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Biological role of adduct formation of the ruthenium(III) complex NAMI-A with serum albumin and serum transferrin

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Abstract

NAMI-A is an innovative ruthenium(III) complex with a very encouraging preclinical profile of metastasis inhibition, which is undergoing initial phases of clinical trials. To assess the pharmacological relevance of the drug fraction associated to plasma proteins, adducts of NAMI-A with either serum albumin or serum transferrin were prepared and their biological effects tested in vitro and in vivo. Specifically, adducts of NAMI-A with either serum albumin or serum transferrin, prepared and characterized at a ruthenium-to-protein molar ratio of 4:1, were evaluated in vitro on the KB human tumor cell line and in vivo on the MCa mammary carcinoma tumor. The effects of NAMI-A/protein adducts on cell viability and on cell cycle progression were found to be far smaller than those produced by free NAMI-A. GFAAS measurements point out that the amount of ruthenium that gets into cells is drastically reduced when NAMI-A is presented in its protein-bound form. In vivo use of NAMI-A adducts with albumin and transferrin resulted markedly less effective on lung metastasis reduction, than free NAMI-A. Overall, the present results suggest that binding to plasma proteins causes a drastic decrease of NAMI-A bioavailability and a subsequent reduction of its biological activity, implying that association to plasma proteins essentially represents a mechanism of drug inactivation.

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References

  1. Sava G, Capozzi I, Clerici K, Gagliardi R, Alessio E, Mestroni G: Pharmacological control of lung metastases of solid tumours by a novel ruthenium complex. Clin Exp Metastasis 16: 371–379, 1998

    Google Scholar 

  2. Sava G, Clerici K, Capozzi I, Cocchietto M, Gagliardi R, Alessio E, Mestroni G, Perbellini A: Reduction of lung metastasis by ImH[trans-RuCl4(DMSO)Im]: mechanism of the selective action investigated on mouse tumors. Anti Cancer Drugs 10: 129–138, 1999

    Google Scholar 

  3. Bergamo A, Gagliardi R, Scarcia V, Furlani A, Alessio E, Mestroni G, Sava G: In vitro cell cycle arrest, in vivo action on solid metastasizing tumors, and host toxicity of the antimetastasis drug NAMI-A and cisplatin. JPET 289: 559–564, 1999

    Google Scholar 

  4. Zorzet S, Bergamo A, Cocchietto M, Sorc A, Gava B, Alessio E, Iengo E, Sava G: 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 Expl Ther 295: 927–933, 2000

    Google Scholar 

  5. Sava G, Bergamo A, Zorzet S, Gava B, Casarsa C, Cocchietto M, Furlani A, Scarcia V, Serli B, Iengo E, Alessio E, Mestroni G: Influence of chemical stability on the activity of the antimetastasis ruthenium compound NAMI-A. Eur J Cancer 38: 427–435, 2002

    Google Scholar 

  6. Vacca A, Bruno M, Boccarelli A, Coluccia M, Ribatti D, Bergamo A, Garbisa S, Sartor L, Sava G: Inhibition of endothelial cell functions and angiogenesis by the metastasis inhibitor NAMI-A. Brit J Cancer 86: 993–998, 2002

    Google Scholar 

  7. Sanna B, Debidda M, Pintus G, Tadolini B, Posadino AM, Bennardini F, Sava G, Ventura C: The antimetastatic agent imidazolium trans-imidazole tetrachlororuthenate induces endothelial cell apoptosis by inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway. Arch Biochem Biophys 403: 209–218, 2002

    Google Scholar 

  8. Pintus G, Tadolini B, Posadino AM, Sanna B, Debidda M, Bennardini F, Sava G, Ventura C: Inhibition of the MEK/ERK Signaling Pathway by the Novel Antimetastatic Agent NAMI-A Down Regulates c-myc Gene Expression and Endothelial Cells Proliferation. Eur J Biochem 269: 5861–5870, 2002

    Google Scholar 

  9. Gallori E, Vettori C, Alessio E, Gonzalez F, Vilchez Vilaplana R, Orioli P, Messori L, Casini A: DNA as a possible target for antitumor ruthenium(III) complexes. A spectroscopic and molecular biology study of the interactions of antineoplastic ruthenium(III) complexes with DNA. Arch Biochem Biophys 376: 156–162, 2000

    Google Scholar 

  10. Malina J, Novakova O, Keppler BK, Alessio E, Brabec V: Biophysical analysis of natural, double-helical DNA modified by anticancer heterocyclic complexes of ruthenium(III) in cell-free media. J Biol Inorg Chem 6: 435–445, 2001

    Google Scholar 

  11. Messori L, Orioli P, Vullo D, Alessio E, Iengo E: A Spectroscopic Study of the Reaction of NAMI, a Novel Ruthenium(III) Antineoplastic Complex, with Bovine Serum Albumin. Eur J Biochem 267: 1206–1213, 2000

    Google Scholar 

  12. Messori L, Kratz F, Alessio E: The interaction of the antitumor complexes Na[trans-RuCl4 (DMSO)(Im)] and Na[trans-RuCl4 (DMSO)(Ind)] with apotransferrin: a spectroscopic study. Metal Based Drugs 3: 1–9, 1996

    Google Scholar 

  13. Messori L, Gonzalez F, Vilchez Vilaplana R, Piccioli F, Alessio E, Keppler B: Binding of antitumor ruthenium(III) complexes to plasma proteins. Metal Based Drugs 7: 335–342, 2000

    Google Scholar 

  14. Kratz F, Hartmann M, Keppler B, Messori L: The binding properties of two antitumor ruthenium(III) complexes to apotransferrin. J Biol Chem 269: 2581–2588, 1994

    Google Scholar 

  15. Kratz F, Keppler BK, Messori L, Smith C, Baker EN: Protein-binding properties of two antitumor Ru(III) complexes to human apotransferrin and apolactoferrin. Metal Based Drugs 1: 169–175, 1994

    Google Scholar 

  16. Chuang VTG, Kragh-Hansen U, Otagiri M: Pharmaceutical strategies utilizing recombinant human serum albumin. Pharmaceut Res 19: 569–577, 2002

    Google Scholar 

  17. Cook JA, Mitchell JB: Viability measurements in mammalian cell systems. Anal Biochem 179: 1–7, 1989

    Google Scholar 

  18. Crissman HA, Steinkamp JA: Rapid simultaneous measurement of DNA, protein and cell volume in single cells from large mammalian populations. J Cell Biol 59: 766–771, 1973

    Google Scholar 

  19. Tamura H, Arai T: Determination of ruthenium in biological tissue by graphite furnace AAS after decomposition of the sample by tetramethylammonium hydroxide. Bunseki Kagaku 41: 13–17, 1992

    Google Scholar 

  20. Poliak-Blazi M, Boranic M, Marzan B, Radacic M: A transplantable aplastic mammary carcinoma of CBA mice. Vet Arh 51: 99–107, 1981

    Google Scholar 

  21. Smith CA, Sutherland-Smith AJ, Keppler B, Kratz F, Baker EN: Binding of ruthenium(III) anti-drugs to human lactoferrin probed by high resolution X-ray crystallographic structure analyses. J Biol Inorg Chem 1: 424–430, 1996

    Google Scholar 

  22. Frausin F, Cocchietto M, Bergamo A, Scarcia V, Furlani A, Sava G: Tumor cell uptake of the metastasis inhibitor ruthenium complex NAMI-A and its in vitro effects on KB cells. Cancer Chemother Pharmacol 50: 405–411, 2002

    Google Scholar 

  23. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K: Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65: 271–284, 2000

    Google Scholar 

  24. Singh M: Transferrin as a targeting ligand for liposome and anticancer drugs. Curr Pharm Des 5: 443–451, 1999

    Google Scholar 

  25. Cavanaugh PG, Jia LB, Zou YY, Nicolson GL: Transferrin receptor overexpression enhances transferrin responsiveness and the metastatic growth of a rat mammary adenocarcinoma cell line. Breast Cancer Res Treat 56: 203–217, 1999

    Google Scholar 

  26. Cocchietto M, Sava G: Blood concentration and toxicity of the antimetastasis agent NAMI-A following repeated intravenous treatment in mice. Pharmacol Toxicol 87: 193–197, 2000

    Google Scholar 

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Authors and Affiliations

  1. Callerio Foundation Onlus, Via A. Fleming 22-31, 34127, Trieste, Italy

    A. Bergamo, M. Cocchietto & G. Sava

  2. Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019, Sesto Fiorentino, Florence, Italy

    L. Messori & F. Piccioli

  3. Department of Biomedical Sciences, University of Trieste, Via L. Giorgieri 7-9, 34127, Trieste, Italy

    G. Sava

Authors
  1. A. Bergamo
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  2. L. Messori
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  3. F. Piccioli
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  4. M. Cocchietto
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  5. G. Sava
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Bergamo, A., Messori, L., Piccioli, F. et al. Biological role of adduct formation of the ruthenium(III) complex NAMI-A with serum albumin and serum transferrin. Invest New Drugs 21, 401–411 (2003). https://doi.org/10.1023/A:1026243000320

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