Anticancer activity of structurally related ruthenium(II) cyclopentadienyl complexes

Abstract

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

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Abbreviations

AcP:

Acid phosphatase

2,2′-Bipy:

2,2′-Bipyridine

3BrP:

3-Bromopyruvate

DCA:

Dichloroacetate

2DG:

2-Deoxyglucose

DTNB:

Dithionitrobenzoic acid

FBS:

Fetal bovine serum

IC50 :

Half-maximal inhibitory concentration

ICP-MS:

Inductively coupled plasma mass spectrometry

Me2bipy:

4,4′-Dimethyl-2,2′-bipyridine

mTPPMS:

m-Diphenylphosphane benzene-3-sulfonate

MTT:

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

NR:

Neutral red

PAO:

Phenylarsine oxide

PBS:

Phosphate-buffered saline

pCMBS:

p-Chloromercuribenzene sulfonate

pNPP:

p-Nitrophenyl phosphate

PPh3 :

Triphenylphosphane

TM34:

[Ru(η5-C5H5)(PPh3)(2,2′-bipy)][CF3SO3]

TM85:

[Ru(η5-C5H5)(mTPPMSNa)(2,2′-bipy)][CF3SO3]

TM102:

[Ru(η5-C5H5)(PPh3)(Me2bpy)[CF3SO3]

TPMET:

Trans-plasma-membrane electron transport

Tris:

Tris(hydroxymethyl)aminomethane

References

  1. 1.

    Wang D, Lippard SJ (2005) Nat Rev Drug Discov 4:307–320

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Zhang CX, Lippard SJ (2003) Curr Opin Chem Biol 7:481–499

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Reedijk J (2009) Eur J Inorg Chem 2009:1303–1312

    Article  Google Scholar 

  4. 4.

    Klein AV, Hambley TW (2009) Chem Rev 109:4911–4920

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Hartinger CG, Zorbas-Seifried S, Jakupec MA, Kynast B, Zorbas H, Keppler BK (2006) J Inorg Biochem 100:891–904

    CAS  PubMed  Article  Google 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 50:2185–2193

    CAS  PubMed  Article  Google 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 5:2140–2155

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Peacock F, Sadler PJ (2008) Chem Asian J 13:1890–1899

    Article  Google Scholar 

  9. 9.

    Levina A, Mitra PA (2009) Metallomics 1:458–470

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Bergamo A, Masi A, Peacock AF, Habtemariam A, Sadler PJ, Sava G (2010) J Inorg Biochem 104:79–86

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Bergamo A, Gaiddon C, Schellens JH, Beijnen JH, Sava G (2012) J Inorg Biochem 106:90–99

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Sancho-Martínez SM, Prieto-García L, Prieto M, López-Novoa JM, López-Hernández FJ (2012) Pharmacol Ther 136:35–55

    PubMed  Article  Google Scholar 

  13. 13.

    Jakupec MA, Galanski M, Arion VB, Hartinger CG, Keppler BK (2008) Dalton Trans 183–194

  14. 14.

    Brabec V, Nováková O (2006) Drug Resist Updates 9:111–122

    CAS  Article  Google 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 51:6773–6781

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Bruijnincx PC, Sadler PJ (2008) Curr Opin Chem Biol 12:197–206

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  17. 17.

    Mura P, Camalli M, Casini A, Gabbiani C, Messori LJ (2010) J Inorg Biochem 104:111–117

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Fricker SP, Ciancetta A, Genheden S, Ryde UJ (2011) J Comput Aided Mol Des 25:729–742

    Article  Google 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 105:241–249

    CAS  PubMed  Article  Google 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 114:65–74

    CAS  PubMed  Article  Google 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 130:1–14

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Morais TS, Santos F, Côrte-Real L, Marques F, Robalo MP, Madeira PJA, Garcia MH (2013) J Inorg Biochem 122:8–17

    CAS  PubMed  Article  Google 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 117:261–269

    CAS  PubMed  Article  Google 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 24:1–9

    Google Scholar 

  25. 25.

    Pedersen PL (2007) J Bioenerg Biomembr 39:1–12

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E (2007) FEBS J 274:1393–1418

    PubMed  Article  Google Scholar 

  27. 27.

    Rodríguez-Enríquez S, Marín-Hernández A, Gallardo-Pérez JC, Carreño-Fuentes L, Moreno-Sánchez R (2009) Mol Nutr Food Res 53:29–48

    PubMed  Article  Google Scholar 

  28. 28.

    Gatenby RA, Gillies RJ (2007) Int J Biochem Cell Biol 39:1358–1366

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Warburgh O (1956) Science 124:269–270

    Google Scholar 

  30. 30.

    Hirschhaeuser F, Sattler UG, Mueller-Klieser W (2011) Cancer Res 71:6921–6925

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    DeBerardinis RJ (2008) Genet Med 10:767–777

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  32. 32.

    Bartrons R, Caro J (2007) J Bioenerg Biomembr 39:223–229

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Scatena R, Bottoni P, Pontoglio A, Mastrototaro L, Giardina B (2008) Expert Opin Investig Drugs 17:1533–1545

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Zhang F, Aft RL (2009) J Cancer Res Ther 5:41–43

    Google Scholar 

  35. 35.

    Mathupala SP (2011) Recent Pat Anticancer Drug Discov 6:6–14

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  36. 36.

    Pedersen PL (2012) J Bioenerg Biomembr 44:1–6

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Shoshan MC (2012) J Bioenerg Biomembr 44:7–15

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Cardaci S, Desideri E, Ciriolo MR (2012) J Bioenerg Biomembr 44:17–29

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Michelakis ED, Webster L, Mackey JR (2008) Br J Cancer 99:989–994

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  40. 40.

    Sutendra G, Michelakis ED (2013) Front Oncol 3:1–11

    Article  Google Scholar 

  41. 41.

    Goldenberg H (1982) Biochim Biophys Acta 694:203–223

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Lane DJ, Lawen A (2008) Biofactors 34:191–200

    PubMed  Article  Google Scholar 

  43. 43.

    Löw H, Crane FL, Morré JD (2012) Int J Biochem Cell Biol 44:1834–1838

    PubMed  Article  Google Scholar 

  44. 44.

    Del Principe D, Avigliano L, Savini I, Catani MV (2011) Antioxid Redox Signal 14:2289–2318

    PubMed  Article  Google Scholar 

  45. 45.

    Marques F, Crespo ME, Bicho M (1995) Redox Rep 1:113–117

    CAS  Google Scholar 

  46. 46.

    Marques F, Bicho MP (1997) Biol Signals 6:52–61

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Marques F, Crespo ME, Silva ZI, Bicho M (1999) Protoplasma 206:168–173

    CAS  Article  Google Scholar 

  48. 48.

    Schipfer W, Neophytou B, Trobisch R, Groiss O, Goldenberg H (1985) Int J Biochem 17:819–823

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Marques F, Crespo ME, Silva ZI, Bicho M (2000) Diabetes Res Clin Pract 47:191–198

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Herst PM, Berridge MV (2007) Biochim Biophys Acta 1767:170–177

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Orringer EP, Roer ME (1979) J Clin Invest 63:53–58

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  52. 52.

    Baker MA, Lane DJ, Ly JD, De Pinto V, Lawen A (2004) J Biol Chem 279:4811–4819

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Lane DJR, Lawen A (2008) Anal Biochem 373:287–295

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Avron M, Shavit N (1963) Anal Biochem 6:549–554

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Pieroni L, Khalil L, Charlotte F, Poynard T, Piton A, Hainque B, Imbert-Bismut F (2001) Clin Chem 47:2059–2061

    CAS  PubMed  Google Scholar 

  56. 56.

    Rodríguez-Alonso J, Montañez R, Rodríguez-Caso L, Ángel Medina M (2008) J Bioenerg Biomembr 40:45–51

    PubMed  Article  Google Scholar 

  57. 57.

    Herst PM, Berridge MV (2006) Curr Mol Med 6:895–904

    CAS  PubMed  Article  Google 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 9:299–306

    CAS  PubMed  Google Scholar 

  60. 60.

    Kim C, Crane FL, Faulk WP, Morré J (2002) J Biol Chem 277:16441–16447

    CAS  PubMed  Article  Google 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 394:616–626

    CAS  Article  Google 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 13:2352–2362

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Fotakis G, Timbrell JA (2006) Toxicol Lett 160:171–177

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Yang TT, Sinai P, Kain SR (1996) Anal Biochem 241:103–108

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Timerbaev AR, Hartinger CG, Aleksenko SS, Keppler BK (2006) Chem Rev 106:2224–2248

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Cohen GL, Bauer WR, Barton JK, Lippard SJ (1979) Science 203:1014–1016

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Bowler BE, Hollis LS, Lippard SJ (1984) J Am Chem Soc 106:6102–6104

    CAS  Article  Google Scholar 

  68. 68.

    Babu E, Ramachandran S, Kandaswamy VC, Elangovan S, Prasad PD, Ganapathy V, Thangaraju M (2011) Oncogene 30:4026–4037

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  69. 69.

    Lane DJR, Robinson SR, Czerwinska H, Lawen A (2010) Biochem J 428:191–200

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Tan AS, Berridge MV (2004) Redox Rep 9:302–306

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Alberti C (2009) Eur Rev Med Pharmacol Sci 13:13–21

    CAS  PubMed  Google Scholar 

  72. 72.

    Ganapathy-Kanniappan S, Geschwind JFH (2013) Mol Cancer 12:152

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

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).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Fernanda Marques.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Côrte-Real, L., Mendes, F., Coimbra, J. et al. Anticancer activity of structurally related ruthenium(II) cyclopentadienyl complexes. J Biol Inorg Chem 19, 853–867 (2014). https://doi.org/10.1007/s00775-014-1120-y

Download citation

Keywords

  • Glycolysis
  • Drug targets
  • Redox enzymes
  • Cancer therapy
  • Ruthenium drugs