Advertisement

Investigational New Drugs

, Volume 29, Issue 5, pp 932–944 | Cite as

Cytotoxicity, apoptosis and study of the DNA-binding properties of bi- and tetranuclear gallium(III) complexes with heterocyclic thiolato ligands

  • Beatriz Gallego
  • Milena R. Kaluđerović
  • Harish Kommera
  • Reinhard Paschke
  • Evamarie Hey-Hawkins
  • Torsten W. Remmerbach
  • Goran N. Kaluđerović
  • Santiago Gómez-Ruiz
PRECLINICAL STUDIES

Summary

The reaction of the heterocyclic thiol derivatives, 2-mercapto-1-methylimidazole (SH-imi), 5-mercapto-1-methyltetrazole (SH-tet), 2-mercaptobenzothiazole (SH-ben) and 5-phenyl-1,3,4-oxadiazole-2-thiol (SH-oxa), with trimethylgallium (1:1) afforded the dimeric or tetrameric complexes [Me2Ga(S-imi)]2 (1), [Me2Ga(S-tet)]2 (2), [Me2Ga(S-ben)]2 (3) and [Me2Ga(S-oxa)]4 (4), respectively. Molecular structures of 2 and 4 were determined by X-ray diffraction studies. The cytotoxicity of the gallium(III) complexes 14 was tested against human cell lines 8505C anaplastic thyroid cancer, A253 head and neck tumor, A549 lung carcinoma, A2780 ovarian cancer, DLD-1 colon carcinoma and compared with those of cisplatin and Ga(NO3)3. Compound 4 seems to be slightly more active against 8505C, A253 and A2780 and substantially more active than all the other complexes against DLD-1, with an IC50 value of 5.49 ± 0.16 µM, very close to that of cisplatin (5.14 ± 0.12 µM). Complexes 14 were less toxic on normal human fibroblasts (WWO70327) than on the investigated tumor cell lines and more selective to cancer cells than cisplatin. DNA laddering method showed that treatment of the DLD-1 cell line with IC90 doses of 14 resulted in the induction of apoptosis. Compound 1 caused apoptosis by upregulation of caspases 2, 3 and 8. Since no activity of caspase 9 is observed, complex 1 is causing apoptosis triggered by an extrinsic pathway. DNA-interaction tests have been also carried out. Solutions of all the studied complexes have been treated with different concentrations of fish sperm DNA (FS-DNA). Modifications of the UV spectra which gave intrinsic binding constants of 3.03 × 105, 4.44 × 105, 3.02 × 106 and 5.56 × 105 M−1 for 14 were observed, however, no notable interaction with pBR322 plasmid DNA was detected.

Keywords

Anticancer drugs Apoptosis Cytotoxicity Gallium Thiolato ligands 

Notes

Acknowledgements

We gratefully acknowledge financial support from the Universidad Rey Juan Carlos (postdoctoral fellowship for S.G.-R.) and Junta de Comunidades de Castilla-La Mancha (postdoctoral fellowship for B.G.). We thank the Ministry of Science and Technological Developments of the Republic of Serbia (Grant No. 142010) and Ministerium für Wirtschaft und Arbeit des Landes Sachsen-Anhalt, Deutschland (Grant No. 6003368706). We would also like to thank S. Prashar and D. Pérez-Quintanilla (Universidad Rey Juan Carlos) for useful discussions and BioSolutions Halle GmbH, Germany, for the cell culture facilities.

References

  1. 1.
    Lippert B (1999) In: Cisplatin: chemistry and biochemistry of a leading anticancer drug. Wiley InterscienceGoogle Scholar
  2. 2.
    Abu-Surrah AS, Kettunen M (2006) Platinum group antitumor chemistry: design and development of new anticancer drugs complementary to cisplatin. Curr Med Chem 13:1337PubMedCrossRefGoogle Scholar
  3. 3.
    Allardyce CS, Dyson PJ (2001) Ruthenium in medicine: current clinical uses and future prospects. Platinum Metals Rev 45:62Google Scholar
  4. 4.
    Ott I, Gust R (2007) Non platinum metal complexes as anti-cancer drugs. Archiv der Pharmazie 340:117PubMedCrossRefGoogle Scholar
  5. 5.
    Jakupec MA, Galanski M, Arion VB, Hartinger CG, Keppler BK (2008) Antitumour metal compounds: more than theme and variations. Dalton Trans 183Google Scholar
  6. 6.
    Yang P, Guo M (1999) Interactions of organometallic anticancer agents with nucleotides and DNA. Chem Rev 185:189Google Scholar
  7. 7.
    Hadjikakou SK, Hadjiliadis N (2009) Antiproliferative and anti-tumor activity of organotin compounds. Coord Chem Rev 253:235CrossRefGoogle Scholar
  8. 8.
    Strohfeldt K, Tacke M (2008) Bioorganometallic fulvene-derived titanocene anticancer drugs. Chem Soc Rev 37:1174PubMedCrossRefGoogle Scholar
  9. 9.
    Abeysinghe PM, Harding MM (2007) Antitumour bis(Cyclopentadienyl) metal complexes: titanocene and molybdocene dichloride and derivatives. Dalton Trans 3474Google Scholar
  10. 10.
    Gust R, Posselt D, Sommer K (2004) Development of cobalt(3, 4-diarylsalen) complexes as tumor therapeutics. J Med Chem 47:5837PubMedCrossRefGoogle Scholar
  11. 11.
    Hartinger CG, Dyson PJ (2009) Bioorganometallic chemistry—from teaching paradigms to medicinal applications. Chem Soc Rev 38:391PubMedCrossRefGoogle Scholar
  12. 12.
    Bernstein LR (1998) Mechanisms of therapeutic activity for gallium. Pharmacol Rev 50:665PubMedGoogle Scholar
  13. 13.
    Green MA, Welch MJ (1989) Gallium radiopharmaceutical chemistry. Int J Radiat Appl Instrum B 16:435Google Scholar
  14. 14.
    Arion VB, Jakupec MA, Galanski M, Unfried P, Keppler BK (2002) Synthesis, structure, spectroscopic and in vitro antitumour studies of a novel gallium(III) complex with 2-acetylpyridine 4N-dimethylthiosemicarbazone. J Inorg Biochem 91:298PubMedCrossRefGoogle Scholar
  15. 15.
    Bernstein LR, Gielen M, Tiekink ERT (2005) Metallotherapeutic drugs and metal-based diagnostic agents. Wiley, Chichester, p 259CrossRefGoogle Scholar
  16. 16.
    Jakupec MA, Keppler BK, Sigel A, Sigel H (2004) Metal ions in biological systems, vol 42. Dekker, NewYork, p 425, Metal Complexes in Tumour Diagnosis and as Anticancer AgentsGoogle Scholar
  17. 17.
    Jakupec MA, Keppler BK (2004) Gallium in cancer treatment. Curr Top Med Chem 4:1575PubMedCrossRefGoogle Scholar
  18. 18.
    Chitambar CR, Zivkovic Z (1987) Uptake of gallium-67 by human leukemic cells: demonstration of transferrin receptor-dependent and transferrin-independent mechanisms. Cancer Res 47:3929PubMedGoogle Scholar
  19. 19.
    Chitambar CR, Seligman PA (1986) Effects of different transferrin forms on transferrin receptor expression, iron uptake, and cellular proliferation of human leukemic HL60 cells. Mechanisms responsible for the specific cytotoxicity of transferrin-gallium. J Clin Invest 78:1538PubMedCrossRefGoogle Scholar
  20. 20.
    Kinuya S, Li X-F, Yokoyama K, Mori H, Shiba K, Watanabe N, Shuke N, Bunko H, Michigishi T, Tonami N (2004) Hypoxia as a factor for 67Ga accumulation in tumour cells. Nucl Med Commun 25:49–54PubMedCrossRefGoogle Scholar
  21. 21.
    Davies NP, Rahmanto YS, Chitambar CR, Richardson DR (2006) Resistance to the antineoplastic agent gallium nitrate results in marked alterations in intracellular iron and gallium trafficking: identification of novel intermediates. J Pharmacol Exp Ther 317:153PubMedCrossRefGoogle Scholar
  22. 22.
    Narasimhan J, Antholine WE, Chitambar CR (1992) Effect of gallium on the tyrosyl radical of the iron-dependent M2 subunit of ribonucleotide reductase. Biochem Pharmacol 44:2403PubMedCrossRefGoogle Scholar
  23. 23.
    Chitambar CR, Wereley JP, Matsuyama S (2006) Gallium-induced cell death in lymphoma: role of transferrin receptor cycling, involvement of bax and the mitochondria, and effects of proteasome inhibition. Mol Cancer Ther 5:2834PubMedCrossRefGoogle Scholar
  24. 24.
    Chen D, Frezza M, Shakya R, Cui QC, Milacic V, Verani CN, Dou QP (2007) Inhibition of the proteasome activity by gallium(III) complexes contributes to their anti-prostate tumor effects. Can Res 67:9258CrossRefGoogle Scholar
  25. 25.
    Thiel M, Schilling T, Gey DC, Ziegler R, Collery P, Keppler BK. Ed Fiebig HH and Burger AM (1999) In Relevance of Tumour Models for Anticancer Drug Development. In Contributions to Oncology, Ed. Queisser W and Scheithauer, W. Karger, Basel, vol. 54, p. 439.Google Scholar
  26. 26.
    Bernstein LR, Tanner T, Godfrey C, Noll B (2000) Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability. Met-Based Drugs 7:33PubMedCrossRefGoogle Scholar
  27. 27.
    Collery P, Lechenault F, Cazabat A, Juvin E, Khassanova L, Evangelou A, Keppler B (2000) Inhibitory effects of gallium chloride and tris (8-Quinolinolato) gallium(III) on A549 human malignant cell line. Anticancer Res 20:955PubMedGoogle Scholar
  28. 28.
    Chua MS, Bernstein LR, So SKS (2006) Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma. Anticancer Res 26:1739PubMedGoogle Scholar
  29. 29.
    Lum BL, Srivanas S, Beck JT, Vesole D, Largey M, Valone FH, Sayre PH (2003) Phase I trial of oral gallium maltolate in refractory malignancies. Proc Am Soc Clin Oncol 22:943Google Scholar
  30. 30.
    Hofheinz R-D, Dittrich C, Jakupec MA, Drescher A, Jaehde U, Gneist M, Keyserlingk NG (2005) Early results from a phase I study on orally administered tris(8-quinolinolato)gallium(III) (FFC11, KP46) in patients with solid tumors—a CESAR study (Central European Society for Anticancer Drug Research—EWIV). Int J Clin Pharmacol Ther 43:590PubMedGoogle Scholar
  31. 31.
    Allamneni KP, Burns RB, Gray DJ, Valone FH, Bucalo LR, Sreedharan SP (2004) Gallium maltolate treatment results in transferrin-bound gallium in patient serum. Proc Am Assoc Cancer Res 45:230Google Scholar
  32. 32.
    Kowol CR, Berger R, Eichinger R, Roller A, Jakupec MA, Schmidt PP, Arion VB, Keppler BK (2007) Gallium(III) and iron(III) complexes of α-N-heterocyclic thiosemicarbazones: synthesis, characterization, cytotoxicity, and interaction with ribonucleotide reductase. J Med Chem 50:1254PubMedCrossRefGoogle Scholar
  33. 33.
    Harpstrite SE, Prior JL, Rath NP, Sharma V (2007) Synthesis, characterization, and potency of a novel gallium(III) complex in human epidurmal carcinoma cells. J Inorg Biochem 101:1347PubMedCrossRefGoogle Scholar
  34. 34.
    Rudnev AV, Foteeva LS, Kowol C, Berger R, Jakupec MA, Arion VB, Timerbaev AR, Keppler BK (2006) Preclinical characterization of anticancer gallium(III) complexes: solubility, stability, lipophilicity, and binding to serum proteins. J Inorg Biochem 100:1819PubMedCrossRefGoogle Scholar
  35. 35.
    Mendes IC, Soares MA, dos Santos RG, Pinheiro C, Beraldo H (2009) Gallium(III) complexes of 2-pyridineformamide thiosemicarbazones: cytotoxic activity against malignant glioblastoma. Eur J Med Chem 44:1870PubMedCrossRefGoogle Scholar
  36. 36.
    García-Vázquez JA, Romero J, Sousa A (1999) Electrochemical synthesis of metallic complexes of bidentate thiolates containing nitrogen as an additional donor atom. Coord Chem Rev 193–195:691CrossRefGoogle Scholar
  37. 37.
    Bandoli G, Dolmella A, Tisato F, Porchia M, Refosco F (2009) Mononuclear six-coordinated Ga(III) complexes: a comprehensive survey. Coord Chem Rev 253:56CrossRefGoogle Scholar
  38. 38.
    Gómez-Ruiz S, Gallego B, Kaluđerović MR, Kommera H, Hey-Hawkins E, Paschke R, Kaluđerović GN (2009) Novel gallium(III) complexes containing phthaloyl derivatives of neutral aminoacids with apoptotic activity in cancer cells. J Organomet Chem 694:2191CrossRefGoogle Scholar
  39. 39.
    Kaluđerović MR, Gómez-Ruiz S, Gallego B, Hey-Hawkins E, Paschke R, Kaluđerović GN (2010) Anticancer activity of dinuclear gallium(III) carboxylate complexes. Eur J Med Chem 45:519PubMedCrossRefGoogle Scholar
  40. 40.
    Valean AM, Gómez-Ruiz S, Lönnecke P, Silaghi-Dumitrescu I, Silaghi-Dumitrescu L, Hey-Hawkins E (2008) When arsine makes the difference: chelating phosphino- and bridging arsinoarylthiolato gallium complexes. Inorg Chem 47:11284PubMedCrossRefGoogle Scholar
  41. 41.
    Valean AM, Gómez-Ruiz S, Lönnecke P, Silaghi-Dumitrescu I, Silaghi-Dumitrescu L, Hey-Hawkins E (2009) Stabilisation of an inorganic digallane by the phosphinobisthiolato P, S, S Pincer Ligand PPh(2-SC6H4)2. New J Chem 33:1771CrossRefGoogle Scholar
  42. 42.
    Cooper DA, Rettig SJ, Storr A, Trotter J (1986) The 2-mercapto-1-methylimidazolyl moiety as a bridging ligand in complexes of gallium, rhenium, and molybdenum. Can J Chem 64:1643CrossRefGoogle Scholar
  43. 43.
    Bellamy LJ (1975) The infra-red spectra of complex molecules, 3rd edn. Wiley, New YorkGoogle Scholar
  44. 44.
    Von Hanisch C, Stahl S (2006) Synthesis of macrocyclic aluminum-phosphorus and gallium-phosphorus compounds. Angew Chem Int Ed 45:2302CrossRefGoogle Scholar
  45. 45.
    Redshaw C, Elsewood MRJ (2001) Novel Organoaluminium (and Gallium) Carboxylate-bridged Ring Systems. Chem Commun 2016Google Scholar
  46. 46.
    Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New Colorimetric Cytotoxicity Assay for Anticancer-drug Screening. J Natl Cancer 82:1107CrossRefGoogle Scholar
  47. 47.
    Kelly TM, Tossi AB, McConnell DJ, Strekas TC (1985) A study of the interactions of some polypyridylruthenium(II) complexes with DNA using fluorescence spectroscopy. Topoisomerisation and thermal denaturation. Nucleic Acids Res 13:6017PubMedCrossRefGoogle Scholar
  48. 48.
    Barton JK, Danishefsky AT, Goldberg JM (1984) Tris(phenanthroline)-ruthenium(II): stereoselectivity in binding to DNA. J Am Chem Soc 106:2172CrossRefGoogle Scholar
  49. 49.
    Tysoe SA, Morgan RJ, Baker AD, Strekas TC (1993) Spectroscopic investigation of differential binding modes of Δ- and Λ-Ru(bpy)2(ppz)2+ with Calf Thymus DNA. J Phys Chem 97:1707CrossRefGoogle Scholar
  50. 50.
    Pasternack RF, Gibbs EJ, Villafranca JJ (1983) Interactions of porphyrins with nucleic acids. Biochemistry 22:2406PubMedCrossRefGoogle Scholar
  51. 51.
    Liu J, Zhang T, Lu T, Qu L, Zhou H, Zhang Q, Ji L (2002) DNA-binding and cleavage studies of macrocyclic copper(II) complexes. J Inorg Biochem 91:269PubMedCrossRefGoogle Scholar
  52. 52.
    Liu C, Zhou JY, Li QX, Wang LJ, Liao ZR, Xu HB (1999) DNA damage by copper(II) complexes: coordination-structural dependence of reactivities. J Inorg Biochem 75:233PubMedCrossRefGoogle Scholar
  53. 53.
    Zhang S, Zhu Y, Tu C, Wei H, Yang Z, Lin L, Ding J, Zhang J, Guo Z (2004) A novel cytotoxic ternary copper(II) complex of 1, 10-phenanthroline and L-threonine with DNA nuclease activity. J Inorg Biochem 98:2099PubMedCrossRefGoogle Scholar
  54. 54.
    Carter MT, Rodriguez M, Bard AJ (1989) Voltammetric studies of the interaction of metal chelates with DNA. 2. Tris-chelated complexes of cobalt (III) and iron (II) with 1, 10-phenanthroline and 2, 2′-bipyridine. J Am Chem Soc 111:8901CrossRefGoogle Scholar
  55. 55.
    Pyle AM, Rehmann JP, Meshoyrer R, Kumar CV, Turro NJ, Barton JK (1989) Mixed-ligand complexes of ruthenium (II): factors governing binding to DNA. J Am Chem Soc 111:3051CrossRefGoogle Scholar
  56. 56.
    Onoa GB, Moreno V (2002) Study of the modifications caused by cisplatin, transplatin, and Pd(II) and Pt(II) mepirizole derivatives on pBR322 DNA by atomic force microscopy. Int J Pharm 245:55PubMedCrossRefGoogle Scholar
  57. 57.
    Ushay HM, Tullius TD, Lippard SJ (1981) Inhibition of the bam HI cleavage and unwinding of pBR3222 deoxyribonucleic acid by the antitumour drug cis-dichlorodiammineplatinum (II). Biochemistry 20:3744PubMedCrossRefGoogle Scholar
  58. 58.
    SCALE3 ABSPACK (2006) Empirical absorption correction, CrysAlis—Software package, Oxford Diffraction LtdGoogle Scholar
  59. 59.
    Sheldrick GM (1997) SHELXS-97. Program for Crystal Structure Solution, GöttingenGoogle Scholar
  60. 60.
    Sheldrick GM (1997) SHELXL-97. Program for the Refinement of Crystal Structures, GöttingenGoogle Scholar
  61. 61.
    Spek AL (2003) Single-crystal structure validation with the program PLATON. J Appl Cryst 36:7CrossRefGoogle Scholar
  62. 62.
    Dietrich A, Mueller T, Paschke R, Kalinowski B, Behlendorf T, Reipsch F, Fruehauf A, Schmoll HJ, Kloft C, Voigt W (2008) 2-(4-(tetrahydro-2H-pyran-2-yloxy)-undecyl)-propane-1, 3-diamminedichloroplatinum(II): a novel platinum compound that overcomes cisplatin resistance and induces apoptosis by mechanisms different from that of cisplatin. J Med Chem 51:5413PubMedCrossRefGoogle Scholar
  63. 63.
    Marmur JA (1961) A procedure for the isolation of deoxyribonucleic acid from micro-organisms. J Mol Biol 3:208CrossRefGoogle Scholar
  64. 64.
    Reichmann MF, Rice SA, Thomas CA, Doty P (1954) A further examination of the molecular weight and size of desoxypentose nucleic acid. J Am Chem Soc 76:3047CrossRefGoogle Scholar
  65. 65.
    Grguric-Sipka SR, Vilaplana RA, Pérez JM, Fuertes MA, Alonso C, Alvarez Y, Sabo TJ, González-Vílchez F (2003) Synthesis, characterization, interaction with DNA and cytotoxicity of the new potential antitumor drug cis-K[Ru(eddp)Cl2]. J Inorg Biochem 97:215PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Beatriz Gallego
    • 1
  • Milena R. Kaluđerović
    • 2
  • Harish Kommera
    • 3
  • Reinhard Paschke
    • 3
  • Evamarie Hey-Hawkins
    • 1
  • Torsten W. Remmerbach
    • 2
  • Goran N. Kaluđerović
    • 3
    • 4
  • Santiago Gómez-Ruiz
    • 1
    • 5
  1. 1.Institut für Anorganische Chemie der Universität LeipzigLeipzigGermany
  2. 2.Department of Oral, Maxillofacial and Facial Plastic SurgeryUniversity of LeipzigLeipzigGermany
  3. 3.BiozentrumMartin-Luther-Universität Halle-WittenbergHalleGermany
  4. 4.Department of Chemistry, Institute of Chemistry, Technology and MetallurgyUniversity of BelgradeBelgradeSerbia
  5. 5.Departamento de Química Inorgánica y Analítica, E.S.C.E.T.Universidad Rey Juan CarlosMóstolesSpain

Personalised recommendations