Download PDF
CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2015; 36(04): 243-248
DOI: 10.4103/0971-5851.171545
ORIGINAL ARTICLE

N-acetylcysteine renoprotection in methotrexate induced nephrotoxicity and its effects on B-cell lymphoma

Ruchi Singh
Texas Tech Health Sciences Center, Amarillo, Texas 97106, USA
,
Rikin Shah
Texas Tech Health Sciences Center, Amarillo, Texas 97106, USA
,
Curtis Turner
Texas Tech Health Sciences Center, Amarillo, Texas 97106, USA
,
Osvaldo Regueira
Baylor College of Medicine, Houston, Texas 77030, USA
,
Tetyana L. Vasylyeva
Texas Tech Health Sciences Center, Amarillo, Texas 97106, USA
› Author Affiliations Financial support and sponsorship Nil.
› Further Information
  PDF Download Permissions and Reprints

Abstract

Background: Nephrotoxicity is one of the known side effects of methotrexate (MTX) therapy despite the use of conventional protective measures. Our objectives were to evaluate the effects of N-acetylcysteine (NAC) on MTX-induced toxicity in renal tubular cells and to evaluate whether adjunctive use of NAC interferes with MTX antitumor activity in the B-cell lymphoma. Methods: Kidney Epithelial (Madin-Darby canine kidney [MDCK]) cells were exposed to MTX (10 μM or 100 μM) alone and with NAC (0.2 mM or 0.4 mM). Reactive oxygen species (ROS) generation at 1, 2, 4, and 24 h was measured by flow cytometer. Quantification of total glutathione (GSH) was performed by using GSH assay kit. To measure the impact of NAC on the antitumor activity of MTX, B lymphoma cells were exposed to MTX alone and with NAC. A percentage of apoptosis was measured using fluorescein isothiocyanate in both cell lines. Quantitative data was presented as a means ± standard deviation, and P values were analyzed using the Student′s t-test. Results: Apoptosis in MDCK cells were observed after 24 h of incubation with both 10 μM and 100 μM MTX. Maximum ROS generation was observed at 4 h and corresponded to GSH production. Treatment with 0.2 and 0.4 mM of NAC led to decrease percentages of apoptotic MDCK cells. NAC did not change either proliferation or apoptosis of B-cell lymphoma. Conclusion: Using NAC for kidney protection may not interfere with the antitumor activity of MTX. Further in vivo studies are warranted to confirm noninterference between MTX and NAC and assess synergistic antitumor effects.

Keywords

B-cell lymphoma - Madin-Darby canine kidney epithelial cells - methotrexate - N-acetylcysteine - nephrotoxicity


Publication History

Article published online:
12 July 2021

© 2015. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

 

  • References

  • 1 Çaglar Y, Özgür H, Matur I, Yenilmez ED, Tuli A, Gönlüsen G, et al. Ultrastructural evaluation of the effect of N-acetylcysteine on methotrexate nephrotoxicity in rats. Histol Histopathol 2013;28:865-74.
  • 2 Dalaklioglu S, Sahin P, Ordueri EG, Celik-Ozenci C, Tasatargil A. Potential role of poly(ADP-ribose) polymerase (PARP) activation in methotrexate-induced nephrotoxicity and tubular apoptosis. Int J Toxicol 2012;31: 430-40.
  • 3 Grönroos MH, Jahnukainen T, Möttönen M, Perkkiö M, Irjala K, Salmi TT. Long-term follow-up of renal function after high-dose methotrexate treatment in children. Pediatr Blood Cancer 2008;51:535-9.
  • 4 Chen N, Aleksa K, Woodland C, Rieder M, Koren G. N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats. Br J Pharmacol 2008;153:1364-72.
  • 5 Crom WR, Evans WE. Methotrexate. In: Evans WE, Schentag JJ, Jusko WJ, editors. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. LWW; Fourth edition (May 19, 2005); 1992. p. 29-1-29-42.
  • 6 Aboleneen H, Simpson J, Backes D. Determination of methotrexate in serum by high-performance liquid chromatography. J Chromatogr B Biomed Appl 1996; 681:317-22.
  • 7 Chan WH, Wu CC, Yu JS. Curcumin inhibits UV irradiation-induced oxidative stress and apoptotic biochemical changes in human epidermoid carcinoma A431 cells. J Cell Biochem 2003;90:327-38.
  • 8 Piskunova TS, Yurova MN, Ovsyannikov AI, Semenchenko AV, Zabezhinski MA, Popovich IG, et al. Deficiency in poly (ADP-ribose) polymerase-1 (PARP-1) accelerates aging and spontaneous carcinogenesis in mice. Curr Gerontol Geriatr Res 2008;2008:754190.
  • 9 Kelly GS. Clinical applications of N-acetylcysteine. Altern Med Rev 1998;3:114-27.
  • 10 De Vries N, De Flora S. N-acetyl-l-cysteine. J Cell Biochem Suppl 1993;17F:270-7.
  • 11 De Flora S, Bennicelli C, Camoirano A, Serra D, Romano M, Rossi GA, et al. In vivo effects of N-acetylcysteine on glutathione metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds. Carcinogenesis 1985;6:1735-45.
  • 12 Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcystine: The treatment of choice for paracetamol poisoning. Br Med J 1979;2:1097-100.
  • 13 Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet 1977;2:432-4.
  • 14 Sehirli AO, Sener G, Satiroglu H, Ayanoglu-Dülger G. Protective effect of N-acetylcysteine on renal ischemia/reperfusion injury in the rat. J Nephrol 2003;16:75-80.
  • 15 Mishima K, Baba A, Matsuo M, Itoh Y, Oishi R. Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity. Free Radic Biol Med 2006;40:1564-77.
  • 16 Tariq M, Morais C, Sobki S, Al Sulaiman M, Al Khader A. N-acetylcysteine attenuates cyclosporin-induced nephrotoxicity in rats. Nephrol Dial Transplant 1999;14:923-9.
  • 17 Momeni A, Hajigholami A, Geshnizjani S, Kheiri S. Effect of silymarin in the prevention of Cisplatin nephrotoxicity, a clinical trial study. J Clin Diagn Res 2015;9:OC11-3.
  • 18 Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist 2006;11:694-703.
  • 19 Chan AJ, Rajakumar I. High-dose methotrexate in adult oncology patients: A case-control study assessing the risk association between drug interactions and methotrexate toxicity. J Oncol Pharm Pract 2014;20:93-9.
  • 20 Skärby T, Jönsson P, Hjorth L, Behrentz M, Björk O, Forestier E, et al. High-dose methotrexate: On the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL). Cancer Chemother Pharmacol 2003;51:311-20.
  • 21 Deray G, Khayat D, Cacoub P, Bourbouze R, Musset L, Baumelou A, et al. The effects of diltiazem on methotrexate-induced nephrotoxicity. Eur J Clin Pharmacol 1989;37:337-40.
  • 22 Perazella MA. Crystal-induced acute renal failure. Am J Med 1999;106:459-65.
  • 23 Genestier L, Paillot R, Quemeneur L, Izeradjene K, Revillard JP. Mechanisms of action of methotrexate. Immunopharmacology 2000;47:247-57.
  • 24 Pias EK, Aw TY. Early redox imbalance mediates hydroperoxide-induced apoptosis in mitotic competent undifferentiated PC-12 cells. Cell Death Differ 2002;9:1007-16.