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High cytotoxicity of vanadium(IV) complexes with 1,10-phenanthroline and related ligands is due to decomposition in cell culture medium

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Abstract

Cytotoxic effects of Metvan (cis-[VIVO(OSO3)(Me2phen)2], where Me2phen = 4,7-dimethyl-1,10-phenanthroline) and its analogues with 1,10-phenanthroline (phen) and 2,2′-bipyridine (bpy) ligands in cultured human lung cancer (A549) cells have been re-investigated in conjunction with reactivity of the V(IV) complexes in neutral aerated aqueous solutions and in cell culture medium. All the V(IV) complexes underwent rapid oxidation to the corresponding V(V) species (cis-[VV(O)2L2]+), followed by release of free ligands (shown by electrospray mass spectrometry). Decomposition of V(IV) complexes in cell culture medium within minutes at 310 K was confirmed by UV–Vis and EPR spectroscopies. High cytotoxicities (low μM or sub-μM IC50 range in 72 h assays) were observed for the phen and Me2phen complexes, but they were not different from that of the corresponding free ligands, which confirmed that the original V(IV) complexes played no significant role in the observed biological activities. The cytotoxicities of the ligands were most likely due to their complexation of redox-active essential metal ions, such as Cu(II) and Fe(II), in the medium, and their increased cellular uptake, leading to oxidative stress-related cell death. These results emphasize the need to assess the stability of metal-based drugs under the conditions of biological assays, particularly when biologically active ligands, such as 1,10-phenanthroline and its derivatives, are used. These ligands have high systemic toxicities in vivo and their release in the GI tract and blood makes the complexes unsuitable for use as anti-cancer drugs.

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References

  1. Johnstone TC, Suntharalingam K, Lippard SJ (2016) Chem Rev 116:3436–3486. doi:10.1021/acs.chemrev.5b00597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Allardyce CS, Dyson PJ (2016) Dalton Trans 45:3201–3209. doi:10.1039/C5DT03919C

    Article  CAS  PubMed  Google Scholar 

  3. Doucette KA, Hassell KN, Crans DC (2016) J Inorg Biochem 165:56–70. doi:10.1016/j.jinorgbio.2016.09.013

    Article  CAS  PubMed  Google Scholar 

  4. Mjos KD, Orvig C (2014) Chem Rev 114:4540–4563. doi:10.1021/cr400460s

    Article  CAS  PubMed  Google Scholar 

  5. Costa Pessoa J, Etcheverry S, Gambino D (2015) Coord Chem Rev 301–302:24–48. doi:10.1016/j.ccr.2014.12.002

    Article  Google Scholar 

  6. Rehder D (2016) Future Med Chem 8:325–338. doi:10.4155/fmc.15.187

    Article  CAS  PubMed  Google Scholar 

  7. Rehder D (2017) Inorg Chim Acta 455:378–389. doi:10.1016/j.ica.2016.06.021

    Article  CAS  Google Scholar 

  8. Lopez V, Stevens T, Lindquist RN (1976) Arch Biochem Biophys 175:31–38. doi:10.1016/0003-9861(76)90482-3

    Article  CAS  PubMed  Google Scholar 

  9. Cantley LC, Josephson L, Warner R, Yanagisawa M, Lechene C, Guidotti G (1977) J Biol Chem 252:7421–7423

    CAS  PubMed  Google Scholar 

  10. Thompson KH, Orvig C (2006) J Inorg Biochem 100:1925–1935. doi:10.1016/j.jinorgbio.2006.08.016

    Article  CAS  PubMed  Google Scholar 

  11. Benitez J, Becco L, Correia I, Leal SM, Guiset H, Costa Pessoa J, Lozenzo J, Tanco S, Escobar P, Moreno V, Garat B, Gambino D (2011) J Inorg Biochem 105:303–312. doi:10.1016/j.jinorgbio.2010.11.001

    Article  CAS  PubMed  Google Scholar 

  12. Kioseoglou E, Petanidis S, Gabriel C, Salifoglou A (2015) Coord Chem Rev 301–302:87–105. doi:10.1016/j.ccr.2015.03.010

    Article  Google Scholar 

  13. D’Cruz OJ, Dong Y, Uckun FM (2000) Anticancer Drugs 11:849–858. doi:10.1097/00001813-200011000-00009

    Article  PubMed  Google Scholar 

  14. Dong Y, Narla RK, Sudbeck E, Uckun FM (2000) J Inorg Biochem 78:321–330. doi:10.1016/S0162-0134(00)00060-X

    Article  CAS  PubMed  Google Scholar 

  15. Narla RK, Dong Y, D’Cruz OJ, Navara C, Uckun FM (2000) Clin Cancer Res 6:1546–1556

    CAS  PubMed  Google Scholar 

  16. Narla RK, Chen C-L, Dong Y, Uckun FM (2001) Clin Cancer Res 7:2124–2133

    CAS  PubMed  Google Scholar 

  17. Narla RK, Dong Y, Uckun FM (2001) Leuk Lymphoma 41:625–634. doi:10.3109/10428190109060353

    Article  CAS  PubMed  Google Scholar 

  18. D’Cruz OJ, Uckun FM (2002) Expert Opin Invest Drugs 11:1829–1836. doi:10.1517/13543784.11.12.1829

    Article  Google Scholar 

  19. Uckun FM, Dong Y, Gosh P (2002) Preparation of vanadium (IV) compounds useful in the treatment of cancer. Patent US6432941B1

  20. Scalese G, Benitez J, Rostan S, Correia I, Bradford L, Vieites M, Minini L, Merlino A, Coitino EL, Birriel E, Varela J, Cerecetto H, Gonzalez M, Costa Pessoa J, Gambino D (2015) J Inorg Biochem 147:116–125. doi:10.1016/j.jinorgbio.2015.03.002

    Article  CAS  PubMed  Google Scholar 

  21. Scalese G, Correia I, Benitez J, Rostan S, Marques F, Mendes F, Matos AP, Costa Pessoa J, Gambino D (2017) J Inorg Biochem 166:162–172. doi:10.1016/j.jinorgbio.2016.11.010

    Article  CAS  PubMed  Google Scholar 

  22. Levina A, Mitra A, Lay PA (2009) Metallomics 1:458–470. doi:10.1039/b904071d

    Article  CAS  PubMed  Google Scholar 

  23. Costa Pessoa J, Tomaz I (2010) Curr Med Chem 17:3701–3738. doi:10.2174/092986710793213742

    Article  PubMed  Google Scholar 

  24. Levina A, Crans DC, Lay PA (2017) Coord Chem Rev. doi:10.1016/j.ccr.2017.01.002

    Google Scholar 

  25. Willsky GR, Halvorsen K, Godzala ME, Chi L-H, Most MJ, Kaszynski P, Crans DC, Glodfine AB, Kostyniak PJ (2013) Metallomics 5:1491–1502. doi:10.1039/c3mt00162h

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yoshikawa Y, Sakurai H, Crans DC, Micera G, Garribba E (2014) Dalton Trans 43:6965–6972. doi:10.1039/c3dt52895b

    Article  CAS  PubMed  Google Scholar 

  27. Levina A, McLeod AI, Kremer LE, Aitken JB, Glover CJ, Johannessen B, Lay PA (2014) Metallomics 6:1880–1888. doi:10.1039/C4MT00146J

    Article  CAS  PubMed  Google Scholar 

  28. Levina A, McLeod AI, Gasparini SJ, Nguyen A, De Silva WGM, Aitken JB, Harris HH, Glover C, Johannessen B, Lay PA (2015) Inorg Chem 54:7753–7766. doi:10.1021/acs.inorgchem.5b00665

    Article  CAS  PubMed  Google Scholar 

  29. Levina A, McLeod AI, Pulte A, Aitken JB, Lay PA (2015) Inorg Chem 54:6707–6718. doi:10.1021/ic5028948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Costa Pessoa J, Cavaco I, Correia I, Tomaz I, Adão P, Vale I, Ribeiro V, Castro MMCA, Geraldes CFGC (2007) In: Vanadium: The Versatile Metal. Ed. Kustin K, Costa Pessoa J, Crans DC, American Chemical Society, Washington DC, pp 340–351

  31. Mohindru A, Fisher JM, Rabinovitz M (1983) Biochem Pharmacol 32:3627–3632. doi:10.1016/0006-2952(83)90314-3

    Article  CAS  PubMed  Google Scholar 

  32. Kellett A, O’Connor M, McCann M, Howe O, Casey A, McCarron P, Kavanagh K, McNamara M, Kennedy S, May DD, Skell PS, O’Shea D, Devereux M (2011) MedChemComm 2:579–584. doi:10.1039/c0md00266f

    Article  CAS  Google Scholar 

  33. McCann M, Santos ALS, da Silva BA, Romanos MTV, Pyrrho AS, Devereux M, Kavanagh K, Fichtner I, Kellett A (2012) Toxicol Res 1:47–54. doi:10.1039/c2tx00010e

    Article  CAS  Google Scholar 

  34. Serment-Guerrero J, Bravo-Gomez ME, Lara-Rivera E, Ruiz-Azuara L (2017) J Inorg Biochem 166:68–75. doi:10.1016/j.jinorgbio.2016.11.007

    Article  CAS  PubMed  Google Scholar 

  35. Acilan C, Cevatemre B, Adiguzel Z, Karakas D, Ulukaya E, Ribeiro N, Correia I, Costa Pessoa J (2017) Biochim Biophys Acta. Gen Subj 1861:218–234. doi:10.1016/j.bbagen.2016.10.014

    Article  CAS  Google Scholar 

  36. Win-EPR, Version 2.11 (1996) Bruker-Franzen Analytic, Bremen

  37. Gochev GP, Yordanov ND, Antov LM (1994) Appl Magn Reson 6:183–194. doi:10.1007/BF03162489

    Article  CAS  Google Scholar 

  38. Farrell RP, Lay PA (1996) Appl Magn Reson 11:509–519. doi:10.1007/BF03162246

    Article  CAS  Google Scholar 

  39. Senko M (1998) IsoPro 3.0, Sunnyvale

  40. Freshney RI (2016) Culture of animal cells: a manual of basic technique and specialized applications, 7th edn. Wiley-Blackwell, Hoboken

    Google Scholar 

  41. Levina A, Harris HH, Lay PA (2007) J Am Chem Soc 129:1065–1075. doi:10.1021/ja063792r

    Article  CAS  PubMed  Google Scholar 

  42. Timm M, Saaby L, Moesby L, Hansen EW (2013) Cytotechnology 65:887–894. doi:10.1007/s10616-012-9530-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mosmann T (1983) J Immunol Methods 65:55–63. doi:10.1016/0022-1759(83)90303-4

    Article  CAS  PubMed  Google Scholar 

  44. Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Cancer Res 48:589–601

    CAS  PubMed  Google Scholar 

  45. Microcal Origin, Version 6.1 (1999) Microcal Software Inc, Northampton

  46. Selbin J (1965) Chem Rev 65:153–175. doi:10.1021/cr60234a001

    Article  CAS  Google Scholar 

  47. Weeks CL, Levina A, Dillon CT, Turner P, Fenton RR, Lay PA (2004) Inorg Chem 43:7844–7856. doi:10.1021/ic049008q

    Article  CAS  PubMed  Google Scholar 

  48. Hitchman ML (1978) Measurement of dissolved oxygen. Wiley, New York

    Google Scholar 

  49. Caravan P, Gelmini L, Glover N, Herring FG, Li H, McNeill JH, Rettig SJ, Setyawati IA, Shuter E, Sun Y, Tracey AS, Yuen VG, Orvig C (1995) J Am Chem Soc 117:12759–12770. doi:10.1021/ja00156a013

    Article  Google Scholar 

  50. Sanna D, Buglyo P, Tomaz AI, Costa Pessoa J, Borovic S, Micera G, Garriba E (2012) Dalton Trans 41:12824–12838. doi:10.1039/c2dt31109g

    Article  CAS  PubMed  Google Scholar 

  51. Hoffmann K, Lakomska I, Wisniewska J, Kaczmarek-Kedziera A, Wietrzyk J (2015) J Coord Chem 68:3193–3208. doi:10.1080/00958972.2015.1070954

    Article  CAS  Google Scholar 

  52. Zheng H, Chen J-N, Yu X, Jiang P, Yuan L, Shen H-S, Zhao L-H, Chen P-F, Yang M (2016) DNA Cell Biol 35:622–627. doi:10.1089/dna.2016.3360

    Article  CAS  PubMed  Google Scholar 

  53. Apohan E, Yilmaz U, Yilmaz O, Serindag A, Kucukbay H, Yesilada O, Baran Y (2017) J Organomet Chem 828:52–58. doi:10.1016/j.jorganchem.2016.11.020

    Article  CAS  Google Scholar 

  54. Scrivens PJ, Alaoui-Jamali MA, Giannini G, Wang T, Loignon M, Batist G, Sandor VA (2003) Mol Cancer Ther 2:1053–1059

    CAS  PubMed  Google Scholar 

  55. Du S, Feng J, Lu X, Wang G (2013) Dalton Trans 42:9699–9705. doi:10.1039/c3dt50865j

    Article  CAS  PubMed  Google Scholar 

  56. Hedges JB, Vahidi S, Yue X, Konermann L (2013) Anal Chem 85:6469–6476. doi:10.1021/ac401020s

    Article  CAS  PubMed  Google Scholar 

  57. Oller AR, Buser CW, Tyo MA, Thilly WG (1989) J Cell Sci 94(Pt 1):43–49

    PubMed  Google Scholar 

  58. Bozym RA, Chimienti F, Giblin LJ, Gross GW, Korichneva I, Li Y, Libert S, Maret W, Parviz M, Frederickson CJ, Thompson RB (2010) Exp Biol Med 235:741–750. doi:10.1258/ebm.2010.009258

    Article  CAS  Google Scholar 

  59. Levina A, Pham THN, Lay PA (2016) Angew Chem Int Ed 55:8104–8107. doi:10.1002/anie.201602996

    Article  CAS  Google Scholar 

  60. Kowol CR, Heffeter P, Miklos W, Gille L, Trondl R, Cappellacci L, Berger W, Keppler BK (2012) J Biol Inorg Chem 17:409–423. doi:10.1007/s00775-011-0864-x

    Article  CAS  PubMed  Google Scholar 

  61. Hasinoff BB, Wu X, Yadav AA, Patel D, Zhang H, Wang D-S, Chen Z-S, Yalowich JC (2015) Biochem Pharmacol 93:266–276. doi:10.1016/j.bcp.2014.12.008

    Article  CAS  PubMed  Google Scholar 

  62. Kato Y, Yamashita T, Ishikawa M (2002) Oncol Rep 9:565–569. doi:10.3892/or.9.3.565

    CAS  PubMed  Google Scholar 

  63. Clark O, Park I, Di Florio A, Cichon A-C, Rustin S, Jugov R, Maeshima R, Stoker AW (2015) Cancer Lett 357:316–327. doi:10.1016/j.canlet.2014.11.039

    Article  CAS  PubMed  Google Scholar 

  64. Correia I, Adao P, Roy S, Wahba M, Matos C, Maurya MR, Marques F, Pavan FR, Leite CQF, Avecilla F, Costa Pessoa J (2014) J Inorg Biochem 141:83–93. doi:10.1016/j.jinorgbio.2014.07.019

    Article  CAS  PubMed  Google Scholar 

  65. Levina A, Aitken JB, Gwee YY, Lim ZJ, Liu M, Mitra Singharay A, Wong PF, Lay PA (2013) Chem Eur J 19:3609–3619. doi:10.1002/chem.201203127

    Article  CAS  PubMed  Google Scholar 

  66. Reytman L, Braitbard O, Hochman J, Tshuva EY (2016) Inorg Chem 55:610–618. doi:10.1021/acs.inorgchem.5b02519

    Article  CAS  PubMed  Google Scholar 

  67. Liao X, Lu J, Ying P, Zhao P, Bai Y, Li W, Liu M (2013) J Biol Inorg Chem 18:975–984. doi:10.1007/s00775-013-1046-9

    Article  CAS  PubMed  Google Scholar 

  68. Fernandez M, Varela J, Correia I, Birriel E, Castiglioni J, Moreno V, Costa Pessoa J, Cerecetto H, Gonzalez M, Gambino D (2013) Dalton Trans 42:11900–11911. doi:10.1039/c3dt50512j

    Article  CAS  PubMed  Google Scholar 

  69. Li SG, Crooks PA, Wei SC, de Leon J (2004) Crit Rev Toxicol 34:447–460

    Article  CAS  PubMed  Google Scholar 

  70. Santodonato J, Howard PH (1981) Azaarenes: Sources, distribution, environmental impact and health effects. In: Saxena J, Fisher F (eds) Hazard assessment of chemicals, vol 1. Academic Press, New York, pp 238–421

    Google Scholar 

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Acknowledgements

The research was supported by Australian Research Council (ARC) Discovery Grants (DP0984722, DP1095310, DP140100176, and DP160104172) and ARC Professorial Fellowship (DP0984722) to P.A.L. The authors acknowledge the facilities and the scientific and technical assistance of the Australian Microscopy and Microanalysis Research Facility at the Australian Centre for Microscopy and Microanalysis at the University of Sydney (Drs. Minh Huynh and Ellie Kable) for the use of cell culture laboratory. We thank Dr. Nicholas Proschogo and Ms. Natalia Kislova (School of Chemistry, University of Sydney) for the help with ESMS and IR data collection, respectively.

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  1. School of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia

    Maria Le, Oliver Rathje, Aviva Levina & Peter A. Lay

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775_2017_1453_MOESM1_ESM.pdf

Figures showing typical solid-state IR and solution EPR and UV–vis spectra of 1–3, and typical results of decomposition studies of 2 and 3 by UV–vis spectroscopy (PDF 256 kb)

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Le, M., Rathje, O., Levina, A. et al. High cytotoxicity of vanadium(IV) complexes with 1,10-phenanthroline and related ligands is due to decomposition in cell culture medium. J Biol Inorg Chem 22, 663–672 (2017). https://doi.org/10.1007/s00775-017-1453-4

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