanmıştır.
Gereç ve Yöntem: Wistar cinsi erkek ratlar eşit sayıda olacak şekilde 4 gruba ayrıldı: Kontrol, NAC-250, sisplatin (CP) ve CP+NAC. Gruplardaki ratlara tek doz sisplatin (10 mg/kg) ve 3 gün NAC (250 mg/kg) intraperitoneal (i.p.) olarak uygulandı.
Bulgular: Deneyin sonunda, nefrotoksisite, kan üre nitrojen ve kreatinin seviyeleri ile doğrulandı ve apoptotik değişiklikler, sıçan böbreklerinde TdT aracılı deoksiüridin trifosfat nick-end etiketleme (TUNEL) ve kaspaz-3 seviyeleri ile gösterildi. TUNEL pozitif hücre sayısı ve kaspaz-3 seviyeleri sisplatin ile önemli ölçüde arttı. Sıçanları NAC ile tedavi etmek, TUNEL pozitif hücreleri ve kaspaz-3 seviyelerini önemli ölçüde azalttı.
Sonuç: Bu veriler, apoptotik hücre ölümünün sisplatin ile indüklenen nefrotoksisitenin patogenezinde etkili olduğunu ve apoptoz inhibisyonunun NAC'ın faydalı etkilerinde merkezi bir rol oynadığını göstermektedir.

Keywords

Sisplatin, N-asetilsistein, Apoptoz

Supporting Institution

Erciyes Üniversitesi

Project Number

TDK-2014-5056

References

• 1. Dilruba S, Kalayda G. Platinum‑based drugs: past, present and future. Cancer Chemother Pharmacol. 2016; 77: 1103-1124.
• 2. Miller RP, Tadagavadi RK, Ramesh G, Reeves WB. Mechanisms of Cisplatin nephrotoxicity. Toxins (Basel). 2010; 2 (11): 2490-2518.
• 3. Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 2008; 73 (9): 994-1007.
• 4. Almanric K, Marceau N, Cantin A, Bertin É. Risk factors for nephrotoxicity associated with cisplatin. Can J Hosp Pharm. 2017; 70 (2) :99-106.
• 5. Nho JH, Jung HK, Lee MJ, Jang JH, Sim MO, Jeong DE, et al. Beneficial Effects of Cynaroside on Cisplatin-Induced Kidney Injury In Vitro and In Vivo. Toxicol Res. 2018; 34 (2): 133-141.
• 6. Lau AH. Apoptosis induced by cisplatin nephrotoxic injury. Kidney Int. 1999; 56 (4): 1295-1298.
• 7. Kaushal GP, Kaushal V, Herzog C, Yang C. Autophagy delays apoptosis in renal tubular epithelial cells in cisplatin cytotoxicity. Autophagy. 2008; 4 (5): 710-712.
• 8. Hanigan MH, Devarajan P. Cisplatin nephrotoxicity: molecular mechanisms. Cancer Ther. 2003; 1: 47-61.
• 9. Manohar S, Leung N. Cisplatin nephrotoxicity: a review of the literature. J Nephrol. 2018; 31 (1): 15-25.
• 10. Mi XJ, Hou JG, Wang Z, Han Y, Ren S, Hu JN, et al. The protective effects of maltol on cisplatin-induced nephrotoxicity through the AMPK mediated pi3k/akt and p53 signaling pathways. Sci Rep. 2018; 29: 8 (1): 15922.
• 11. Tanase DM, Gosav EM, Radu S, Costea CF, Ciocoiu M, Carauleanu A, et al. the predictive role of the biomarker kidney molecule-1 (KIM-1) in acute kidney injury (AKI) cisplatin-induced nephrotoxicity. Int J Mol Sci. 2019; 20 (20): 5238.
• 12. Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, et al. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018; 52 (7): 751-762.
• 13. 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.
• 14. Gunturk EE, Yucel B, Gunturk I, Yazici C, Yay A, Kose K. The effects of N-acetylcysteine on cisplatin induced cardiotoxicity. Bratisl Lek Listy. 2019; 120 (6): 423-428.
• 15. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry. 1951; 193: 265-275.
• 16. Sánchez-González PD, López-Hernández FJ, López-Novoa JM, Morales AI. An integrative view of the pathophysiological events leading to cisplatin nephrotoxicity. Crit Rev Toxicol. 2011; 41: 803-821.
• 17. Holditch SJ, Brown CN, Lombardi AM, Nguyen KN, Edelstein CL. Recent Advances in Models, Mechanisms, Biomarkers, and Interventions in Cisplatin-Induced Acute Kidney Injury. Int J Mol Sci. 2019; 20 (12): 3011.
• 18. Volarevic V, Djokovic B, Jankovic MG, Harrell CR, Fellabaum C, Djonov V, et al. Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity. J Biomed Sci. 2019; 26 (1): 25.
• 19. Yano T, Itoh Y, Matsuo M, Kawashiri T, Egashira N, Oishi R. Involvement of both tumor necrosis factor-alpha-induced necrosis and p53-mediated caspase-dependent apoptosis in nephrotoxicity of cisplatin. Apoptosis. 2007; 12: 1901-1909.
• 20. Guada M, Ganugula R, Vadhanam M, Ravi Kumar MNV. Urolithin A Mitigates Cisplatin-Induced Nephrotoxicity by Inhibiting Renal Inflammation and Apoptosis in an Experimental Rat Model. J Pharmacol Exp Ther. 2017; 363 (1): 58-65.
• 21. Santos NA, Catão CS, Martins NM, Curti C, Bianchi ML, Santos AC. Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Arch Toxicol. 2007; 81 (7): 495-504.
• 22. Crona DJ, Faso A, Nishijima TF, McGraw KA, Galsky MD, Milowsky MI. A Systematic Review of Strategies to Prevent Cisplatin-Induced Nephrotoxicity. Oncologist. 2017; 22 (5): 609-619.
• 23. Šalamon Š, Kramar B, Marolt TP, Poljšak B, Milisav I. Medical and Dietary Uses of N-Acetylcysteine. Antioxidants (Basel). 2019; 8(5):111.
• 24. 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.
• 25. Sancho-Martínez SM, Prieto-García L, Prieto M, Fuentes-Calvo I, López-Novoa JM, Morales AI, et al. N-acetylcysteine transforms necrosis into apoptosis and affords tailored protection from cisplatin cytotoxicity. Toxicol Appl Pharmacol. 2018; 349: 83-93.
• 26. 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.
• 27. 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.
• 28. Liu Y, Liu K, Wang N, Zhang H. N acetylcysteine induces apoptosis via the mitochondria dependent pathway but not via endoplasmic reticulum stress in H9c2 cells. Mol Med Rep. 2017; 16 (5): 6626-6633.