JBIC Journal of Biological Inorganic Chemistry

, Volume 19, Issue 6, pp 853–867 | Cite as

Anticancer activity of structurally related ruthenium(II) cyclopentadienyl complexes

  • Leonor Côrte-Real
  • Filipa Mendes
  • Joana Coimbra
  • Tânia S. Morais
  • Ana Isabel Tomaz
  • Andreia Valente
  • M. Helena Garcia
  • Isabel Santos
  • Manuel Bicho
  • Fernanda Marques
Original Paper


A set of structurally related Ru(η5-C5H5) complexes with bidentate N,N′-heteroaromatic ligands have been evaluated as prospective metallodrugs, with focus on exploring the uptake and cell death mechanisms and potential cellular targets. We have extended these studies to examine the potential of these complexes to target cancer cell metabolism, the energetic-related phenotype of cancer cells. The observations that these complexes can enter cells, probably facilitated by binding to plasma transferrin, and can be retained preferentially at the membranes prompted us to explore possible membrane targets involved in cancer cell metabolism. Most malignant tumors present the Warburg effect, which consists in increasing glycolytic rates with production of lactate, even in the presence of oxygen. The reliance of glycolytic cancer cells on trans-plasma-membrane electron transport (TPMET) systems for their continued survival raises the question of their appropriateness as a target for anticancer drug development strategies. Considering the interesting findings that some anticancer drugs in clinical use are cytotoxic even without entering cells and can inhibit TPMET activity, we investigated whether redox enzyme modulation could be a potential mechanism of action of antitumor ruthenium complexes. The results from this study indicated that ruthenium complexes can inhibit lactate production and TPMET activity in a way dependent on the cancer cell aggressiveness and the concentration of the complex. Combination approaches that target cell metabolism (glycolytic inhibitors) as well as proliferation are needed to successfully cure cancer. This study supports the potential use of some of these ruthenium complexes as adjuvants of glycolytic inhibitors in the treatment of aggressive cancers.

Graphical abstract

A simplified hypothetical model showing the possible relationship between the trans-plasma-membrane electron transport (tPMET) system (ferricyanide reductase), the transferrin receptor, and the Na+/H+ antiporter. This tPMET might be involved in iron uptake and in regulating the NADH-to-NAD+ ratio. As a consequence of tPMET activity, the antiport is probably activated by proton release. (Adapted from Crane et al., 1991; Herst and Berridge, Curr. Mol. Med. 6:895–904, 2006). MET mitochondrial electron transport, TCA tricarboxylic acid


Glycolysis Drug targets Redox enzymes Cancer therapy Ruthenium drugs 



Acid phosphatase










Dithionitrobenzoic acid


Fetal bovine serum


Half-maximal inhibitory concentration


Inductively coupled plasma mass spectrometry




m-Diphenylphosphane benzene-3-sulfonate


3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide


Neutral red


Phenylarsine oxide


Phosphate-buffered saline


p-Chloromercuribenzene sulfonate


p-Nitrophenyl phosphate










Trans-plasma-membrane electron transport





This work was financed by national funds through FCT, the Portuguese Foundation for Science and Technology, within the scope of projects PTDC/QUI-QUI/101187/2008, PTDC/QUI-QUI/118077/2010, PEst-OE/QUI/UI0100/2011, and PEst-OE/QUI/UI0536/2011, as well as the Ciência2007 initiative. T.S.M. thanks FCT for her PhD grant (SFRH/BD/45871/2008), and A.V. thanks FCT for her postdoctoral grant (SFRH/BPD/80459/2011).


  1. 1.
    Wang D, Lippard SJ (2005) Nat Rev Drug Discov 4:307–320PubMedCrossRefGoogle Scholar
  2. 2.
    Zhang CX, Lippard SJ (2003) Curr Opin Chem Biol 7:481–499PubMedCrossRefGoogle Scholar
  3. 3.
    Reedijk J (2009) Eur J Inorg Chem 2009:1303–1312CrossRefGoogle Scholar
  4. 4.
    Klein AV, Hambley TW (2009) Chem Rev 109:4911–4920PubMedCrossRefGoogle Scholar
  5. 5.
    Hartinger CG, Zorbas-Seifried S, Jakupec MA, Kynast B, Zorbas H, Keppler BK (2006) J Inorg Biochem 100:891–904PubMedCrossRefGoogle Scholar
  6. 6.
    Groessl M, Reisner E, Hartinger CG, Eichinger R, Semenova O, Timerbaev AR, Jakupec MA, Arion VB, Keppler BK (2007) J Med Chem 50:2185–2193PubMedCrossRefGoogle Scholar
  7. 7.
    Hartinger CG, Jakupec MA, Zorbas-Seifried S, Groessl M, Egger A, Berger W, Zorbas H, Dyson PJ, Keppler BK (2008) Chem Biodivers 5:2140–2155PubMedCrossRefGoogle Scholar
  8. 8.
    Peacock F, Sadler PJ (2008) Chem Asian J 13:1890–1899CrossRefGoogle Scholar
  9. 9.
    Levina A, Mitra PA (2009) Metallomics 1:458–470PubMedCrossRefGoogle Scholar
  10. 10.
    Bergamo A, Masi A, Peacock AF, Habtemariam A, Sadler PJ, Sava G (2010) J Inorg Biochem 104:79–86PubMedCrossRefGoogle Scholar
  11. 11.
    Bergamo A, Gaiddon C, Schellens JH, Beijnen JH, Sava G (2012) J Inorg Biochem 106:90–99PubMedCrossRefGoogle Scholar
  12. 12.
    Sancho-Martínez SM, Prieto-García L, Prieto M, López-Novoa JM, López-Hernández FJ (2012) Pharmacol Ther 136:35–55PubMedCrossRefGoogle Scholar
  13. 13.
    Jakupec MA, Galanski M, Arion VB, Hartinger CG, Keppler BK (2008) Dalton Trans 183–194Google Scholar
  14. 14.
    Brabec V, Nováková O (2006) Drug Resist Updates 9:111–122CrossRefGoogle Scholar
  15. 15.
    Casini A, Gabbiani C, Sorrentino F, Rigobello MP, Bindoli A, Geldbach TJ, Marrone A, Re N, Hartinger CG, Dyson PJ, Messori L (2008) J Med Chem 51:6773–6781PubMedCrossRefGoogle Scholar
  16. 16.
    Bruijnincx PC, Sadler PJ (2008) Curr Opin Chem Biol 12:197–206PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Mura P, Camalli M, Casini A, Gabbiani C, Messori LJ (2010) J Inorg Biochem 104:111–117PubMedCrossRefGoogle Scholar
  18. 18.
    Fricker SP, Ciancetta A, Genheden S, Ryde UJ (2011) J Comput Aided Mol Des 25:729–742CrossRefGoogle Scholar
  19. 19.
    Moreno V, Font-Bardia M, Calvet T, Lorenzo J, Avilés FX, Garcia MH, Morais TS, Valente A, Robalo MP (2011) J Inorg Biochem 105:241–249PubMedCrossRefGoogle Scholar
  20. 20.
    Morais TS, Silva TJ, Marques F, Robalo MP, Avecilla F, Madeira PJ, Mendes PJ, Santos I, Garcia MH (2012) J Inorg Biochem 114:65–74PubMedCrossRefGoogle Scholar
  21. 21.
    Morais TS, Santos FC, Jorge TF, Côrte-Real L, Madeira PJA, Marques F, Robalo MP, Matos A, Santos I, Garcia MH (2014) J Inorg Biochem 130:1–14PubMedCrossRefGoogle Scholar
  22. 22.
    Morais TS, Santos F, Côrte-Real L, Marques F, Robalo MP, Madeira PJA, Garcia MH (2013) J Inorg Biochem 122:8–17PubMedCrossRefGoogle Scholar
  23. 23.
    Tomaz AI, Jakusch T, Morais TS, Marques F, Almeida RF, Mendes F, Enyedy EA, Santos I, Pessoa JC, Kiss T, Garcia MH (2012) J Inorg Biochem 117:261–269PubMedCrossRefGoogle Scholar
  24. 24.
    Côrte-Real L, Matos AP, Alho I, Morais TS, Tomaz AI, Garcia MH, Santos I, Bicho MP, Marques F (2013) Microsc Microanal 24:1–9Google Scholar
  25. 25.
    Pedersen PL (2007) J Bioenerg Biomembr 39:1–12PubMedCrossRefGoogle Scholar
  26. 26.
    Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E (2007) FEBS J 274:1393–1418PubMedCrossRefGoogle Scholar
  27. 27.
    Rodríguez-Enríquez S, Marín-Hernández A, Gallardo-Pérez JC, Carreño-Fuentes L, Moreno-Sánchez R (2009) Mol Nutr Food Res 53:29–48PubMedCrossRefGoogle Scholar
  28. 28.
    Gatenby RA, Gillies RJ (2007) Int J Biochem Cell Biol 39:1358–1366PubMedCrossRefGoogle Scholar
  29. 29.
    Warburgh O (1956) Science 124:269–270Google Scholar
  30. 30.
    Hirschhaeuser F, Sattler UG, Mueller-Klieser W (2011) Cancer Res 71:6921–6925PubMedCrossRefGoogle Scholar
  31. 31.
    DeBerardinis RJ (2008) Genet Med 10:767–777PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Bartrons R, Caro J (2007) J Bioenerg Biomembr 39:223–229PubMedCrossRefGoogle Scholar
  33. 33.
    Scatena R, Bottoni P, Pontoglio A, Mastrototaro L, Giardina B (2008) Expert Opin Investig Drugs 17:1533–1545PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang F, Aft RL (2009) J Cancer Res Ther 5:41–43Google Scholar
  35. 35.
    Mathupala SP (2011) Recent Pat Anticancer Drug Discov 6:6–14PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Pedersen PL (2012) J Bioenerg Biomembr 44:1–6PubMedCrossRefGoogle Scholar
  37. 37.
    Shoshan MC (2012) J Bioenerg Biomembr 44:7–15PubMedCrossRefGoogle Scholar
  38. 38.
    Cardaci S, Desideri E, Ciriolo MR (2012) J Bioenerg Biomembr 44:17–29PubMedCrossRefGoogle Scholar
  39. 39.
    Michelakis ED, Webster L, Mackey JR (2008) Br J Cancer 99:989–994PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Sutendra G, Michelakis ED (2013) Front Oncol 3:1–11CrossRefGoogle Scholar
  41. 41.
    Goldenberg H (1982) Biochim Biophys Acta 694:203–223PubMedCrossRefGoogle Scholar
  42. 42.
    Lane DJ, Lawen A (2008) Biofactors 34:191–200PubMedCrossRefGoogle Scholar
  43. 43.
    Löw H, Crane FL, Morré JD (2012) Int J Biochem Cell Biol 44:1834–1838PubMedCrossRefGoogle Scholar
  44. 44.
    Del Principe D, Avigliano L, Savini I, Catani MV (2011) Antioxid Redox Signal 14:2289–2318PubMedCrossRefGoogle Scholar
  45. 45.
    Marques F, Crespo ME, Bicho M (1995) Redox Rep 1:113–117Google Scholar
  46. 46.
    Marques F, Bicho MP (1997) Biol Signals 6:52–61PubMedCrossRefGoogle Scholar
  47. 47.
    Marques F, Crespo ME, Silva ZI, Bicho M (1999) Protoplasma 206:168–173CrossRefGoogle Scholar
  48. 48.
    Schipfer W, Neophytou B, Trobisch R, Groiss O, Goldenberg H (1985) Int J Biochem 17:819–823PubMedCrossRefGoogle Scholar
  49. 49.
    Marques F, Crespo ME, Silva ZI, Bicho M (2000) Diabetes Res Clin Pract 47:191–198PubMedCrossRefGoogle Scholar
  50. 50.
    Herst PM, Berridge MV (2007) Biochim Biophys Acta 1767:170–177PubMedCrossRefGoogle Scholar
  51. 51.
    Orringer EP, Roer ME (1979) J Clin Invest 63:53–58PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Baker MA, Lane DJ, Ly JD, De Pinto V, Lawen A (2004) J Biol Chem 279:4811–4819PubMedCrossRefGoogle Scholar
  53. 53.
    Lane DJR, Lawen A (2008) Anal Biochem 373:287–295PubMedCrossRefGoogle Scholar
  54. 54.
    Avron M, Shavit N (1963) Anal Biochem 6:549–554PubMedCrossRefGoogle Scholar
  55. 55.
    Pieroni L, Khalil L, Charlotte F, Poynard T, Piton A, Hainque B, Imbert-Bismut F (2001) Clin Chem 47:2059–2061PubMedGoogle Scholar
  56. 56.
    Rodríguez-Alonso J, Montañez R, Rodríguez-Caso L, Ángel Medina M (2008) J Bioenerg Biomembr 40:45–51PubMedCrossRefGoogle Scholar
  57. 57.
    Herst PM, Berridge MV (2006) Curr Mol Med 6:895–904PubMedCrossRefGoogle Scholar
  58. 58.
    Prata C, Grasso C, Loizzo S, Vieceli Dalla Sega F, Caliceti C, Zambonin L, Fiorentini D, Hakim G, Berridge MV, Landia L (2010) Leuk Res. doi: 10.1016/j.leukres.2010.02.032
  59. 59.
    Sun IL, Crane FL (1984) Biochem Int 9:299–306PubMedGoogle Scholar
  60. 60.
    Kim C, Crane FL, Faulk WP, Morré J (2002) J Biol Chem 277:16441–16447PubMedCrossRefGoogle Scholar
  61. 61.
    Matos CP, Valente A, Marques F, Adão P, Robalo MP, Almeida RFM, Pessoa JC, Santos I, Garcia MH, Tomaz AI (2013) Inorg Chim Acta 394:616–626CrossRefGoogle Scholar
  62. 62.
    Gama S, Mendes F, Esteves T, Marques F, Matos A, Rino J, Coimbra J, Ravera M, Gabano E, Santos I, Paulo A (2012) ChemBioChem 13:2352–2362PubMedCrossRefGoogle Scholar
  63. 63.
    Fotakis G, Timbrell JA (2006) Toxicol Lett 160:171–177PubMedCrossRefGoogle Scholar
  64. 64.
    Yang TT, Sinai P, Kain SR (1996) Anal Biochem 241:103–108PubMedCrossRefGoogle Scholar
  65. 65.
    Timerbaev AR, Hartinger CG, Aleksenko SS, Keppler BK (2006) Chem Rev 106:2224–2248PubMedCrossRefGoogle Scholar
  66. 66.
    Cohen GL, Bauer WR, Barton JK, Lippard SJ (1979) Science 203:1014–1016PubMedCrossRefGoogle Scholar
  67. 67.
    Bowler BE, Hollis LS, Lippard SJ (1984) J Am Chem Soc 106:6102–6104CrossRefGoogle Scholar
  68. 68.
    Babu E, Ramachandran S, Kandaswamy VC, Elangovan S, Prasad PD, Ganapathy V, Thangaraju M (2011) Oncogene 30:4026–4037PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Lane DJR, Robinson SR, Czerwinska H, Lawen A (2010) Biochem J 428:191–200PubMedCrossRefGoogle Scholar
  70. 70.
    Tan AS, Berridge MV (2004) Redox Rep 9:302–306PubMedCrossRefGoogle Scholar
  71. 71.
    Alberti C (2009) Eur Rev Med Pharmacol Sci 13:13–21PubMedGoogle Scholar
  72. 72.
    Ganapathy-Kanniappan S, Geschwind JFH (2013) Mol Cancer 12:152PubMedCrossRefGoogle Scholar

Copyright information

© SBIC 2014

Authors and Affiliations

  • Leonor Côrte-Real
    • 1
    • 3
  • Filipa Mendes
    • 1
  • Joana Coimbra
    • 2
  • Tânia S. Morais
    • 3
  • Ana Isabel Tomaz
    • 3
  • Andreia Valente
    • 3
  • M. Helena Garcia
    • 3
  • Isabel Santos
    • 1
  • Manuel Bicho
    • 4
    • 5
  • Fernanda Marques
    • 1
  1. 1.Unidade Ciências Químicas e Radiofarmacêuticas, Instituto Superior TécnicoUniversidade de LisboaBobadela LRS SacavémPortugal
  2. 2.Laboratório Central de AnálisesUniversidade de AveiroAveiroPortugal
  3. 3.Centro de Ciências Moleculares e Materiais, Faculdade de Ciências,Universidade de LisboaLisbonPortugal
  4. 4.Laboratório de Genética, Faculdade de MedicinaUniversidade de LisboaLisbonPortugal
  5. 5.Instituto Bento da Rocha CabralLisbonPortugal

Personalised recommendations