Neurochemical Research

, Volume 35, Issue 3, pp 437–443 | Cite as

Protective Effects of Acetyl-l-Carnitine on Cisplatin Cytotoxicity and Oxidative Stress in Neuroblastoma

  • Zekiye Sultan Altun
  • Dilek Güneş
  • Safiye Aktaş
  • Zübeyde Erbayrktar
  • Nur Olgun
Original Paper


The most widely used platinum-derived drug is cisplatin in neuroblastoma (NB) chemotherapy, which is severely neurotoxic. Acetyl-l-Carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms. The aim of this study was to determine the effects of ALC on cisplatin induced cytotoxicity and oxidative stress in NB cells. SH-SY5Y (N-Myc negative) and KELLY (N-Myc positive) human NB cell lines were used. Cisplatin induced apoptosis was assessed by using a Cell Death Detection ELISAPLUS kit. Lipid peroxidation levels were determined by HPLC analysis. Glutathione levels were determined spectrophotometrically. ALC was used prophylactic or after cisplatin application. The level of cisplatin doses were determined in both type of NB cells at which 50% cell death occurred along with synchronized apoptosis induced. Prophylactic 10 and 50 μmol of ALC concentrations were decreased cisplatin induced lipid peroxidation compared to controls that normally exhibited apoptosis especially in SH-SY5Y cells. Cisplatin caused oxidative stress through decreasing glutathione levels in both cell types. ALC were effectively inhibited the increase in cisplatin induced oxidized glutathione and lipid peroxidation formation in NB cells. We suggested that prophylactic ALC would be a useful agent for cisplatin induced toxicity in NB cells.


Acetyl-l-carnitine Cisplatin toxicity Neuroblastoma Neuroprotection Apoptosis Oxidative stress 



This study was supported by a grant from Dokuz Eylul University Research Foundation (Project 2007.KB.SAG.022). This research has been carried out at Dokuz Eylul University Medical School Learning Resources Centre Research Laboratory and Dokuz Eylul University Institute of Oncology Basic Oncology Laboratory.


  1. 1.
    Quasthoff S, Hartung HP (2002) Chemotherapy-induced peripheral neuropathy. J Neurol 249:9–17CrossRefPubMedGoogle Scholar
  2. 2.
    Meijer C, de Vries EG, Marmiroli P et al (1999) Cisplatin-induced DNA-platination in experimental dorsal root ganglia neuronopathy. Neurotoxicology 20:883–887PubMedGoogle Scholar
  3. 3.
    Huang H, Zhu L, Reid BR et al (1995) Solution structure of a cisplatin-induced DNA interstrand cross-link. Science 270:1842–1845CrossRefPubMedGoogle Scholar
  4. 4.
    Donzelli E, Carfì M, Miloso M et al (2004) Neurotoxicity of platinum compounds: comparison of the effects of cisplatin and oxaliplatin on the human neuroblastoma cell line SH-SY5Y. J Neurooncol 67:65–73CrossRefPubMedGoogle Scholar
  5. 5.
    Albers J, Chaudhry V, Cavaletti G, Donehower R (2007) Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev CD005228Google Scholar
  6. 6.
    De Grandis D (2007) Acetyl-l-carnitine for the treatment of chemotherapy-induced peripheral neuropathy: a short review. CNS Drugs 21(Suppl 1):39–43 discussion 45-6CrossRefPubMedGoogle Scholar
  7. 7.
    Fritz IB (1963) Carnitine and its role in fatty acid metabolism. Adv Lipid Res 1:285–334PubMedGoogle Scholar
  8. 8.
    Bremer J (1983) Carnitine metabolism and functions. Physiol Rev 63:1420–1480PubMedGoogle Scholar
  9. 9.
    Stanley CA (1987) New genetic defects in mitochondrial fatty acid oxidation and carnitine deficiency. Adv Pediatr 34:59–88PubMedGoogle Scholar
  10. 10.
    Bieber LL (1988) Carnitine. Annu Rev Biochem 57:261–283CrossRefPubMedGoogle Scholar
  11. 11.
    Zhang H, Jia H, Liu J et al (2008) Combined R-alpha-lipoic acid and acetyl-l-carnitine exerts efficient preventative effects in a cellular model of Parkinson’s disease. J Cell Mol Med 2008 Jun 20 [Epub ahead of print]Google Scholar
  12. 12.
    Lowitt S, Malone JI, Salem AF et al (1995) Acetyl-l-carnitine corrects the altered peripheral nerve function of experimental diabetes. Metabolism 44:677–680CrossRefPubMedGoogle Scholar
  13. 13.
    Di Giulio AM, Lesma E, Gorio A (1995) Diabetic neuropathy in the rat: 1. Alcar augments the reduced levels and axoplasmic transport of substance P. J Neurosci Res 40:414–419CrossRefPubMedGoogle Scholar
  14. 14.
    Kano M, Kawakami T, Hori H et al (1999) Effects of ALCAR on the fast axoplasmic transport in cultured sensory neurons of streptozotocin-induced diabetic rats. Neurosci Res 33:207–213CrossRefPubMedGoogle Scholar
  15. 15.
    Fernandez E, Pallini R, Tamburrini G et al (1995) Effects of levo-acetylcarnitine on second motorneuron survival after axotomy. Neurol Res 17:373–376PubMedGoogle Scholar
  16. 16.
    Kadikoylu G, Bolaman Z, Demir S et al (2004) The effects of desferrioxamine on cisplatin-induced lipid peroxidation and the activities of antioxidant enzymes in rat kidneys. Hum Exp Toxicol 23:29–34CrossRefPubMedGoogle Scholar
  17. 17.
    Rybak LP, Husain K, Morris C et al (2000) Effect of protective agents against cisplatin ototoxicity. Am J Otol 21:513–520PubMedGoogle Scholar
  18. 18.
    Das B, Yeger H, Baruchel H et al (2003) In vitro cytoprotective activity of squalene on a bone marrow versus neuroblastoma model of cisplatin-induced toxicity implications in cancer chemotherapy. Eur J Cancer 39:2556–2565CrossRefPubMedGoogle Scholar
  19. 19.
    Olgun N, Kansoy S, Aksoylar S et al (2003) Experience of the Izmir Pediatric Oncology Group on neuroblastoma: IPOG-NBL-92 Protocol. Pediatr Hematol Oncol 20:211–218PubMedGoogle Scholar
  20. 20.
    Ross RA, Spengler BA, Biedler JL (1983) Coordinate morphological and biochemical interconversion of human neuroblastoma cells. J Natl Cancer Inst 71:741–747PubMedGoogle Scholar
  21. 21.
    Nicolini G, Miloso M, Zoia C et al (1998) Retinoic acid differentiated SH-SY5Y human neuroblastoma cells: an in vitro model to assess drug neurotoxicity. Anticancer Res 18:2477–2481PubMedGoogle Scholar
  22. 22.
    Nicolini G, Rigolio R, Miloso M et al (2001) Anti-apoptotic effect of trans-resveratrol on paclitaxel-induced apoptosis in the human neuroblastoma SH-SY5Y cell line. Neurosci Lett 302:41–44CrossRefPubMedGoogle Scholar
  23. 23.
    Greggi Antunes LM, Darin JD, Bianchi MD (2000) Protective effects of vitamin c against cisplatin-induced nephrotoxicity and lipid peroxidation in adult rats: a dose-dependent study. Pharmacol Res 41:405–411CrossRefGoogle Scholar
  24. 24.
    Rybak LP, Husain K, Whitworth C et al (1999) Dose dependent protection by lipoic acid against cisplatin-induced ototoxicity in rats: Antioxidant defense system. Toxicol Sci 47:195–202CrossRefPubMedGoogle Scholar
  25. 25.
    Fetoni AR, Quaranta N, Marchese R et al (2004) The protective role of tiopronin in cisplatin ototoxicity in Wistar rats. Int J Audiol 43:465–470CrossRefPubMedGoogle Scholar
  26. 26.
    Lykkesfeldt J (2001) Determination of malondialdehyde as dithiobarbituric acid adduct in biological samples by HPLC with fluorescence detection: comparison with ultraviolet–visible spectrophotometry. Clin Chem 47:1725–1727PubMedGoogle Scholar
  27. 27.
    Aktas S, Altun Z, Erbayraktar Z, Aygun N, Olgun N (2009) Effect of cytotoxic agents and retinoic acid on Myc-N protein expression in neuroblastoma. Appl Immunohistochem Mol Morphol 2009 Jun 22 [Epub ahead of print]. doi: 10.1097/PAI.0b013e3181aa432d
  28. 28.
    Hino K, Nishikawa M, Sato E, Inoue M (2005) l-carnitine inhibits hypoglycemia-induced brain damage in the rat. Brain Res 1053:77–87CrossRefPubMedGoogle Scholar
  29. 29.
    Kwiecień I, Rokita H, Lorenc-Koci E et al (2007) The effect of modulation of gamma-glutamyl transpeptidase and nitric oxide synthase activity on GSH homeostasis in HepG2 cells. Fundam Clin Pharmacol 21:95–103CrossRefPubMedGoogle Scholar
  30. 30.
    Mattson DM, Ahmad IM, Dayal D et al (2009) Cisplatin combined with zidovudine enhances cytotoxicity and oxidative stress in human head and neck cancer cells via a thiol-dependent mechanism. Free Radic Biol Med 46:232–237CrossRefPubMedGoogle Scholar
  31. 31.
    Qian W, Nishikawa M, Haque AM et al (2005) Mitochondrial density determines the cellular sensitivity to cisplatin-induced cell death. Am J Physiol Cell Physiol 289:1466–1475CrossRefGoogle Scholar
  32. 32.
    Das B, Antoon R, Tsuchida R et al (2008) Squalene selectively protects mouse bone marrow progenitors against cisplatin and carboplatin-induced cytotoxicity in vivo without protecting tumor growth. Neoplasia 10:1105–1119PubMedGoogle Scholar
  33. 33.
    Pisano C, Pratesi G, Laccabue D et al (2003) Paclitaxel and cisplatin-induced neurotoxicity: a protective role of acetyl-l-carnitine. Clin Cancer Res 9:5756–5767PubMedGoogle Scholar
  34. 34.
    Tufekci O, Gunes D, Özoğul C et al (2009) Evaluation of the effect of acetyl-l-carnitine on experimental cisplatin nephrotoxicity. (Article has been accepted for publication in Journal of Chemotherapy) doi: 10.1159/000240020
  35. 35.
    Aloe L, Manni L, Properzi F et al (2000) Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysis. Auton Neurosci 86:84–93CrossRefPubMedGoogle Scholar
  36. 36.
    Piovesan P, Pacifici L, Taglialatela G et al (1994) Acetyl-l-carnitine treatment increases choline acetyltransferase activity and NGF levels in the CNS of adult rats following total fimbria-fornix transection. Brain Res 633:77–82CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Zekiye Sultan Altun
    • 1
  • Dilek Güneş
    • 2
  • Safiye Aktaş
    • 1
  • Zübeyde Erbayrktar
    • 3
  • Nur Olgun
    • 2
  1. 1.Department of Basic Oncology, Institute of OncologyDokuz Eylul UniversityIzmirTurkey
  2. 2.Department of Pediatric Oncology, Institute of OncologyDokuz Eylul UniversityIzmirTurkey
  3. 3.Izmir Vocational SchoolDokuz Eylul UniversityIzmirTurkey

Personalised recommendations