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Increased generation of intracellular reactive oxygen species initiates selective cytotoxicity against the MCF-7 cell line resultant from redox active combination therapy using copper–thiosemicarbazone complexes

  • Fady N. Akladios
  • Scott D. Andrew
  • Christopher J. Parkinson
Original Paper

Abstract

The combination of cytotoxic copper–thiosemicarbazone complexes with phenoxazines results in an up to 50-fold enhancement in the cytotoxic potential of the thiosemicarbazone against the MCF-7 human breast adenocarcinoma cell line over the effect attributable to drug additivity—allowing minimization of the more toxic copper–thiosemicarbazone component of the therapy. The combination of a benzophenoxazine with all classes of copper complex examined in this study proved more effective than combinations of the copper complexes with related isoelectronic azines. The combination approach results in rapid elevation of intracellular reactive oxygen levels followed by apoptotic cell death. Normal fibroblasts representative of non-cancerous cells (MRC-5) did not display a similar elevation of reactive oxygen levels when exposed to similar drug levels. The minimization of the copper–thiosemicarbazone component of the therapy results in an enhanced safety profile against normal fibroblasts.

Keywords

Copper Cytotoxicity Reactive oxygen species (ROS) Thiosemicarbazone Benzophenoxazine 

Notes

Acknowledgements

We wish to acknowledge the contribution of Dr Gregg Maynard for assistance in setting up flow cytometry studies. F Akladios acknowledges the receipt of an Australian Postgraduate Award (APA). CJP wishes to thank the CSU Pharmacy Foundation for a grant partially funding this study. CJP and SDA thank the Kolling Institute (Royal North Shore Hospital) for the donation and characterization of the MCF-7 cell line employed in this study and Dr N Proschogo (University of Sydney) for the provision of mass spectrometry expertise.

Supplementary material

775_2016_1350_MOESM1_ESM.pdf (726 kb)
Supplementary material 1 (PDF 725 kb)

References

  1. 1.
    Peña MO, Lee J, Thiele DJ (1999) J Nutr 129(7):1251–1260PubMedGoogle Scholar
  2. 2.
    Evans GW (1973) Physiol Rev 53(3):535–570PubMedGoogle Scholar
  3. 3.
    Kouremenou-Dona E, Dona A, Papoutsis J, Spiliopoulou C (2006) Sci Total Environ 359(1–3):76–81CrossRefPubMedGoogle Scholar
  4. 4.
    Kuo HW, Chen SF, Wu CC, Chen DR, Lee JH (2002) Biol Trace Elem Res 89:1–11CrossRefPubMedGoogle Scholar
  5. 5.
    Gupte A, Mumper RJ (2009) Cancer Treat Rev 35(1):32–46CrossRefPubMedGoogle Scholar
  6. 6.
    Gupta SK, Shukla VK, Vaidya MP, Roy SK, Gupta S (1991) J Surg Oncol 46:178–181CrossRefPubMedGoogle Scholar
  7. 7.
    Buettner GR, Jurkiewicz BA (1996) Radiat Res 145:532–541CrossRefPubMedGoogle Scholar
  8. 8.
    Schumaker PT (2006) Cancer Cell 10(3):175–176CrossRefGoogle Scholar
  9. 9.
    Ma B, Goh BC, Tan EH, Lam KC, Soo R, Leong SS, Wang LZ, Mo F, Chan AT (2008) Investig New Drug 26(2):169–173CrossRefGoogle Scholar
  10. 10.
    Kalinowski DS, Richardson DR (2005) Pharmacol Rev 57(4):547–583CrossRefPubMedGoogle Scholar
  11. 11.
    Whitnall M, Howard J, Ponka P, Richardson DR (2006) Proc Natl Acad Sci USA 103(40):14901–14906CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Jansson PJ, Sharpe PC, Bernhardt PV, Richardson DR (2010) J Med Chem 53(15):5759–5769CrossRefPubMedGoogle Scholar
  13. 13.
    Lovejoy DB, Jansson PJ, Brunk U, Wong J, Ponka P, Richardson DR (2011) Cancer Res 71(17):5871–5880CrossRefPubMedGoogle Scholar
  14. 14.
    Kalinowski DS, Jansson PJ, Kovacevic Z, Richardson DR (2013) Redox Rep 18(2):48–50CrossRefPubMedGoogle Scholar
  15. 15.
    Gaál A, Orgován G, Polgári Z, Réti A, Mihucz VG, Bősze S, Szoboszlai N, Streli C (2014) J Inorg Biochem 130:52–58CrossRefPubMedGoogle Scholar
  16. 16.
    Hancock CN, Stockwin LH, Han B, Divelbiss RD, Jun JH, Malhotra SV, Hollingshead MG, Newton DL (2011) Free Rad Biol Med 2011, 50(1) 110-121Google Scholar
  17. 17.
    Stefani C, El-Eisawi Z, Jansson PJ, Kalinowski DS, Richardson DR (2015) J Inorg Biochem 152:20–37CrossRefPubMedGoogle Scholar
  18. 18.
    Giles GI (2006) Curr Pharm Design 12(34):4427–4443CrossRefGoogle Scholar
  19. 19.
    Tew KD, Townsend DM (2011) Curr Opin Chem Biol 15(1):156–161CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kalinina E, Chernov N, Saprin A (2008) Biochemistry- Moscow 73(13):1493–1510CrossRefPubMedGoogle Scholar
  21. 21.
    Nolan KA, Zhao H, Faulder PF, Frenkel AD, Timson DJ, Siegel D, Ross D, Burke TR Jr, Stratford IJ, Bryce RA (2007) J Med Chem 50(25):6316–6325CrossRefPubMedGoogle Scholar
  22. 22.
    Li R, Bianchet MA, Talalay P, Amzel LM (1995) Proc Natl Acad Sci USA 92(19):8846–8850CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Van Rensburg C, Van Staden A, Anderson R (1993) Cancer Res 53(2):318–323PubMedGoogle Scholar
  24. 24.
    Van Rensburg C, Anderson R, O’Sullivan J (1997) Crit Rev Oncol Hemat 25(1):55–67CrossRefGoogle Scholar
  25. 25.
    Akladios FN, Andrew SD, Parkinson CJ (2015) Bioorg. Med. Chem. 23:3097–3104CrossRefPubMedGoogle Scholar
  26. 26.
    Crossley ML, Turner RJ, Hofmann CM, Dreisbach PF, Parker RP (1952) J Am Chem Soc 74(3):578–584CrossRefGoogle Scholar
  27. 27.
    Kalinowski DS, Yu Y, Sharpe PC, Islam M, Liao Y-T, Lovejoy DB, Kumar N, Bernhardt PV, Richardson DR (2007) J Med Chem 50(15):3716–3729CrossRefPubMedGoogle Scholar
  28. 28.
    Richardson DR, Sharpe PC, Lovejoy DB, Senaratne D, Kalinowski DS, Islam M, Bernhardt PV (2006) J Med Chem 49(22):6510–6521CrossRefPubMedGoogle Scholar
  29. 29.
    Lovejoy DB, Richardson DR (2002) Blood 100(2):666–676CrossRefPubMedGoogle Scholar
  30. 30.
    Brown CA, West DX (2003) Transit Metal Chem 28(2):154–159CrossRefGoogle Scholar
  31. 31.
    Chou T-C (2010) Cancer Res 70(2):440–446CrossRefPubMedGoogle Scholar
  32. 32.
    Tütem E, Apak R, Baykut F (1991) Analyst 116:89–94CrossRefGoogle Scholar
  33. 33.
    Cobine PA, Pierrel F, Bestwick ML, Winge DR (2006) J Biol Chem 281:36552–36559CrossRefPubMedGoogle Scholar
  34. 34.
    Samuni Y, Goldstein S, Dean OM, Berk M (2013) Biochim Biophys Acta 1830:4117–4129CrossRefPubMedGoogle Scholar
  35. 35.
    Zheng J, Lou JR, Benbrook DM, Hanigan MH, Lind SE, Ding W-Q (2010) Cancer Lett 298:186–194CrossRefPubMedGoogle Scholar
  36. 36.
    Saito M, Kobayashi M, Iwabuchi S, Morita Y, Takamura Y, Tamiya E (2004) J Biochem 136(6):813–823CrossRefPubMedGoogle Scholar
  37. 37.
    Wlodkowic D, Skommer J, Darzynkiewicz Z (2009) Methods Mol Biol 559:  10.1007/978-1-60327-017-5_2

Copyright information

© SBIC 2016

Authors and Affiliations

  • Fady N. Akladios
    • 1
  • Scott D. Andrew
    • 1
  • Christopher J. Parkinson
    • 1
  1. 1.School of Biomedical SciencesCharles Sturt UniversityOrangeAustralia

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