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.
Graphical abstract
Similar content being viewed by others
References
Johnstone TC, Suntharalingam K, Lippard SJ (2016) Chem Rev 116:3436–3486. doi:10.1021/acs.chemrev.5b00597
Allardyce CS, Dyson PJ (2016) Dalton Trans 45:3201–3209. doi:10.1039/C5DT03919C
Doucette KA, Hassell KN, Crans DC (2016) J Inorg Biochem 165:56–70. doi:10.1016/j.jinorgbio.2016.09.013
Mjos KD, Orvig C (2014) Chem Rev 114:4540–4563. doi:10.1021/cr400460s
Costa Pessoa J, Etcheverry S, Gambino D (2015) Coord Chem Rev 301–302:24–48. doi:10.1016/j.ccr.2014.12.002
Rehder D (2016) Future Med Chem 8:325–338. doi:10.4155/fmc.15.187
Rehder D (2017) Inorg Chim Acta 455:378–389. doi:10.1016/j.ica.2016.06.021
Lopez V, Stevens T, Lindquist RN (1976) Arch Biochem Biophys 175:31–38. doi:10.1016/0003-9861(76)90482-3
Cantley LC, Josephson L, Warner R, Yanagisawa M, Lechene C, Guidotti G (1977) J Biol Chem 252:7421–7423
Thompson KH, Orvig C (2006) J Inorg Biochem 100:1925–1935. doi:10.1016/j.jinorgbio.2006.08.016
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
Kioseoglou E, Petanidis S, Gabriel C, Salifoglou A (2015) Coord Chem Rev 301–302:87–105. doi:10.1016/j.ccr.2015.03.010
D’Cruz OJ, Dong Y, Uckun FM (2000) Anticancer Drugs 11:849–858. doi:10.1097/00001813-200011000-00009
Dong Y, Narla RK, Sudbeck E, Uckun FM (2000) J Inorg Biochem 78:321–330. doi:10.1016/S0162-0134(00)00060-X
Narla RK, Dong Y, D’Cruz OJ, Navara C, Uckun FM (2000) Clin Cancer Res 6:1546–1556
Narla RK, Chen C-L, Dong Y, Uckun FM (2001) Clin Cancer Res 7:2124–2133
Narla RK, Dong Y, Uckun FM (2001) Leuk Lymphoma 41:625–634. doi:10.3109/10428190109060353
D’Cruz OJ, Uckun FM (2002) Expert Opin Invest Drugs 11:1829–1836. doi:10.1517/13543784.11.12.1829
Uckun FM, Dong Y, Gosh P (2002) Preparation of vanadium (IV) compounds useful in the treatment of cancer. Patent US6432941B1
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
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
Levina A, Mitra A, Lay PA (2009) Metallomics 1:458–470. doi:10.1039/b904071d
Costa Pessoa J, Tomaz I (2010) Curr Med Chem 17:3701–3738. doi:10.2174/092986710793213742
Levina A, Crans DC, Lay PA (2017) Coord Chem Rev. doi:10.1016/j.ccr.2017.01.002
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
Yoshikawa Y, Sakurai H, Crans DC, Micera G, Garribba E (2014) Dalton Trans 43:6965–6972. doi:10.1039/c3dt52895b
Levina A, McLeod AI, Kremer LE, Aitken JB, Glover CJ, Johannessen B, Lay PA (2014) Metallomics 6:1880–1888. doi:10.1039/C4MT00146J
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
Levina A, McLeod AI, Pulte A, Aitken JB, Lay PA (2015) Inorg Chem 54:6707–6718. doi:10.1021/ic5028948
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
Mohindru A, Fisher JM, Rabinovitz M (1983) Biochem Pharmacol 32:3627–3632. doi:10.1016/0006-2952(83)90314-3
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
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
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
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
Win-EPR, Version 2.11 (1996) Bruker-Franzen Analytic, Bremen
Gochev GP, Yordanov ND, Antov LM (1994) Appl Magn Reson 6:183–194. doi:10.1007/BF03162489
Farrell RP, Lay PA (1996) Appl Magn Reson 11:509–519. doi:10.1007/BF03162246
Senko M (1998) IsoPro 3.0, Sunnyvale
Freshney RI (2016) Culture of animal cells: a manual of basic technique and specialized applications, 7th edn. Wiley-Blackwell, Hoboken
Levina A, Harris HH, Lay PA (2007) J Am Chem Soc 129:1065–1075. doi:10.1021/ja063792r
Timm M, Saaby L, Moesby L, Hansen EW (2013) Cytotechnology 65:887–894. doi:10.1007/s10616-012-9530-6
Mosmann T (1983) J Immunol Methods 65:55–63. doi:10.1016/0022-1759(83)90303-4
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
Microcal Origin, Version 6.1 (1999) Microcal Software Inc, Northampton
Selbin J (1965) Chem Rev 65:153–175. doi:10.1021/cr60234a001
Weeks CL, Levina A, Dillon CT, Turner P, Fenton RR, Lay PA (2004) Inorg Chem 43:7844–7856. doi:10.1021/ic049008q
Hitchman ML (1978) Measurement of dissolved oxygen. Wiley, New York
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
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
Hoffmann K, Lakomska I, Wisniewska J, Kaczmarek-Kedziera A, Wietrzyk J (2015) J Coord Chem 68:3193–3208. doi:10.1080/00958972.2015.1070954
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
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
Scrivens PJ, Alaoui-Jamali MA, Giannini G, Wang T, Loignon M, Batist G, Sandor VA (2003) Mol Cancer Ther 2:1053–1059
Du S, Feng J, Lu X, Wang G (2013) Dalton Trans 42:9699–9705. doi:10.1039/c3dt50865j
Hedges JB, Vahidi S, Yue X, Konermann L (2013) Anal Chem 85:6469–6476. doi:10.1021/ac401020s
Oller AR, Buser CW, Tyo MA, Thilly WG (1989) J Cell Sci 94(Pt 1):43–49
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
Levina A, Pham THN, Lay PA (2016) Angew Chem Int Ed 55:8104–8107. doi:10.1002/anie.201602996
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
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
Kato Y, Yamashita T, Ishikawa M (2002) Oncol Rep 9:565–569. doi:10.3892/or.9.3.565
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
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
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
Reytman L, Braitbard O, Hochman J, Tshuva EY (2016) Inorg Chem 55:610–618. doi:10.1021/acs.inorgchem.5b02519
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
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
Li SG, Crooks PA, Wei SC, de Leon J (2004) Crit Rev Toxicol 34:447–460
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
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.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
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)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00775-017-1453-4