Cancer Chemotherapy and Pharmacology

, Volume 66, Issue 1, pp 1–9 | Cite as

Ruthenium-based chemotherapeutics: are they ready for prime time?

  • Emmanuel S. Antonarakis
  • Ashkan Emadi
Mini Review


Since the discovery of cis-platinum, many transition metal complexes have been synthesized and assayed for antineoplastic activity. In recent years, ruthenium-based molecules have emerged as promising antitumor and antimetastatic agents with potential uses in platinum-resistant tumors or as alternatives to platinum. Ruthenium compounds theoretically possess unique biochemical features allowing them to accumulate preferentially in neoplastic tissues and to convert to their active state only after entering tumor cells. Intriguingly, some ruthenium agents show significant activity against cancer metastases but have minimal effects on primary tumors. Two ruthenium-based drugs, NAMI-A and KP1019, have reached human clinical testing. This review will highlight the chemical properties, mechanism of action, preclinical data, and early phase clinical results of these two lead ruthenium compounds. Other promising ruthenium agents will also be reviewed with emphasis on the novel ruthenium compound ONCO4417, and DW1/2 that has demonstrated Pim-1 kinase inhibition in preclinical systems. Further development of these and other ruthenium agents may rely on novel approaches including rational combination strategies as well as identification of potential pharmacodynamic biomarkers of drug activity aiding early phase clinical studies.


Ruthenium Chemotherapy NAMI-A KP1019 ONCO4417 


Conflict of interest statement

The authors indicate no financial or other conflicts of interest.


  1. 1.
    Galanski M, Jakupec MA, Keppler BK (2005) Update of the preclinical situation of anticancer platinum complexes: novel design strategies and innovative analytical approaches. Curr Med Chem 12:2075–2094CrossRefPubMedGoogle Scholar
  2. 2.
    Galanski M (2006) Recent developments in the field of anticancer platinum complexes. Recent Pat Anticancer Drug Discov 1:285–295CrossRefPubMedGoogle Scholar
  3. 3.
    Brabec V, Kasparkova J (2005) Modifications of DNA by platinum complexes. Relation to resistance of tumors to platinum antitumor drugs. Drug Resist Updat 8:131–146CrossRefPubMedGoogle Scholar
  4. 4.
    Ott I, Gust R (2007) Non platinum metal complexes as anti-cancer drugs. Arch Pharm (Weinheim) 340:117–126CrossRefGoogle Scholar
  5. 5.
    Sava G, Bergamo A (2009) Ruthenium drugs for cancer chemotherapy: an ongoing challenge to treat solid tumours. In: Bonetti A et al (eds) Platinum and other heavy metal compounds in cancer chemotherapy. Humana Press, New York, pp 57–66. doi: 10.1007/978-1-60327-459-3 CrossRefGoogle Scholar
  6. 6.
    Kostova I (2006) Ruthenium complexes as anticancer agents. Curr Med Chem 13:1085–1107CrossRefPubMedGoogle Scholar
  7. 7.
    Heffeter P, Jungwirth U, Jakupec M, Hartinger C, Galanski M et al (2008) Resistance against novel anticancer metal compounds: differences and similarities. Drug Resist Updat 11:1–16CrossRefPubMedGoogle Scholar
  8. 8.
    Sava G, Zorzet S, Giraldi T, Mestroni G, Zassinovich G (1984) Antineoplastic activity and toxicity of an organometallic complex of ruthenium(II) in comparison with cis-PDD in mice bearing solid malignant neoplasms. Eur J Cancer Clin Oncol 20:841–847CrossRefPubMedGoogle Scholar
  9. 9.
    Sava G, Bergamo A (2000) Ruthenium-based compounds and tumour growth control (review). Int J Oncol 17:353–365PubMedGoogle Scholar
  10. 10.
    Schluga P, Hartinger CG, Egger A, Reisner E, Galanski M et al (2006) Redox behavior of tumor-inhibiting ruthenium(III) complexes and effects of physiological reductants on their binding to GMP. Dalton Trans 14:1796–1802Google Scholar
  11. 11.
    Rockwell S, Dobrucki IT, Kim EY, Marrison ST, Vu VT (2009) Hypoxia and radiation therapy: past history, ongoing research, and future promise. Curr Mol Med 9:442–458CrossRefPubMedGoogle Scholar
  12. 12.
    Gagliardi R, Sava G, Pacor S, Mestroni G, Alessio E (1994) Antimetastatic action and toxicity on healthy tissues of Na[trans-RuCl4(DMSO)Im] in the mouse. Clin Exp Metastasis 12:93–100CrossRefPubMedGoogle Scholar
  13. 13.
    Bergamo A, Masi A, Dyson PJ, Sava G (2008) Modulation of the metastatic progression of breast cancer with an organometallic ruthenium compound. Int J Oncol 33:1281–1289PubMedGoogle Scholar
  14. 14.
    Sava G, Alessio E, Bergamo A, Mestroni G (1999) Sulfoxide ruthenium complexes. Top Biol Inorg Chem 1:143–169Google Scholar
  15. 15.
    Pieper T, Borsky K, Keppler BK (1999) Non-platinum antitumor compounds. Top Biol Inorg Chem 1:171–199Google Scholar
  16. 16.
    Sava G, Pacor S, Mestroni G, Alessio E (1992) Na[trans-RuCl4(DMSO)Im], a metal complex of ruthenium with antimetastatic properties. Clin Exp Metastasis 10:273–280CrossRefPubMedGoogle Scholar
  17. 17.
    Sava G, Pacor S, Bergamo A, Cocchietto M, Mestroni G et al (1995) Effects of ruthenium complexes on experimental tumors: irrelevance of cytotoxicity for metastasis inhibition. Chem Biol Interact 95:109–126CrossRefPubMedGoogle Scholar
  18. 18.
    Jakupec MA, Arion VB, Kapitza S, Reisner E, Eichinger A et al (2005) KP1019 (FFC14A) from bench to bedside: preclinical and early clinical development—an overview. Int J Clin Pharmacol Ther 43:595–596PubMedGoogle Scholar
  19. 19.
    Hartinger CG, Jakupec MA, Zorbas-Seifried S, Groessl M, Egger A et al (2008) KP1019, a new redox-active anticancer agent–preclinical development and results of a clinical phase I study in tumor patients. Chem Biodivers 5:2140–2155CrossRefPubMedGoogle Scholar
  20. 20.
    Clarke MJ, Zhu F, Frasca DR (1999) Non-platinum chemotherapeutic metallopharmaceuticals. Chem Rev 99:2511–2534CrossRefPubMedGoogle Scholar
  21. 21.
    Bloemink MJ, Reedijk J (1996) Cisplatin and derived anticancer drugs: mechanism and current status of DNA binding. Met Ions Biol Syst 32:641–685PubMedGoogle Scholar
  22. 22.
    Reedijk J (2003) New clues for platinum antitumor chemistry: kinetically controlled metal binding to DNA. Proc Natl Acad Sci USA 100:3611–3616CrossRefPubMedGoogle Scholar
  23. 23.
    Yamada H, Koike T, Hurst JK (2001) Water exchange rates in the diruthenium μ-oxo ion cis, cis-[(bpy)2Ru(OH)2]2O4+. J Am Chem Soc 123:12775–12780CrossRefPubMedGoogle Scholar
  24. 24.
    Chakravarty J, Bhattacharya S (1996) Ruthenium phenolates. Synthesis, characterization and electron-transfer properties of some salicylaldiminato and 2-(arylazo)phenolato complexes of ruthenium. Polyhedron 15:1047–1055CrossRefGoogle Scholar
  25. 25.
    Baitalik S, Adhikary B (1997) Heterochelates of ruthenium(II): electrochemistry, absorption spectra, and luminescence properties. Polyhedron 16:4073–4080CrossRefGoogle Scholar
  26. 26.
    Kratz F, Messori L (1993) Spectral characterization of ruthenium(III) transferrin. J Inorg Biochem 49:79–82CrossRefPubMedGoogle Scholar
  27. 27.
    Pongratz M, Schluga P, Jakupec MA, Arion VB, Hartinger CG et al (2004) Transferrin binding and transferrin-mediated cellular uptake of the ruthenium coordination compound KP1019, studied by means of AAS, ESI-MS and CD spectroscopy. J Anal At Spectrom 19:46–51CrossRefGoogle Scholar
  28. 28.
    Mestroni G, Alessio E, Sava G (1998) International Patent PCT C 07F 15/00, A61 K 31/28, WO 98/0043Google Scholar
  29. 29.
    Bergamo A, Gagliardi R, Scarcia V, Furlani A, Alessio E et al (1999) In vitro cell cycle arrest, in vivo action on solid metastasizing tumors, and host toxicity of the antimetastatic drug NAMI-A and cisplatin. J Pharmacol Exp Ther 289:559–564PubMedGoogle Scholar
  30. 30.
    Zorzet S, Bergamo A, Cocchietto M, Sorc A, Gava B et al (2000) Lack of in vitro cytotoxicity, associated to increased G2-M cell fraction and inhibition of matrigel invasion, may predict in vivo-selective antimetastasis activity of ruthenium complexes. J Pharmacol Exp Ther 295:927–933PubMedGoogle Scholar
  31. 31.
    Vacca A, Bruno M, Boccarelli A, Coluccia M, Ribatti D et al (2002) Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A. Br J Cancer 86:993–998CrossRefPubMedGoogle Scholar
  32. 32.
    Pluim D, van Waardenburg RC, Beijnen JH, Schellens JH (2004) Cytotoxicity of the organic ruthenium anticancer drug NAMI-A is correlated with DNA binding in four different human tumor cell lines. Cancer Chemother Pharmacol 54:71–78CrossRefPubMedGoogle Scholar
  33. 33.
    Sava G, Gagliardi R, Bergamo A, Alessio E, Mestroni G (1999) Treatment of metastases of solid mouse tumours by NAMI-A: comparison with cisplatin, cyclophosphamide and dacarbazine. Anticancer Res 19:969–972PubMedGoogle Scholar
  34. 34.
    Sava G, Capozzi I, Clerici K, Gagliardi G, Alessio E et al (1998) Pharmacological control of lung metastases of solid tumours by a novel ruthenium complex. Clin Exp Metastasis 16:371–379CrossRefPubMedGoogle Scholar
  35. 35.
    Sava G, Clerici K, Capozzi I, Cocchietto M, Gagliardi R et al (1999) Reduction of lung metastasis by ImH[trans-RuCl4(DMSO)Im]: mechanism of the selective action investigated on mouse tumors. Anticancer Drugs 10:129–138CrossRefPubMedGoogle Scholar
  36. 36.
    Cocchietto M, Sava G (2000) Blood concentration and toxicity of the antimetastasis agent NAMI-A following repeated intravenous treatment in mice. Pharmacol Toxicol 87:193–197CrossRefPubMedGoogle Scholar
  37. 37.
    Rademaker-Lakhai JM, van den Bongard D, Pluim D, Beijnen JH, Schellens JH (2004) A Phase I and pharmacological study with imidazolium-trans-DMSO-imidazole-tetrachlororuthenate, a novel ruthenium anticancer agent. Clin Cancer Res 10:3717–3727CrossRefPubMedGoogle Scholar
  38. 38.
    Brouwers EE, Tibben MM, Rosing H, Schellens JH, Beijnen JH (2007) Determination of ruthenium originating from the investigational anti-cancer drug NAMI-A in human plasma ultrafiltrate, plasma, and urine by inductively coupled plasma mass spectrometry. Rapid Commun Mass Spectrom 21:1521–1530CrossRefPubMedGoogle Scholar
  39. 39.
    Galanski M, Arion VB, Jakupec MA, Keppler BK (2003) Recent developments in the field of tumor-inhibiting metal complexes. Curr Pharm Des 9:2078–2089CrossRefPubMedGoogle Scholar
  40. 40.
    Kapitza S, Pongratz M, Jakupec MA, Heffeter P, Berger W et al (2005) Heterocyclic complexes of ruthenium(III) induce apoptosis in colorectal carcinoma cells. J Cancer Res Clin Oncol 131:101–110CrossRefPubMedGoogle Scholar
  41. 41.
    Kapitza S, Jakupec MA, Uhl M, Keppler BK, Marian B (2005) The heterocyclic ruthenium(III) complex KP1019 (FFC14A) causes DNA damage and oxidative stress in colorectal tumor cells. Cancer Lett 226:115–121CrossRefPubMedGoogle Scholar
  42. 42.
    Heffeter P, Pongratz M, Steiner E, Chiba P, Jakupec MA et al (2005) Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A). J Pharmacol Exp Ther 312:281–289CrossRefPubMedGoogle Scholar
  43. 43.
    Hartinger CG, Zorbas-Seifried S, Jakupec MA, Kynast B, Zorbas H et al (2006) From bench to bedside–preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A). J Inorg Biochem 100:891–904CrossRefPubMedGoogle Scholar
  44. 44.
    Lentz F, Drescher A, Lindauer A, Henke M, Hilger RA et al (2009) Pharmacokinetics of a novel anticancer ruthenium complex (KP1019, FFC14A) in a phase I dose-escalation study. Anticancer Drugs 20:97–103CrossRefPubMedGoogle Scholar
  45. 45.
    Henke MM, Richly H, Drescher A, Grubert M, Alex D et al (2009) Pharmacokinetic study of sodium trans[tetrachlorobis(1H-indazole)-ruthenate (III)]/-indazole hydrochloride (1:1.1) (FFC14A) in patients with solid tumors. Int J Clin Pharmacol Ther 47:58–60PubMedGoogle Scholar
  46. 46.
    Morris RE, Aird RE, Murdoch Pdel S, Chen H, Cummings J et al (2001) Inhibition of cancer cell growth by ruthenium(II) arene complexes. J Med Chem 44:3616–3621CrossRefPubMedGoogle Scholar
  47. 47.
    Chen H, Parkinson JA, Parsons S, Coxall RA, Gould RO et al (2002) Organometallic ruthenium(II) diamine anticancer complexes: arene-nucleobase stacking and stereospecific hydrogen-bonding in guanine adducts. J Am Chem Soc 124:3064–3082CrossRefPubMedGoogle Scholar
  48. 48.
    Chen H, Parkinson JA, Morris RE, Sadler PJ (2003) Highly selective binding of organometallic ruthenium ethylenediamine complexes to nucleic acids: novel recognition mechanisms. J Am Chem Soc 125:173–186CrossRefPubMedGoogle Scholar
  49. 49.
    Hayward RL, Schornagel QC, Tente R, Macpherson JS, Aird RE et al (2005) Investigation of the role of Bax, p21/Waf1 and p53 as determinants of cellular responses in HCT116 colorectal cancer cells exposed to the novel cytotoxic ruthenium(II) organometallic agent, RM175. Cancer Chemother Pharmacol 55:577–583CrossRefPubMedGoogle Scholar
  50. 50.
    Gaiddon C, Jeannequin P, Bischoff P, Pfeffer M, Sirlin C et al (2005) Ruthenium (II)-derived organometallic compounds induce cytostatic and cytotoxic effects on mammalian cancer cell lines through p53-dependent and p53-independent mechanisms. J Pharmacol Exp Ther 315:1403–1411CrossRefPubMedGoogle Scholar
  51. 51.
    Aird RE, Cummings J, Ritchie AA, Muir M, Morris RE et al (2002) In vitro and in vivo activity and cross resistance profiles of novel ruthenium (II) organometallic arene complexes in human ovarian cancer. Br J Cancer 86:1652–1657CrossRefPubMedGoogle Scholar
  52. 52.
    Foster RE, Cole DA, Mead S, Sadler PJ, Grimshaw KM (2009) Investigation into the mechanism of action of the ruthenium(II) organometallic complex, ONCO 4417. In: Proceedings of the American association for cancer research, April 18–22: Abstract 889Google Scholar
  53. 53.
    Scolaro C, Bergamo A, Brescacin L, Delfino R, Cocchietto M et al (2005) In vitro and in vivo evaluation of ruthenium(II)-arene PTA complexes. J Med Chem 48:4161–4171CrossRefPubMedGoogle Scholar
  54. 54.
    Vock CA, Scolaro C, Phillips AD, Scopelliti R, Sava G et al (2006) Synthesis, characterization, and in vitro evaluation of novel ruthenium(II) η6-arene imidazole complexes. J Med Chem 49:5552–5561CrossRefPubMedGoogle Scholar
  55. 55.
    Scolaro C, Geldbach TJ, Rochat S (2006) Influence of hydrogen-bonding substituents on the cytotoxicity of RAPTA compounds. Organometallics 25:756–765CrossRefGoogle Scholar
  56. 56.
    Scolaro C, Chaplin AB, Hartinger CG, Bergamo A, Cocchietto M et al. (2007) Tuning the hydrophobicity of ruthenium(II)-arene (RAPTA) drugs to modify uptake, biomolecular interactions and efficacy. Dalton Trans 43:5065–5072Google Scholar
  57. 57.
    Chatterjee S, Kundu S, Bhattacharyya A, Hartinger CG, Dyson PJ (2008) The ruthenium(II)-arene compound RAPTA-C induces apoptosis in EAC cells through mitochondrial and p53-JNK pathways. J Biol Inorg Chem 13:1149–1155CrossRefPubMedGoogle Scholar
  58. 58.
    Schäfer S, Ott I, Gust R, Sheldrick WS (2007) Influence of the polypyridyl (pp) ligand size on the DNA binding properties, cytotoxicity and cellular uptake of organoruthenium(II) complexes of the type [(η6-C6Me6)Ru(L)(pp)]n+ [L = Cl, n = 1; L = (NH2)2CS, n = 2]. Eur J Inorg Chem 19:3034–3046Google Scholar
  59. 59.
    Schatzschneider U, Niesel J, Ott I, Gust R, Alborzinia H et al (2008) Cellular uptake, cytotoxicity, and metabolic profiling of human cancer cells treated with ruthenium(II) polypyridyl complexes [Ru(bpy)2(N–N)]Cl2 with N–N = bpy, phen, dpq, dppz, and dppn. Chem Med Chem 3:1104–1109PubMedGoogle Scholar
  60. 60.
    Meggers E, Atilla-Gokcumen GE, Bregman H, Maksimoska J, Mulcahy SP et al (2007) Exploring chemical space with organometallics: ruthenium complexes as protein kinase inhibitors. Synlett 8:1177–1189Google Scholar
  61. 61.
    Smalley KS, Contractor R, Haass NK, Kulp AN, Atilla-Gokcumen GE et al (2007) An organometallic protein kinase inhibitor pharmacologically activates p53 and induces apoptosis in human melanoma cells. Cancer Res 67:209–217CrossRefPubMedGoogle Scholar
  62. 62.
    Debreczeni JE, Bullock AN, Atilla GE, Williams DS, Bregman H et al (2006) Ruthenium half-sandwich complexes bound to protein kinase Pim-1. Angew Chem Int Ed Engl 45:1580–1585CrossRefPubMedGoogle Scholar
  63. 63.
    Kim KT, Baird K, Ahn JY, Meltzer P, Lilly M et al (2005) Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival. Blood 105:1759–1767CrossRefPubMedGoogle Scholar
  64. 64.
    Adam M, Pogacic V, Bendit M, Chappuis R, Nawijn MC et al (2006) Targeting PIM kinases impairs survival of hematopoietic cells transformed by kinase inhibitor-sensitive and kinase inhibitor-resistant forms of Fms-like tyrosine kinase 3 and BCR/ABL. Cancer Res 66:3828–3835CrossRefPubMedGoogle Scholar
  65. 65.
    US Department of Health and Human Services Food and Drug Administration (2004) Innovation or stagnation: challenges and opportunity on the critical path to new medical products. [last accessed 02/05/2010]
  66. 66.
    LoRusso PM (2009) Phase 0 clinical trials: an answer to drug development stagnation? J Clin Oncol 27:2586–2588CrossRefPubMedGoogle Scholar

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© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins UniversityBaltimoreUSA

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