International Journal of Cancer Management

Published by: Kowsar

Modulatory Effects of Dexrazoxane Against Genotoxicity and Lipid Peroxidation Induced by Idarubicin in HepG2 Cells

Farzane Zarifi 1 , Mahmoud Etebari 1 , * and Abbas Jafarian- Dehkordi 1
Authors Information
1 Department of Pharmacology and Toxicology, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
Article information
  • International Journal of Cancer Management: January 2018, 11 (1); e9675
  • Published Online: January 14, 2018
  • Article Type: Research Article
  • Received: December 7, 2016
  • Revised: January 17, 2017
  • Accepted: January 9, 2018
  • DOI: 10.5812/ijcm.9675

How to Cite: Zarifi F, Etebari M, Jafarian- Dehkordi A. Modulatory Effects of Dexrazoxane Against Genotoxicity and Lipid Peroxidation Induced by Idarubicin in HepG2 Cells, Int J Cancer Manag. 2018 ; 11(1):e9675. doi: 10.5812/ijcm.9675.

Copyright © 2018, Cancer Research Center (CRC), Shahid Beheshti University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited
1. Background
2. Methods
3. Results
4. Discussion
  • 1. Eastman A, Barry MA. The origins of DNA breaks: a consequence of DNA damage, DNA repair, or apoptosis?. Cancer Invest. 1992;10(3):229-40. [PubMed: 1316202].
  • 2. Bates DA, Winterbourn CC. Deoxyribose breakdown by the adriamycin semiquinone and H2O2: evidence for hydroxyl radical participation. FEBS Letters. 1982;145(1):137-42. doi: 10.1016/0014-5793(82)81222-2.
  • 3. Muindi JRF, Sinha BK, Gianni L, Myers CE. Hydroxyl radical production and DNA damage induced by anthracycline-iron complex. FEBS Letters. 1984;172(2):226-30. doi: 10.1016/0014-5793(84)81130-8.
  • 4. Gutteridge JM, Quinlan GJ. Free radical damage to deoxyribose by anthracycline, aureolic acid and aminoquinone antitumour antibiotics. An essential requirement for iron, semiquinones and hydrogen peroxide. Biochem Pharmacol. 1985;34(23):4099-103. [PubMed: 2998399].
  • 5. Griffin-Green EA, Zaleska MM, Erecinska M. Adriamycin-induced lipid peroxidation in mitochondria and microsomes. Biochem Pharmacol. 1988;37(16):3071-7. [PubMed: 3401238].
  • 6. Fumiyasu F, Mitsuo K, Toshiharu H, Shoji A. Evaluation of adriamycin-induced lipid peroxidation. Biochemical Pharmacol. 1992;44(4):755-60. doi: 10.1016/0006-2952(92)90413-d.
  • 7. Earnshaw WC, Halligan B, Cooke CA, Heck MM, Liu LF. Topoisomerase II is a structural component of mitotic chromosome scaffolds. J Cell Biol. 1985;100(5):1706-15. [PubMed: 2985625].
  • 8. Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999;57(7):727-41. [PubMed: 10075079].
  • 9. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56(2):185-229. doi: 10.1124/pr.56.2.6. [PubMed: 15169927].
  • 10. Dos Santos N, Waterhouse D, Masin D, Tardi PG, Karlsson G, Edwards K, et al. Substantial increases in idarubicin plasma concentration by liposome encapsulation mediates improved antitumor activity. J Control Release. 2005;105(1-2):89-105. doi: 10.1016/j.jconrel.2005.03.007. [PubMed: 15878792].
  • 11. Lu T, Lokerse WJM, Seynhaeve ALB, Koning GA, Ten Hagen TLM. Formulation and optimization of idarubicin thermosensitive liposomes provides ultrafast triggered release at mild hyperthermia and improves tumor response. J Control Release. 2015;220(Pt A):425-37. doi: 10.1016/j.jconrel.2015.10.056. [PubMed: 26541464].
  • 12. Ozluer C, Kara HE. In vitro DNA binding studies of anticancer drug idarubicin using spectroscopic techniques. J Photochem Photobiol B. 2014;138:36-42. doi: 10.1016/j.jphotobiol.2014.05.015. [PubMed: 24911270].
  • 13. Boogerd W, Tjahja IS, van de Sandt MM, Beijnen JH. Penetration of idarubicin into malignant brain tumor tissue. J Neurooncol. 1999;44(1):65-9. [PubMed: 10582671].
  • 14. Chitra P, Saiprasad G, Manikandan R, Sudhandiran G. Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-kappaB dependant TGF-beta activation: a biphasic experimental study. Toxicol Lett. 2013;219(2):178-93. doi: 10.1016/j.toxlet.2013.03.009. [PubMed: 23523906].
  • 15. Vogler WR, Velez-Garcia E, Weiner RS, Flaum MA, Bartolucci AA, Omura GA, et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol. 1992;10(7):1103-11. doi: 10.1200/JCO.1992.10.7.1103. [PubMed: 1607916].
  • 16. Ames M, Spreafico F. Selected pharmacologic characteristics of idarubicin and idarubicinol. 6 ed. Leukemia; 1991. p. 70-5.
  • 17. Ma P, Dong X, Swadley CL, Gupte A, Leggas M, Ledebur HC, et al. Development of idarubicin and doxorubicin solid lipid nanoparticles to overcome Pgp-mediated multiple drug resistance in leukemia. J Biomed Nanotechnol. 2009;5(2):151-61. [PubMed: 20055093].
  • 18. Von Hoff D, Howser D, Lewis B, Holcenberg J, Weiss R, Young R. Phase I study of ICRF-187 using a daily for 3 days schedule. Cancer treatment reports. 1980;65(3-4):249-52.
  • 19. Jones RL. Utility of dexrazoxane for the reduction of anthracycline-induced cardiotoxicity. Expert Rev Cardiovasc Ther. 2008;6(10):1311-7. doi: 10.1586/14779072.6.10.1311. [PubMed: 19018683].
  • 20. Pearlman M, Jendiroba D, Pagliaro L, Keyhani A, Liu B, Freireich EJ. Dexrazoxane in combination with anthracyclines lead to a synergistic cytotoxic response in acute myelogenous leukemia cell lines. Leukemia Res. 2003;27(7):617-26. doi: 10.1016/s0145-2126(02)00273-4.
  • 21. Cvetkovic RS, Scott LJ. Dexrazoxane : a review of its use for cardioprotection during anthracycline chemotherapy. Drugs. 2005;65(7):1005-24. [PubMed: 15892593].
  • 22. Malisza KL, Hasinoff BB. Inhibition of anthracycline semiquinone formation by ICRF-187 (Dexrazoxane) in cells. Free Radical Biol Med. 1996;20(7):905-14. doi: 10.1016/0891-5849(95)02188-4.
  • 23. Hasinoff BB, Kuschak TI, Yalowich JC, Creighton AM. A QSAR study comparing the cytotoxicity and DNA topoisomerase II inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane). Biochem Pharmacol. 1995;50(7):953-8. [PubMed: 7575679].
  • 24. Galetta F, Franzoni F, Cervetti G, Regoli F, Fallahi P, Tocchini L, et al. In vitro and in vivo study on the antioxidant activity of dexrazoxane. Biomed Pharmacother. 2010;64(4):259-63. doi: 10.1016/j.biopha.2009.06.018. [PubMed: 19932589].
  • 25. Conde-Estevez D, Mateu-de Antonio J. Treatment of anthracycline extravasations using dexrazoxane. Clin Transl Oncol. 2014;16(1):11-7. doi: 10.1007/s12094-013-1100-7. [PubMed: 23949792].
  • 26. Sassi A, Bouhlel I, Mustapha N, Mokdad-Bzeouich I, Chaabane F, Ghedira K, et al. Assessment in vitro of the genotoxicity, antigenotoxicity and antioxidant of Ceratonia siliqua L. extracts in murine leukaemia cells L1210 by comet assay. Regul Toxicol Pharmacol. 2016;77:117-24. doi: 10.1016/j.yrtph.2016.02.009. [PubMed: 26946406].
  • 27. Ghassemi-Barghi N, Varshosaz J, Etebari M, Jafarian Dehkordi A. Role of recombinant human erythropoietin loading chitosan-tripolyphosphate nanoparticles in busulfan-induced genotoxicity: Analysis of DNA fragmentation via comet assay in cultured HepG2 cells. Toxicol In Vitro. 2016;36:46-52. doi: 10.1016/j.tiv.2016.07.001. [PubMed: 27395035].
  • 28. Tice RR, Agurell E, Anderson D, Burlinson B, Hartmann A, Kobayashi H, et al. Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen. 2000;35(3):206-21. [PubMed: 10737956].
  • 29. Attia SM, Al-Anteet AA, Al-Rasheed NM, Alhaider AA, Al-Harbi MM. Protection of mouse bone marrow from etoposide-induced genomic damage by dexrazoxane. Cancer Chemother Pharmacol. 2009;64(4):837-45. doi: 10.1007/s00280-009-0934-8. [PubMed: 19184016].
  • 30. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351-8. [PubMed: 36810].
  • 31. Markwell MA, Haas SM, Bieber LL, Tolbert NE. A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem. 1978;87(1):206-10. [PubMed: 98070].
  • 32. Singh NP, McCoy MT, Tice RR, Schneider EL. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res. 1988;175(1):184-91. [PubMed: 3345800].
  • 33. Graham MA, Newell DR, Butler J, Hoey B, Patterson LH. The effect of the anthrapyrazole antitumour agent CI941 on rat liver microsome and cytochrome P-450 reductase mediated free radical processes. Inhibition of doxorubicin activation in vitro. Biochem Pharmacol. 1987;36(20):3345-51. [PubMed: 2823819].
  • 34. Nitiss JL, Liu YX, Hsiung Y. A temperature sensitive topoisomerase II allele confers temperature dependent drug resistance on amsacrine and etoposide: a genetic system for determining the targets of topoisomerase II inhibitors. Cancer Res. 1993;53(1):89-93. [PubMed: 8380128].
  • 35. Gieseler F, Nussler V, Brieden T, Kunze J, Valsamas S. Intracellular pharmacokinetics of anthracyclines in human leukemia cells: correlation of DNA-binding with apoptotic cell death. Int J Clin Pharmacol Ther. 1998;36(1):25-8. [PubMed: 9476145].
  • 36. Lips J, Kaina B. DNA double-strand breaks trigger apoptosis in p53-deficient fibroblasts. Carcinogenesis. 2001;22(4):579-85. [PubMed: 11285192].
  • 37. Bakheet SA, Attia SM, Al-Rasheed NM, Al-Harbi MM, Ashour AE, Korashy HM, et al. Salubrious effects of dexrazoxane against teniposide-induced DNA damage and programmed cell death in murine marrow cells. Mutagenesis. 2011;26(4):533-43. doi: 10.1093/mutage/ger013. [PubMed: 21430063].
  • 38. Attia SM, Ahmad SF, Saquib Q, Harisa GI, Al-Khedhairy AA, Bakheet SA. Dexrazoxane mitigates epirubicin-induced genotoxicity in mice bone marrow cells. Mutagenesis. 2016;31(2):137-45. doi: 10.1093/mutage/gev065. [PubMed: 26399706].
  • 39. Hochster H, Liebes L, Wadler S, Oratz R, Wernz JC, Meyers M, et al. Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin. J Natl Cancer Inst. 1992;84(22):1725-30. [PubMed: 1433357].
  • 40. Roti Roti EC, Salih SM. Dexrazoxane ameliorates doxorubicin-induced injury in mouse ovarian cells. Biol Reprod. 2012;86(3):96. doi: 10.1095/biolreprod.111.097030. [PubMed: 22190700].
  • 41. Mateos R, Goya L, Bravo L. Determination of malondialdehyde by liquid chromatography as the 2,4-dinitrophenylhydrazone derivative: a marker for oxidative stress in cell cultures of human hepatoma HepG2. J Chromatogr B Analyt Technol Biomed Life Sci. 2004;805(1):33-9. doi: 10.1016/j.jchromb.2004.02.004. [PubMed: 15113537].
  • 42. Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. Future Cardiol. 2012;8(4):647-70. doi: 10.2217/fca.12.44. [PubMed: 22871201].
Creative Commons License Except where otherwise noted, this work is licensed under Creative Commons Attribution Non Commercial 4.0 International License .

Search Relations:



Create Citiation Alert
via Google Reader

Readers' Comments