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BioMetals

, Volume 27, Issue 3, pp 459–469 | Cite as

The ruthenium complexes cis-(dichloro)tetramineruthenium(III) chloride and cis-tetraammine(oxalato)ruthenium(III) dithionate overcome resistance inducing apoptosis on human lung carcinoma cells (A549)

  • Cesar Augusto Sam Tiago Vilanova-Costa
  • Hellen Karine Paes Porto
  • Flávia de Castro Pereira
  • Aliny Pereira de Lima
  • Wagner Batista dos Santos
  • Elisângela de Paula Silveira-LacerdaEmail author
Article

Abstract

Lung cancer is one of the leading causes of death in the world, and non-small cell lung carcinoma accounts for approximately 75–85 % of all lung cancers. In the present work, we studied the antitumor activity of the compound cis-(dichloro)tetramineruthenium(III) chloride {cis-[RuCl2(NH3)4]Cl} against human lung carcinoma tumor cell line A549. The present study aimed to investigate the relationship between the expression of MDR1 and CYP450 genes in human lung carcinoma cell lines A549 treated with cisCarboPt, cisCRu(III) and cisDRu(III). The ruthenium-based coordinated complexes presented low cytotoxic and antiproliferative activities, with high IC50 values, 196 (±15.49), 472 (±20.29) and 175 (±1.41) for cisCarboPt, cisCRu(III) and cisDRu(III), respectively. The tested compounds induced apoptosis in A549 tumor cells as evidenced by caspase 3 activation, but only at high concentrations. Results also revealed that the amplification of P-gp gene is greater in A549 cells exposed to cisCarboPt and cisCRu(III) than cisDRu(III). Taken together all these results strongly demonstrate that MDR-1 over-expression in A549 cells could be associated to a MDR phenotype of these cells and moreover, it is also contributing to the platinum, and structurally-related compound, resistance in these cells. The identification and characterization of novel mechanisms of drug resistance will enable the development of a new generation of anti-cancer drugs that increase cancer sensitivity and/or represent more effective chemotherapeutic agents.

Keywords

Carboplatin cis-(Dichloro)tetrammineruthenium(III) chloride cis-Tetraammine(oxalato)ruthenium(III) dithionate A549 MDR-1 CYPs 

Notes

Acknowledgments

The authors gratefully acknowledge the financial support of Research and Projects Financing (FINEP) (Grant No.01.06.0941.00/CT-Saúde to Elisângela de Paula Silveira-Lacerda) and Foundation for the Support of Research in the State of Goias (FAPEG). Coordination for the Advancement of Higher Education Staff (CAPES) through fellowship to Cesar Augusto Sam Tiago Vilanova-Costa, Flávia de Castro Pereira and Hellen Karine Paes Porto; and Brazilian National Council of Technological and Scientific Development (CNPq) through fellowship to Aliny Pereira de Lima (Grant No. 141648/2010-4). There are no financial or personal interests that might be viewed as inappropriate influences on the work presented herein. This manuscript was completely financed by governmental and nonprofit institutions, the Brazilian National Counsel of Technological and Scientific Development (CNPq), Research and Projects Financing (FINEP), Coordination for the Advancement of Higher Education Staff (CAPES) and Foundation for the Support of Research in the State of Goias (FAPEG).

Ethical Approval

No studies involving humans or experimental animals were conducted in this work. The human lung carcinoma A549 cells were purchased from the American Type Culture Collection (ATCC, Rockville, MD, USA) and cultured in vitro.

References

  1. Allardyce CS, Dyson PJ, Ellis DJ, Salter PA, Scopelliti R (2003) Synthesis and characterisation of some water soluble Ruthenium(II)–arene complexes and an investigation of their antibiotic and antiviral properties. J Organomet Chem 668:35–42CrossRefGoogle Scholar
  2. American Cancer Society (2013) Cancer Facts & Figures. American Cancer Society, AtlantaGoogle Scholar
  3. Bacac M, Hotze ACG, van der Schilden K, Haasnoot JG, Pacor S, Alessio E, Sava G, Reedijk J (2004) The hydrolysis of the anti-cancer ruthenium complexNAMI-Aaffects itsDNAbinding and antimetastatic activity: an NMR evaluation. J Inorg Biochem 98:402–412PubMedCrossRefGoogle Scholar
  4. Bergamo A, Gagliardi R, Scarcia V, Furlani A, Alessio E, Mestroni G, Sava G (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
  5. Brabec V, Nováková O (2006) DNA binding mode of ruthenium complexes and relationship to tumor cell toxicity. Drug Resist Updates 9:111–122CrossRefGoogle Scholar
  6. Bugarcic T, Habtemariam A, Deeth RJ, Fabbiani FPA, Parsons S, Sadler PJ (2009) Ruthenium(II) arene anticancer complexes with redox-active diamine ligands. Inorg Chem 48:9444–9453PubMedCrossRefGoogle Scholar
  7. Casini A, Gabbiani C, Michelucci E, Pieraccini G, Moneti G, Dyson PJ, Messori L (2009) Exploring metallodrug-protein interactions by mass spectrometry: comparisons between platinum coordination complexes and an organometallic ruthenium compound. J Biol Inorg Chem 14:761–770PubMedCrossRefGoogle Scholar
  8. Clarke MJ (2003) Ruthenium metallopharmaceuticals. Coord Chem Rev 236:209–233CrossRefGoogle Scholar
  9. Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326:1–16PubMedCentralPubMedGoogle Scholar
  10. Gallori E, Vettori C, Alessio E, Vilchez FG, Vilaplana R, Orioli P, Casini A, Messori L (2000) DNA as a possible target for antitumor ruthenium(III) complexes. A spectroscopic and molecular biology study of the interactions of two representative antineoplastic ruthenium(III) complexes with DNA. Arch Biochem Biophys 376:156–162PubMedCrossRefGoogle Scholar
  11. Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nuñez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon H-U, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G (2012) Molecular definitions of cell death subroutines: recommendations of lhe Nomenclature Commitee on Cell Death. Cell Differ 10:107–120CrossRefGoogle Scholar
  12. Hartinger CG, Zorbas-Seifried S, Jakupec MA, Kynast B, Zorbas H, Keppler BK (2006) From bench to beside- preclinical and early clinical development of the anticancer agent indazolium trans- [tetrachlorobis (1 H-indazazole)ruthenate (III)] KP1019 or FFC14A). J Inorg Biochem 100:891–904PubMedCrossRefGoogle Scholar
  13. Karki SS, Thota S, Darj SY, Balzarini J, Clercq E (2007) Synthesis, anticancer, and cytotoxic activities of some mononuclear Ru(II) compounds. Bioorg Med Chem 15:6632–6641PubMedCrossRefGoogle Scholar
  14. Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev 7:573–584CrossRefGoogle Scholar
  15. Kim R, Tanabe K, Uchida Y, Emi M, Inoue H, Toge T (2002) Current status of the molecular mechanisms of anticancer drug-induced apoptosis e the contribution of molecular-level analysis to cancer chemotherapy. Cancer Chemother Pharmacol 50:343–352PubMedCrossRefGoogle Scholar
  16. Krajewska M, Kim H, Shin E et al (2005) Tumor-associated alterations in caspase-14 expression in epithelial malignancies. Clin Cancer Res 11:5462–5471PubMedCrossRefGoogle Scholar
  17. Lima AP, Pereira FC, Vilanova-Costa CAST, Mello FMS, Ribeiro ASBB, Benfica PL, Valadares MC, Pavanin LA, Santos WB, Silveira-Lacerda EP (2010a) The compound cis-(dichloro)tetrammineruthenium(III) chloride induces caspase-mediated apoptosis in K562 cells. Toxicol In Vitro 24:1562–1568PubMedCrossRefGoogle Scholar
  18. Lima AP, Pereira FC, Vilanova-Costa CAST, Ribeiro ASBB, Pavanin LA, Santos WB, Silveira-Lacerda EP (2010b) The ruthenium complex cis-(dichloro)tetrammineruthenium(III) chloride induces apoptosis and damages DNA in murine sarcoma 180 (S-180) cells. J Biosci 35:371–378PubMedCrossRefGoogle Scholar
  19. Lima AP, Pereira FC, Vilanova-Costa CAST, Soares JR, Pereira LCG, Porto HKP, Pavanin LA, Santos WB, Silveira-Lacerda EP (2012) Induction of cell cycle arrest and apoptosis by ruthenium complex cis-(dichloro)tetramineruthenium(III) Chloride in human lung carcinoma cells A549. Biol Trace Elem Res 147:8–15PubMedCrossRefGoogle Scholar
  20. Liu H-K, Wang F, Parkinson JA, Bella J, Sadler PJ (2006) Ruthenation of duplex and single-stranded d(CGGCCG) by organometallic anticancer complexes. Chem Eur J 12:6151–6165PubMedCrossRefGoogle Scholar
  21. Lobner D (2000) Comparison of the LDH and MTT assays for quantifying cell death: validity for neuronal apopotosis. J Neurosci Meth 96:147–152CrossRefGoogle Scholar
  22. Malina J, Novakova O, Keppler BK, Alessio E, Brabec V (2001) Biophysical analysis of natural, double-helical DNA modified by anticancer heterocyclic complexes of ruthenium(III) in cell-free media. J Biol Inorg Chem 6:435–445PubMedCrossRefGoogle Scholar
  23. Masubuchi Y, Horie T (2007) Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs. Crit Rev Toxicol 37:389–412PubMedCrossRefGoogle Scholar
  24. Menezes C, Depaulacosta L, Ávila VMR, Ferreira MVC, Pavanin L, Homsi-Brandeburgo MI, Hamaguchi A, Silveira-Lacerda EP (2007) Analysis in vivo of antitumor activity, Cytotoxicity and Interaction between plasmid DNA and the cis-dichlorotetraammineruthenium(III) chloride. Chem Biol Interact 167:116–124PubMedCrossRefGoogle Scholar
  25. Mosman T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation an cytotoxicity assays. J Immunol Meth 16:55–63 CrossRefGoogle Scholar
  26. Novakova O, Chen H, Vrana O, Rodger A, Sadler PJ, Brabec V (2003) DNA interactions of monofunctional organometallic ruthenium(II) antitumor complexes in cell-free media. Biochemistry 42:11544–11554PubMedCrossRefGoogle Scholar
  27. Nováková O, Vrana O, Kiseleva VI, Brabec V (1995) DNA interactions of antitumor platinum(IV) complexes. Eur J Biochem 228:616–624PubMedCrossRefGoogle Scholar
  28. Pavanin LA, Giesbrecht E, Tfouni E (1985) Synthesis and properties of the ruthenium(II) complexes cis-Ru(NH3)4(isn)L2+ spectra and reduction potentials. Inorg Chem 24:4444–4446Google Scholar
  29. Pereira FC, Vilanova-Costa CAST, Lima AP, Ribeiro ASBB, Silva HD, Pavanin LA, Silveira-Lacerda EP (2009) Cytotoxic and genotoxic effects of cis-tetraammine(oxalato)ruthenium(III) dithionate on the root meristem cells of Allium cepa. Biol Trace Elem Res 128:258–268CrossRefGoogle Scholar
  30. 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 10:3717–3727PubMedCrossRefGoogle Scholar
  31. Ribeiro ASBB, da Silva CC, Pereira FC, Lima AP, Vilanova-Costa CAST, Aguiar SS, Pavanin LA, da Cruz AD, Silveira-Lacerda EP (2009) Mutagenic and genotoxic effects of cis-(dichloro)tetraammineruthenium(III) chloride on human peripheral blood lymphocytes. Biol Trace Elem Res 130:249–261CrossRefGoogle Scholar
  32. Rosell R, Reginald VNL, Taron M, Reguart N (2002) DNA repair and cisplatin resistance in non-small-cell lung cancer. Lung Cancer 38:217–227PubMedCrossRefGoogle Scholar
  33. Schluga P, Hartinger CG, Egger A, Reisner E, Galanski M, Jakupec MA, Keppler BK (2006) Redox behavior of tumor inhibiting ruthenium(III) complexes and effects of physiological reductants on their binding to GMP. Dalton Trans. 14:1796–1802PubMedCrossRefGoogle Scholar
  34. Scolaro C, Bergamo A, Brescacin L, Delfino R, Cocchietto M, Laurenczy G, Geldbach TJ, Sava G, Dyson PJ (2005) In vitro e in vivo evaluation of ruthenium (II)–arene PTA complexes. J Med Chem 48:4161–4171PubMedCrossRefGoogle Scholar
  35. Silveira-Lacerda EP, Vilanova-Costa CAST, Pereira FC, Hamaguchi A, Pavanin LA, Goulart LR, Homsi-Brandeburgo MI, Soares AM, Santos WB, Nomizo A (2010a) The ruthenium complex cis-(dichloro)tetraammineruthenium(III) chloride presents immune stimulatory activity on human peripheral blood mononuclear cells. Biol Trace Elem Res 133:270–283CrossRefGoogle Scholar
  36. Silveira-Lacerda EP, Vilanova-Costa CAST, Pereira FC, Hamaguchi A, Pavanin LA, Goulart LR, Homsi-Brandeburgo MI, Soares AM, Santos WB, Nomizo A (2010b) The Ruthenium Complex cis-(dichloro)tetraammineruthenium(III) chloride presents selective cytotoxicity against murine B cell lymphoma (A-20), murine ascitic sarcoma 180 (S-180), human breast adenocarcinoma (SK-BR-3), and human T cell leukemia (Jurkat) tumor cell lines. Biol Trace Elem Res 135:98–111CrossRefGoogle Scholar
  37. Socinski MA (2004) Cytotoxic chemotherapy in advanced non-small cell lung cancer: a review of standard treatment paradigms. Clin Cancer Res 10:4210–4214CrossRefGoogle Scholar
  38. Tang J, Wang Y, Wang D, Wang Y, Xu Z, Racette K, Liu F (2013) Key structure of Brij for overcoming multidrug resistance in cancer. Biomacromolecules 14:424–430PubMedCentralPubMedCrossRefGoogle Scholar
  39. Varbanov HP, Valiahdi SM, Kowol CR, Jakupec MA, Galanski M, Keppler BK (2012) Novel tetracarboxylatoplatinum(IV) complexes as carboplatin prodrugs. Dalton Trans 41(47):14404–14415Google Scholar
  40. Vock CA, Ang WH, Scolaro C, Phillips AD, Lagopoulos L, Juillerat-Jeanneret L, Sava G, Scopelliti R, Dyson PJ (2007) Development of ruthenium antitumor drugs that overcome multidrug resistance mechanisms. J Med Chem 50:2166–2175PubMedCrossRefGoogle Scholar
  41. Wagner JM, Karnitz LM (2009) Cisplatin-induced DNA damage activates replication checkpoint signaling components that differentially affect tumor cell survival. Mol Pharmacol 76:208–214PubMedCentralPubMedCrossRefGoogle Scholar
  42. Wang F, Chen H, Parsons S, Oswald IDH, Davidson JE, Sadler PJ (2003) Kinetics of aquation and anation of ruthenium(II) arene anticancer complexes, acidity and X-ray structures of aqua adducts. Chem Eur J 9:5810–5820PubMedCrossRefGoogle Scholar
  43. Wu J, Hu C, Gu Q, Li Y, Song M (2010) Trichostatin A sensitizes cisplatin-resistant A549 cells to apoptosis by up-regulating death-associated protein kinase. Acta Pharmacol Sin 31:93–101PubMedCrossRefGoogle Scholar
  44. Yan YK, Melchart M, Habtemariam A, Sadler PJ (2005) Organometallic chemistry, biology and medicine: ruthenium arene anticancer complexes. Chem Commun 38:4764–4776CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Cesar Augusto Sam Tiago Vilanova-Costa
    • 1
  • Hellen Karine Paes Porto
    • 1
  • Flávia de Castro Pereira
    • 1
  • Aliny Pereira de Lima
    • 1
  • Wagner Batista dos Santos
    • 2
  • Elisângela de Paula Silveira-Lacerda
    • 1
    Email author
  1. 1.Laboratório de Genética Molecular e Citogenética, Instituto de Ciências BiológicasUniversidade Federal de Goiás - UFGGoiâniaBrazil
  2. 2.Instituto de Ciências Exatas e da TerraUniversidade Federal de Mato Grosso - UFMTBarra do GarçasBrazil

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