Advertisement

BioMetals

, Volume 28, Issue 4, pp 765–781 | Cite as

The effect of 1:2 Ag(I) thiocyanate complexes in MCF-7 breast cancer cells

  • Eloise Ferreira
  • Appollinaire Munyaneza
  • Bernard Omondi
  • Reinout Meijboom
  • Marianne J. Cronjé
Article

Abstract

There is much interest currently in the design of metal compounds as drugs and various metal compounds are already in clinical use. These include gold(I) compounds such as auranofin and the anti-cancer platinum(II) complex, cisplatin. Bis-chelated gold(I) phosphine complexes have also shown great potential as anticancer agents, however, their efficacy has been limited by their high toxicity. In this study, silver(I) thiocyanate compounds linked to four specific ligands, were synthesized and characterized. These silver-phosphine adducts included [AgSCN{P(4-MeC6H4)3}2]2 (1); [AgSCN{P(4-ClC6H4)3}2]2 (2); [AgSCN{P(4-MeOC6H4)3}2]2 (3); [AgSCN(PPh3)2]2 (4). The compounds were found to be toxic to MCF-7 breast cancer cells while the ligands on their own were not toxic. Our findings further indicate that the silver(I) phosphine compounds induce apoptotic cell death in these breast cancer cells. In addition, the compounds were not toxic to nonmalignant fibroblast cells at the IC50 concentrations. This is an indication that the compounds show selectivity towards the cancer cells.

Keywords

Silver-phosphine complexes Apoptosis Flow-cytometry MCF-7 breast cancer cells Anti-cancer Drug discovery 

Abbreviations

13C

Carbon 13 NMR

CDCl3

Deuterated chloroform

CDDP

Cis-diamine-dichloro platinum (cisplatin)

CHNS

Carbon, hydrogen, nitrogen, sulphur elemental analysis

DMSO

Dimethyl sulfoxide

FITC

Fluorescein isothiocyanate

1H

Proton NMR

IC50

Half maximal inhibitory concentration

IR

Infra red spectrometry

J

J-coupling constant

LMS

Leiomyosarcoma cell

Mp

Melting point

NMR

Nuclear magnetic resonance spectrometry

31P

Phosphorous 31 NMR

PI

Propidium iodide

PPh3

Triphenylphosphine

PS

Phosphatidylserine

SEM

Standard error of the mean

Notes

Acknowledgments

This work is based on the research supported in the part by the National Research Foundation of South Africa (Grant specific unique reference number (UID 85386)). We would like also to thank the University of Johannesburg for funding.

References

  1. Abeysinghe PM, Harding MM (2007) Antitumour bis(cyclopentadienyl) metal complexes: titanocene and molybdocene dichloride and derivatives. Dalton Trans 32:3474–3482PubMedCrossRefGoogle Scholar
  2. Ahmad A (2013) Pathways to breast cancer recurrence. ISRN Oncol 2013:16Google Scholar
  3. Anthoney DA, Mclllwrath AJ, Gallagher WM, Edlin ARM, Brown R (1996) Microsatellite instability, apoptosis and loss of p53 function in drug-resistant tumor cells. Cancer Res 56:1374–1381PubMedGoogle Scholar
  4. Arnesano F, Natile G (2009) Mechanistic insight into the cellular uptake and processing of cisplatin 30 years after its approval by FDA. Coord Chem Rev 253:2070–2081CrossRefGoogle Scholar
  5. Barnes KR, Lippard SJ (2004) Cisplatin and related anticancer drugs: recent advances and insights. Met Ions Biol Syst 42:143–177PubMedGoogle Scholar
  6. Berners-Price SJ, Sadler PJ (1988) Structure and bonding, Phosphine and metal phosphine complexes: relationship of chemistry to anticancer and other biological activity. Bioinorg Chem Struct Bonding 70:27–102CrossRefGoogle Scholar
  7. Berners-Price SJ, Mirabelli CK, Johnson RK, Mattern MR, McCabe FL, Faucette LF, MeiSung C, Mong S-M, Sadler PJ, Crooke ST (1986) In vivo antitumour activity and in vitro cytotoxic properties of bis[1,2-bis(diphenylphosphino)ethane]gold(I) chloride. Cancer Res 46(11):5486–5493PubMedGoogle Scholar
  8. Berners-Price SJ, Johnson RK, Giovenella AJ, Faucette LF, Mirabelli CK, Sadler PJ (1988) Antimicrobial and anticancer activity of tetrahedral, chelated, diphosphine silver(I) complexes: comparison with copper and gold. J Inor Biochem 33(4):285–295CrossRefGoogle Scholar
  9. Bowmaker GA, Effendy Kildea JD, de Silva EN, White AH (1997) Lewis-base adducts of group 11 metal(I) compounds. LXXI Synthesis, spectroscopy and structural systematics of some 1: 2 binuclear adducts of silver(I) compounds with triphenylarsine, [(Ph3As)2Ag(µ-X)2Ag(AsPh3)2], X = Cl, Br, I, SCN. Aust J Chem 50:627–640CrossRefGoogle Scholar
  10. Brandys MC, Puddephatt RJ (2002) Polymeric complexes of silver(I) with diphosphine ligands: self-assembly of a puckered sheet network structure. J Am Chem Soc 124(15):3946–3950PubMedCrossRefGoogle Scholar
  11. Bray F, Ren J-S, Masuyer E, Ferlay J (2013) Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer 132:1133–1145PubMedCrossRefGoogle Scholar
  12. Bruijnincx PC, Sadler PJ (2008) New trends for metal complexes with anticancer activity. Curr Opin Chem Biol 12(2):197–206PubMedCentralPubMedCrossRefGoogle Scholar
  13. Caruso F, Villa R, Rossi M, Pettinari C, Paduano F, Pennati M, Daidone MG, Zaffaroni N (2007) Mitochondria are primary targets in apoptosis induced by the mixed phosphine gold species chlorotriphenylphosphine-1,3 bis(diphenylphosphino)propanegold(I) in melanoma cell lines. Biochem Pharmacol 73:773–781PubMedCrossRefGoogle Scholar
  14. Chan FK-M, Moriwaki K, José De Rosa M (2013) Detection of necrosis by release of lactate dehydrogenase (LDH) activity. Methods Mol Biol 979:65–70PubMedCentralPubMedCrossRefGoogle Scholar
  15. Chandler JM, Cohen GM, MacFarlane M (1998) Different subcellular distribution of caspase-3 and caspase-7 following Fas-induced apoptosis in mouse liver. J Biol Chem 273:10815–10818PubMedCrossRefGoogle Scholar
  16. Chang LK, Putcha GV, Deshmukh M, Johnson EM Jr (2002) Mitochondrial involvement in the point of no return in neuronal apoptosis. Biochimie 84:223–231PubMedCrossRefGoogle Scholar
  17. Cohen GM, Sun XM, Fearnhead H, MacFarlane M, Brown DG, Snowden RT, Dinsdale D (1994) Formation of large molecular weight fragments of DNA is a key committed step of apoptosis in thymocytes. J Immunol 153(2):507–516Google Scholar
  18. De Pas T, de Braud F, Mandalà M, Curigliano G, Catania C, Ferretti G, Sozzi P, Solli P, Goldhirsch A (2001) Cisplatin and vinorelbine as second-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) resistant to taxol plus gemcitabine. Lung Cancer 31(2–3):267–270PubMedCrossRefGoogle Scholar
  19. Dey SK, Bose D, Hazra A, Naskar S, Nandy A, Munda RN, Das S, Chatterjee N, Mondal NB, Banerjee S, Saha KD (2013) Cytotoxic activity and apoptosis-inducingpotential of di-spiropyrrolidino and di-spiropyrrolizidino oxindole andrographolide derivatives. PLoS ONE 8(3):e58055PubMedCentralPubMedCrossRefGoogle Scholar
  20. Eastman A (1990) Activation of programmed cell death by anticancer agents: cisplatin as a model system. Cancer Cells 2:275–280PubMedGoogle Scholar
  21. Fiers W, Beyaert R, Declercq W, Vandenabeele P (1999) More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene 18:7719–7730PubMedCrossRefGoogle Scholar
  22. Florea A-M, Büsselberg D (2011) Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers 3:1351–1371PubMedCentralPubMedCrossRefGoogle Scholar
  23. Gatti L, Supino R, Perego P, Pavesi R, Caserini C, Carenini N, Righetti SC, Zuco V, Zunino F (2002) Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response. Cell Death Differ 9(12):1352–1359PubMedCrossRefGoogle Scholar
  24. Guo Z, Sadler PJ (1999) Metals in medicine. Angew Chem Int Ed 38:1512–1531CrossRefGoogle Scholar
  25. Gust R, Posselt D, Sommer K (2004) Development of cobalt(3,4-diarylsalen) complexes as tumor therapeutics. J Med Chem 47(24):5837–5846PubMedCrossRefGoogle Scholar
  26. Hadjikakou SK, Hadjiliadis N (2009) Antiproliferative and antitumor activity of organotin compounds. Coord Chem Rev 253:235–249CrossRefGoogle Scholar
  27. Hambley TW (2007) Metal-based therapeutics. Science 318(5855):1392–1393PubMedCrossRefGoogle Scholar
  28. Hartinger CG, Dyson PJ (2009) Bioorgano- metallic chemistry from teaching paradigms to me- dicinal applications. Chem Soc Rev 38:391–401PubMedCrossRefGoogle Scholar
  29. Ho AT, Zacksenhaus E (2004) Splitting the apoptosome. Cell Cycle 3:446–448PubMedCrossRefGoogle Scholar
  30. Hoke GD, Rush GF, Bossard GF, McArdle JV, Jensen BD, Mirabelli CK (1988) Mechanism of alterations in isolated rat liver mitochondrial function induced by gold complexes of bidentate phosphines. J Biol Chem 263(23):11203–11210PubMedGoogle Scholar
  31. Hoke GD, Macia RA, Meunier PC, Bugelski PJ, Mirabelli CK, Rush GF, Matthews WD (1989) In vivo and in vitro cardiotoxicity of a gold-containing antineoplastic drug candidate in the rabbit. Toxicol Appl Pharmacol 100(2):293–306PubMedCrossRefGoogle Scholar
  32. Inoue S, Browne G, Melino G, Cohen GM (2009) Ordering of caspases in cells undergoing apoptosis by the intrinsic pathway. Cell Death Differ 16:1053–1061PubMedCrossRefGoogle Scholar
  33. Jakupec MA, Galanski M, Arion VB, Hartinger CG, Keppler BK (2008) Antitumour metal compounds: more than theme and variations. Dalton Trans 2:183–194PubMedCrossRefGoogle Scholar
  34. Khumalo NM, Meijboom R, Muller A, Omondi B (2010) Di-thiocyanato-bis[bis(tri-p-tolylphosphine)silver(I)] hydrate. Acta Cryst E66: m451–m452Google Scholar
  35. Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK et al (2008) Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4(2):151–175PubMedCentralPubMedCrossRefGoogle Scholar
  36. Konstantakou EG, Voutsinas GE, Karkoulis PK, Aravantinos G, Margaritis LH, Stravopodis DJ (2009) Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses. Int J Oncol 35(2):401–416PubMedGoogle Scholar
  37. Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nunez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G (2009) Classification of cell death: recommendations of the nomenclature committee on cell death 2009. Cell Death Differ 16:3–11PubMedCentralPubMedCrossRefGoogle Scholar
  38. Kyros L, Kourkoumelis N, Kubicki M, Male L, Hursthouse MB, Verginadis II, Gouma E, Karkabounas S, Charalabopoulos K, Hadjikakou SK (2010) Structural properties, cytotoxicity, and anti-inflammatory activity of silver(I) complexes with tris(p-tolyl)phosphine and 5-chloro-2-mercaptobenzothiazole. Bioinorg Chem Appl 2010:12CrossRefGoogle Scholar
  39. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489PubMedCrossRefGoogle Scholar
  40. Liu JJ, Galettis P, Farr A, Maharaj L, Samarasinha H, McGechan AC, Baguley BC, Bowen RJ, Berners-Price SJ, McKeage MJ (2008) In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake. J Inorg Biochem 102(2):303–310PubMedCrossRefGoogle Scholar
  41. Mann FG, Wells AF, Purdie D (1937) The constitution of complex metallic salts. Part VI. The constitution of the phosphine and arsine derivatives of silver and aurous halides. The configuration of the co-ordinated argentous and aurous complex. J Chem Soc 1937:1828–1836CrossRefGoogle Scholar
  42. Martin SJ, Green DR (1995) Protease activation during apoptosis: death by a thousand cuts? Cell 82:349–352PubMedCrossRefGoogle Scholar
  43. McKeage MJ, Papathanasiou P, Salem G, Sjaarda A, Swiegers GF, Waring P, Wild SB (1998) Antitumor activity of gold(i), silver(i) and copper(i) complexes containing chiral tertiary phosphines. Met Based Drugs 5(4):217–223PubMedCentralPubMedCrossRefGoogle Scholar
  44. Meggers E (2007) Exploring biologically relevant chemical space with metal complexes. Curr Opin Chem Biol 11(3):287–292PubMedCrossRefGoogle Scholar
  45. Meijboom R, Bowen RJ, Berners-Price SJ (2009) Coordination complexes of silver(I) with tertiary phosphine and related ligands. Coord Chem Rev 253(3–4):325–342CrossRefGoogle Scholar
  46. Mirabelli CK, Hill DT, Faucette LF, McCabe FL, Girard GR, Bryan DB, Sutton BM, Bartus JO, Crooke ST, Johnson RK (1987) Antitumor activity of bis(diphenylphosphino)alkanes, their gold(I) coordination complexes, and related compounds. J Med Chem 30(12):2181–2190PubMedCrossRefGoogle Scholar
  47. Mizushima N (2004) Methods for monitoring autophagy. Int J Biochem Cell Biol 36(12):2491–2502PubMedCrossRefGoogle Scholar
  48. Nandy A, Dey SK, Das S, Munda RN, Dinda J, Saha KD (2014) Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulation. Mol Cancer 13:57PubMedCentralPubMedCrossRefGoogle Scholar
  49. Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C (1991) A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139(2):271–279PubMedCrossRefGoogle Scholar
  50. Omondi B, Meijboom R (2010) Concomitant polymorphic behavior of di-mu-thiocyanato-kappa2 N:s;kappa2S:N-bis[bis(tri-p-fluorophenylphosphine-kappaP)silver(I)]. Acta Crystallogr B 66(Pt 1):69–75PubMedCrossRefGoogle Scholar
  51. Ott I, Gust R (2007) Non platinum metal complexes as anti-cancer drugs. Arch Pharm Chem Life 340(3):117–126CrossRefGoogle Scholar
  52. Papathanasiou P, Salem G, Waring P, Willis AC (1997) Synthesis of gold(I), silver(I) and copper(I) complexes containing substituted (2-aminophenyl)phosphines. Molecular structures of [AuI(2-H2NC6H4PPh2)], [AuI{(±)-2-H2NC6H4PMePh}] and (±)-[Cu(2-H2NC6H4PPh2)2];PF6. J Chem Soc Dalton Trans 19:3435–3443CrossRefGoogle Scholar
  53. Porchia M, Dolmella A, Gandin V, Marzano C, Pellei M, Peruzzo V, Refosco F, Santini C, Tisato F (2013) Neutral and charged phosphine/scorpionate copper(I) complexes: effects of ligand assembly on their antiproliferative activity. Eur J Med Chem 59:218–226PubMedCrossRefGoogle Scholar
  54. Rackham O, Nichols SJ, Leedman PJ, Berners-Price SJ, Filipovska A (2007) A gold(I) phosphine complex selectively induces apoptosis in breast cancer cells: implications for anticancer therapeutics targeted to mitochondria. Biochem Pharmacol 74(7):992–1002PubMedCrossRefGoogle Scholar
  55. Reed E, Dabholkar M, Chabner BA (1996) Platinum analogues. In: Chabner BA, Longo DL (eds) Cancer chemotherapy and biotherapy: principles and practice, 2nd edn. Lippincott-Raven Publishers, Philadelphia, pp 357–378Google Scholar
  56. Rigobello MP, Folda A, Dani B, Menabò R, Scutari G, Bindoli A (2008) Gold(I) complexes determine apoptosis with limited oxidative stress in Jurkat T cells. Eur J Pharmacol 582(1–3):26–34PubMedCrossRefGoogle Scholar
  57. Rosenberg B (1971) Some biological effects of platinum compounds. New agents for the control of tumours. Platin Met Rev 15(2):42–51Google Scholar
  58. Santini C, Pellei M, Papini G, Morresi B, Galassi R, Ricci S, Tisato F, Porchia M, Rigobello MP, Gandin V, Marzano C (2011) In vitro antitumour activity of water soluble Cu(I), Ag(I) and Au(I) complexes supported by hydrophilic alkyl phosphine ligands. J Inorg Biochem 105(2):232–240PubMedCrossRefGoogle Scholar
  59. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin K-M, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17(6):1675–1687PubMedCentralPubMedCrossRefGoogle Scholar
  60. Sorenson CM, Eastman A (1988) Mechanism of cis-diamminedichloroplatinum(ll)-induced cytotoxicity: role of G2 arrest and DNA double-strand breaks. Cancer Res 48:4484–4488PubMedGoogle Scholar
  61. Sorenson CM, Barry MA, Eastman A (1990) Analysis of events associated with cell cycle arrest at G, phase and cell death induced by cisplatin. J Nat Cancer Inst 82:749–755PubMedCrossRefGoogle Scholar
  62. Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES (1998) Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Mol Cell 1:949–957PubMedCrossRefGoogle Scholar
  63. Strohfeldt K, Tacke M (2008) Bioorganometallic fulvene-derived titanocene anti-cancer drugs. Chem Soc Rev 37(6):1174–1180PubMedCrossRefGoogle Scholar
  64. Susin SA, Zamzami N, Kroemer G (1998) Mitochondria as regulators of apoptosis: doubt no more. Biochim Biophys Acta 1366(1–2):151–165PubMedCrossRefGoogle Scholar
  65. Vaughn DJ, Malkowicz SB (2001) Recent developments in chemotherapy for bladder cancer. Oncol (Williston Park) 15(6):763–771Google Scholar
  66. Venter GJS, Meijboom R, Roodt A (2007) Di-µ2-thiocyanato-bis[bis(tri-p-tolylphosphine)silver(I)] acetonitrile disolvate. Acta Cryst E63:m3076–m3077Google Scholar
  67. Wang CH, Shih WC, Chang HC, Kuo YY, Hung WC, Ong TG, Li WS (2011) Preparation and characterization of amino-linked heterocyclic carbene palladium, gold, and silver complexes and their use as anticancer agents that act by triggering apoptotic cell death. J Med Chem 54(14):5245–5249PubMedCrossRefGoogle Scholar
  68. Zartilas S, Hadjikakou SK, Hadjiliadis N, Kourkoumelis N, Kyros L, Kubicki M, Baril M, Butler IS, Karkabounas S, Balzarini J (2009) Tetrameric 1:1 and monomeric 1:3 complexes of silver(I) halides with tri(p-tolyl)-phosphine: a structural and biological study. Inorganic Chim Acta 362:1003–1010CrossRefGoogle Scholar
  69. Zeiss CJ (2003) The apoptosis-necrosis continuum: insights from genetically altered mice. Vet Pathol 40:481–495PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Eloise Ferreira
    • 1
  • Appollinaire Munyaneza
    • 2
  • Bernard Omondi
    • 2
  • Reinout Meijboom
    • 2
  • Marianne J. Cronjé
    • 1
  1. 1.Department of BiochemistryUniversity of JohannesburgJohannesburgSouth Africa
  2. 2.Department of Chemistry, Research Centre for Synthesis and CatalysisUniversity of JohannesburgJohannesburgSouth Africa

Personalised recommendations