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Bioinorganic Chemistry and Applications
Volume 2012, Article ID 140284, 14 pages
http://dx.doi.org/10.1155/2012/140284
Review Article

On the Discovery, Biological Effects, and Use of Cisplatin and Metallocenes in Anticancer Chemotherapy

1Departamento de Química Inorgánica y Analítica, E.S.C.E.T., Universidad Rey Juan Carlos, 28933 Móstoles, Spain
2Institute for Biological Research “Sinisa Stankovic”, University of Belgrade, Boulevard of Despot Stefan 142, 11060 Belgrade, Serbia
3Institut für Chemie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Straße 2, 06120 Halle, Germany

Received 11 March 2012; Accepted 19 May 2012

Academic Editor: Zhe-Sheng Chen

Copyright © 2012 Santiago Gómez-Ruiz et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. F. Arnesano and G. Natile, “Mechanistic insight into the cellular uptake and processing of cisplatin 30 years after its approval by FDA,” Coordination Chemistry Reviews, vol. 253, no. 15-16, pp. 2070–2081, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. D. J. Higby, H. J. Wallace, D. J. Albert, and J. F. Holland, “Diaminodichloroplatinum: a phase I study showing responses in testicular and other tumors,” Cancer, vol. 33, no. 5, pp. 1219–1225, 1974. View at Google Scholar · View at Scopus
  3. T. W. Hambley, “Developing new metal-based therapeutics: challenges and opportunities,” Dalton Transactions, vol. 21, no. 43, pp. 4929–4937, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. E. R. Jamieson and S. J. Lippard, “Structure, recognition, and processing of cisplatin-DNA adducts,” Chemical Reviews, vol. 99, no. 9, pp. 2467–2498, 1999. View at Google Scholar · View at Scopus
  5. G. Giaccone, “Clinical perspectives on platinum resistance,” Drugs, vol. 59, no. 4, pp. 9–17, 2000, discussion 37-38. View at Google Scholar · View at Scopus
  6. M. A. Fuertes, C. Alonso, and J. M. Pérez, “Biochemical modulation of cisplatin mechanisms of action: enhancement of antitumor activity and circumvention of drug resistance,” Chemical Reviews, vol. 103, no. 3, pp. 645–662, 2003. View at Publisher · View at Google Scholar · View at Scopus
  7. B. Köberle, J. R. W. Masters, J. A. Hartley, and R. D. Wood, “Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours,” Current Biology, vol. 9, no. 5, pp. 273–276, 1999. View at Publisher · View at Google Scholar · View at Scopus
  8. E. L. Mamenta, E. E. Poma, W. K. Kaufmann, D. A. Delmastro, H. L. Grady, and S. G. Chaney, “Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines,” Cancer Research, vol. 54, no. 13, pp. 3500–3505, 1994. View at Google Scholar · View at Scopus
  9. A. G. Eliopoulos, D. J. Kerr, J. Herod et al., “The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2,” Oncogene, vol. 11, no. 7, pp. 1217–1228, 1995. View at Google Scholar · View at Scopus
  10. A. I. Ivanov, J. Christodoulou, J. A. Parkinson et al., “Cisplatin binding sites on human albumin,” The Journal of Biological Chemistry, vol. 273, no. 24, pp. 14721–14730, 1998. View at Publisher · View at Google Scholar · View at Scopus
  11. R. C. DeConti, B. R. Toftness, R. C. Lange, and W. A. Creasey, “Clinical and pharmacological studies with cis diamminedichloroplatinum(II),” Cancer Research, vol. 33, no. 6, pp. 1310–1315, 1973. View at Google Scholar · View at Scopus
  12. D. P. Gately and S. B. Howell, “Cellular accumulation of the anticancer agent cisplatin: a review,” British Journal of Cancer, vol. 67, no. 6, pp. 1171–1176, 1993. View at Google Scholar · View at Scopus
  13. S. Ishida, J. Lee, D. J. Thiele, and I. Herskowitz, “Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 22, pp. 14298–14302, 2002. View at Publisher · View at Google Scholar · View at Scopus
  14. R. A. Alderden, M. D. Hall, and T. W. Hambley, “The discovery and development of cisplatin,” Journal of Chemical Education, vol. 83, no. 5, pp. 728–734, 2006. View at Google Scholar · View at Scopus
  15. A. R. Timerbaev, C. G. Hartinger, S. S. Aleksenko, and B. K. Keppler, “Interactions of antitumor metallodrugs with serum proteins: advances in characterization using modern analytical methodology,” Chemical Reviews, vol. 106, no. 6, pp. 2224–2248, 2006. View at Publisher · View at Google Scholar · View at Scopus
  16. E. Volckova, F. Evanics, W. W. Yang, and R. N. Bose, “Unwinding of DNA polymerases by the antitumor drug, cis-diamminedichloroplatinum(II),” Chemical Communications, vol. 9, no. 10, pp. 1128–1129, 2003. View at Google Scholar · View at Scopus
  17. S. Ahmad, “Platinum-DNA interactions and subsequent cellular processes controlling sensitivity to anticancer platinum complexes,” Chemistry and Biodiversity, vol. 7, no. 3, pp. 543–566, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. R. J. Knox, F. Friedlos, D. A. Lydall, and J. J. Roberts, “Mechanism of cytotoxicity of anticancer platinum drugs: evidence that cis-diamminedichloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) differ only in the kinetics of their interaction with DNA,” Cancer Research, vol. 46, no. 4, pp. 1972–1979, 1986. View at Google Scholar · View at Scopus
  19. L. L. Munchausen and R. O. Rahn, “Physical studies on the binding of cis dichlorodiamine platinum(II) to DNA and homopolynucleotides,” Biochimica et Biophysica Acta, vol. 414, no. 3, pp. 242–255, 1975. View at Google Scholar · View at Scopus
  20. A. Eastman, “Characterization of the adducts produced in DNA by cis-diamminedichloroplatinum(II) and cis-dichloro(ethylenediamine)platinum(II),” Biochemistry, vol. 22, no. 16, pp. 3927–3933, 1983. View at Google Scholar · View at Scopus
  21. A. C. M. Plooy, A. M. J. Fichtinger-Schepman, and H. H. Schutte, “The quantitative detection of various Pt-DNA-adducts in Chinese hamster ovary cells treated with cisplatin: application of immunochemical techniques,” Carcinogenesis, vol. 6, no. 4, pp. 561–566, 1985. View at Google Scholar · View at Scopus
  22. A. E. Egger, C. G. Hartinger, H. B. Hamidane, Y. O. Tsybin, B. K. Keppler, and P. J. Dyson, “High resolution mass spectrometry for studying the interactions of cisplatin with oligonucleotides,” Inorganic Chemistry, vol. 47, no. 22, pp. 10626–10633, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. D. B. Zamble, D. Mu, J. T. Reardon, A. Sancar, and S. J. Lippard, “Repair of cisplatin-DNA adducts by the mammalian excision nuclease,” Biochemistry, vol. 35, no. 31, pp. 10004–10013, 1996. View at Publisher · View at Google Scholar · View at Scopus
  24. J. T. Reardon, A. Vaisman, S. G. Chaney, and A. Sancar, “Efficient nucleotide excision repair of cisplatin, oxaliplatin, and bis- acetoammine-dichloro-cyclohexylamine-platinum(IV) (JM216) platinum intrastrand DNA diadducts,” Cancer Research, vol. 59, no. 16, pp. 3968–3971, 1999. View at Google Scholar · View at Scopus
  25. S. W. Johnson, R. P. Perez, A. K. Godwin et al., “Role of platinum-DNA adduct formation and removal in cisplatin resistance in human ovarian cancer cell lines,” Biochemical Pharmacology, vol. 47, no. 4, pp. 689–697, 1994. View at Publisher · View at Google Scholar · View at Scopus
  26. K. V. Ferry, T. C. Hamilton, and S. W. Johnson, “Increased nucleotide excision repair in cisplatin-resistant ovarian cancer cells: role of ERCC1-XPF,” Biochemical Pharmacology, vol. 60, no. 9, pp. 1305–1313, 2000. View at Publisher · View at Google Scholar · View at Scopus
  27. D. Fink, H. Zheng, S. Nebel et al., “In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair,” Cancer Research, vol. 57, no. 10, pp. 1841–1845, 1997. View at Google Scholar · View at Scopus
  28. E. D. Scheeff, J. M. Briggs, and S. B. Howell, “Molecular modeling of the intrastrand guanine-guanine DNA adducts produced by cisplatin and oxaliplatin,” Molecular Pharmacology, vol. 56, no. 3, pp. 633–643, 1999. View at Google Scholar · View at Scopus
  29. A. Vaisman, M. Varchenko, A. Umar et al., “The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: correlation with replicative bypass of platinum-DNA adducts,” Cancer Research, vol. 58, no. 16, pp. 3579–3585, 1998. View at Google Scholar · View at Scopus
  30. S. G. Chaney, S. L. Campbell, E. Bassett, and Y. Wu, “Recognition and processing of cisplatin- and oxaliplatin-DNA adducts,” Critical Reviews in Oncology/Hematology, vol. 53, no. 1, pp. 3–11, 2005. View at Publisher · View at Google Scholar · View at Scopus
  31. V. Cepeda, M. A. Fuertes, J. Castilla, C. Alonso, C. Quevedo, and J. M. Pérez, “Biochemical mechanisms of cisplatin cytotoxicity,” Anti-Cancer Agents in Medicinal Chemistry, vol. 7, no. 1, pp. 3–18, 2007. View at Publisher · View at Google Scholar · View at Scopus
  32. K. M. Henkels and J. J. Turchi, “Induction of apoptosis in cisplatin-sensitive and -resistant human ovarian cancer cell lines,” Cancer Research, vol. 57, no. 20, pp. 4488–4492, 1997. View at Google Scholar · View at Scopus
  33. D. Wang and S. J. Lippard, “Cellular processing of platinum anticancer drugs,” Nature Reviews Drug Discovery, vol. 4, no. 4, pp. 307–320, 2005. View at Publisher · View at Google Scholar · View at Scopus
  34. Z. S. Juo, T. K. Chiu, P. M. Leiberman, I. Baikalov, A. J. Berk, and R. E. Dickerson, “How proteins recognize the TATA box,” Journal of Molecular Biology, vol. 261, no. 2, pp. 239–254, 1996. View at Publisher · View at Google Scholar · View at Scopus
  35. J. Yaneva, S. H. Leuba, K. Van Holde, and J. Zlatanova, “The major chromatin protein his tone H1 binds preferentially to cis-platinum-damaged DNA,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 25, pp. 13448–13451, 1997. View at Google Scholar · View at Scopus
  36. M. Kartalou, L. D. Samson, and J. M. Essigmann, “Cisplatin adducts inhibit 1,N6-ethenoadenine repair by interacting with the human 3-methyladenine DNA glycosylase,” Biochemistry, vol. 39, no. 27, pp. 8032–8038, 2000. View at Publisher · View at Google Scholar · View at Scopus
  37. C. Söti, A. Rácz, and P. Csermely, “A nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90. N-terminal nucleotide binding unmasks a C-terminal binding pocket,” The Journal of Biological Chemistry, vol. 277, no. 9, pp. 7066–7075, 2002. View at Publisher · View at Google Scholar · View at Scopus
  38. T. Peleg-Shulman and D. Gibson, “Cisplatin-protein adducts are efficiently removed by glutathione but not by 5′-guanosine monophosphate,” Journal of the American Chemical Society, vol. 123, no. 13, pp. 3171–3172, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. H. Daino, I. Matsumura, K. Takada et al., “Induction of apoptosis by extracellular ubiquitin in human hematopoietic cells: possible involvement of STAT3 degradation by proteasome pathway in interleukin 6-dependent hematopoietic cells,” Blood, vol. 95, no. 8, pp. 2577–2585, 2000. View at Google Scholar · View at Scopus
  40. P. A. Nguewa, M. A. Fuertes, V. Cepeda et al., “Pentamidine is an antiparasitic and apoptotic drug that selectively modifies ubiquitin,” Chemistry and Biodiversity, vol. 2, no. 10, pp. 1387–1400, 2005. View at Publisher · View at Google Scholar · View at Scopus
  41. D. Maksimovic-Ivanic, S. Mijatovic, D. Miljkovic et al., “The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt,” Molecular Cancer Therapeutics, vol. 8, no. 5, pp. 1169–1178, 2009. View at Publisher · View at Google Scholar · View at Scopus
  42. A. Casini, C. Gabbiani, G. Mastrobuoni et al., “Insights into the molecular mechanisms of protein platination from a case study: the reaction of anticancer platinum(II) iminoethers with horse heart cytochrome C,” Biochemistry, vol. 46, no. 43, pp. 12220–12230, 2007. View at Publisher · View at Google Scholar · View at Scopus
  43. F. Arnesano and G. Natile, ““Platinum on the road”: interactions of antitumoral cisplatin with proteins,” Pure and Applied Chemistry, vol. 80, no. 12, pp. 2715–2725, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. S. R. Datta, A. Brunet, and M. E. Greenberg, “Cellular survival: a play in three akts,” Genes and Development, vol. 13, no. 22, pp. 2905–2927, 1999. View at Publisher · View at Google Scholar · View at Scopus
  45. M. Fraser, B. M. Leung, X. Yan, H. C. Dan, J. Q. Cheng, and B. K. Tsang, “p53 is a determinant of X-linked inhibitor of apoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells,” Cancer Research, vol. 63, no. 21, pp. 7081–7088, 2003. View at Google Scholar · View at Scopus
  46. H. C. Dan, M. Sun, S. Kaneko et al., “Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP),” The Journal of Biological Chemistry, vol. 279, no. 7, pp. 5405–5412, 2004. View at Publisher · View at Google Scholar · View at Scopus
  47. J. G. Viniegra, J. H. Losa, V. J. Sánchez-Arévalo et al., “Modulation of PI3K/Akt pathway by E1a mediates sensitivity to cisplatin,” Oncogene, vol. 21, no. 46, pp. 7131–7136, 2002. View at Publisher · View at Google Scholar · View at Scopus
  48. Y. Shaul, “c-Abl: activation and nuclear targets,” Cell Death and Differentiation, vol. 7, no. 1, pp. 10–16, 2000. View at Google Scholar · View at Scopus
  49. J. Gong, A. Costanzo, H. Q. Yang et al., “The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage,” Nature, vol. 399, no. 6738, pp. 806–809, 1999. View at Publisher · View at Google Scholar · View at Scopus
  50. L. Harhaji-Trajkovic, U. Vilimanovich, T. Kravic-Stevovic, V. Bumbasirevic, and V. Trajkovic, “AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells,” Journal of Cellular and Molecular Medicine, vol. 13, no. 9, pp. 3644–3654, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. X. Wang, J. L. Martindale, and N. J. Holbrook, “Requirement for ERK activation in cisplatin-induced apoptosis,” The Journal of Biological Chemistry, vol. 275, no. 50, pp. 39435–39443, 2000. View at Publisher · View at Google Scholar · View at Scopus
  52. W. Cui, E. M. Yazlovitskaya, M. S. Mayo et al., “Cisplatin-induced response of c-jun N-terminal kinase 1 and extracellular signal—regulated protein kinases 1 and 2 in a series of cisplatin-resistant ovarian carcinoma cell lines,” Molecular Carcinogenesis, vol. 29, pp. 219–228, 2000. View at Google Scholar
  53. S. Mijatovic, D. Maksimovic-Ivanic, J. Radovic et al., “Aloe emodin decreases the ERK-dependent anticancer activity of cisplatin,” Cellular and Molecular Life Sciences, vol. 62, no. 11, pp. 1275–1282, 2005. View at Publisher · View at Google Scholar · View at Scopus
  54. S. Mijatovic, D. Maksimovic-Ivanic, J. Radovic et al., “Anti-glioma action of aloe emodin: the role of ERK inhibition,” Cellular and Molecular Life Sciences, vol. 62, no. 5, pp. 589–598, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. A. Mansouri, L. D. Ridgway, A. L. Korapati et al., “Sustained activation of JNK/p38 MAPK pathways in response to cisplatin leads to Fas ligand induction and cell death in ovarian carcinoma cells,” The Journal of Biological Chemistry, vol. 278, no. 21, pp. 19245–19256, 2003. View at Publisher · View at Google Scholar · View at Scopus
  56. I. Sánchez-Perez, J. R. Murguía, and R. Perona, “Cisplatin induces a persistent activation of JNK that is related to cell death,” Oncogene, vol. 16, no. 4, pp. 533–540, 1998. View at Google Scholar · View at Scopus
  57. J. Hayakawa, M. Ohmichi, H. Kurachi et al., “Inhibition of extracellular signal-regulated protein kinase or c-Jun N- terminal protein kinase cascade, differentially activated by cisplatin, sensitizes human ovarian cancer cell line,” The Journal of Biological Chemistry, vol. 274, no. 44, pp. 31648–31654, 1999. View at Publisher · View at Google Scholar · View at Scopus
  58. R. J. Davis, “Signal transduction by the JNK group of MAP kinases,” Cell, vol. 103, no. 2, pp. 239–252, 2000. View at Google Scholar · View at Scopus
  59. P. Pandey, J. Raingeaud, M. Kaneki et al., “Activation of p38 mitogen-activated protein kinase by c-Abl-dependent and -independent mechanisms,” The Journal of Biological Chemistry, vol. 271, no. 39, pp. 23775–23779, 1996. View at Publisher · View at Google Scholar · View at Scopus
  60. J. Hernández Losa, C. Parada Cobo, J. Guinea Viniegra, V. J. Sánchez-Arevalo Lobo, S. Ramón y Cajal, and R. Sánchez-Prieto, “Role of the p38 MAPK pathway in cisplatin-based therapy,” Oncogene, vol. 22, no. 26, pp. 3998–4006, 2003. View at Publisher · View at Google Scholar · View at Scopus
  61. D. Wang and S. J. Lippard, “Cisplatin-induced post-translational modification of histones H3 and H4,” The Journal of Biological Chemistry, vol. 279, no. 20, pp. 20622–20625, 2004. View at Publisher · View at Google Scholar · View at Scopus
  62. V. M. Gonzalez, M. A. Fuertes, C. Alonso, and J. M. Perez, “Is cisplatin-induced cell death always produced by apoptosis?” Molecular Pharmacology, vol. 59, no. 4, pp. 657–663, 2001. View at Google Scholar · View at Scopus
  63. W. Lieberthal, V. Triaca, and J. Levine, “Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis,” American Journal of Physiology, vol. 270, no. 4, pp. F700–F708, 1996. View at Google Scholar · View at Scopus
  64. Y. Eguchi, S. Shimizu, and Y. Tsujimoto, “Intracellular ATP levels determine cell death fate by apoptosis or necrosis,” Cancer Research, vol. 57, no. 10, pp. 1835–1840, 1997. View at Google Scholar · View at Scopus
  65. R. Zhou, M. G. Vander Heiden, and C. M. Rudin, “Genotoxic exposure is associated with alterations in glucose uptake and metabolism,” Cancer Research, vol. 62, no. 12, pp. 3515–3520, 2002. View at Google Scholar · View at Scopus
  66. Z. Herceg and Z. Q. Wang, “Failure of poly(ADP-ribose) polymerase cleavage by caspases leads to induction of necrosis and enhanced apoptosis,” Molecular and Cellular Biology, vol. 19, no. 7, pp. 5124–5133, 1999. View at Google Scholar · View at Scopus
  67. T. Hirsch, P. Marchetti, S. A. Susin et al., “The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death,” Oncogene, vol. 15, no. 13, pp. 1573–1581, 1997. View at Google Scholar · View at Scopus
  68. L. Ding, C. Yuan, F. Wei et al., “Cisplatin restores TRAIL apoptotic pathway in glioblastoma-derived stem cells through up-regulation of DR5 and down-regulation of c-FLIP,” Cancer Investigation, vol. 29, pp. 511–520, 2011. View at Publisher · View at Google Scholar
  69. O. Vondálová Blanárová, I. Jelínková, A. Szöor et al., “Cisplatin and a potent platinum(IV) complex-mediated enhancement of TRAIL-induced cancer cells killing is associated with modulation of upstream events in the extrinsic apoptotic pathway,” Carcinogenesis, vol. 32, no. 1, pp. 42–51, 2011. View at Google Scholar · View at Scopus
  70. D. Maksimovic-Ivanic, S. Stosic-Grujicic, F. Nicoletti, and S. Mijatovic, “Resistance to TRAIl and how to surmount it,” Immunology Research, vol. 52, no. 1-2, pp. 157–168, 2012. View at Publisher · View at Google Scholar
  71. M. P. Decatris, S. Sundar, and K. J. O'Byrne, “Platinum-based chemotherapy in metastatic breast cancer: current status,” Cancer Treatment Reviews, vol. 30, no. 1, pp. 53–81, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. M. D. Shelley, K. Burgon, and M. D. Mason, “Treatment of testicular germ-cell cancer: a cochrane evidence-based systematic review,” Cancer Treatment Reviews, vol. 28, no. 5, pp. 237–253, 2002. View at Publisher · View at Google Scholar · View at Scopus
  73. M. S. Kim, M. Blake, J. H. Baek, G. Kohlhagen, Y. Pommier, and F. Carrier, “Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA,” Cancer Research, vol. 63, no. 21, pp. 7291–7300, 2003. View at Google Scholar · View at Scopus
  74. N. J. Long, Metallocenes, Blackwell Science, Oxford, UK, 1998.
  75. A. Korfel, M. E. Scheulen, H. J. Schmoll et al., “Phase I clinical and pharmacokinetic study of titanocene dichloride in adults with advanced solid tumors,” Clinical Cancer Research, vol. 4, no. 11, pp. 2701–2708, 1998. View at Google Scholar · View at Scopus
  76. C. V. Christodoulou, D. R. Ferry, D. W. Fyfe et al., “Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer,” Journal of Clinical Oncology, vol. 16, no. 8, pp. 2761–2769, 1998. View at Google Scholar · View at Scopus
  77. K. Mross, P. Robben-Bathe, L. Edler et al., “Phase I clinical trial of a day-1, -3, -5 every 3 weeks schedule with titanocene dichloride (MKT 5) in patients with advanced cancer: a study of the phase I study group of the association for medical oncology (AIO) of the German Cancer Society,” Onkologie, vol. 23, no. 6, pp. 576–579, 2000. View at Publisher · View at Google Scholar · View at Scopus
  78. B. W. Müller, R. Müller, S. Lucks, and W. Mohr, “Medac Gesellschaft fur Klinische Spzeilpräparate GmbH,” US Patent 5, 296, 237, 1994.
  79. N. Kröger, U. R. Kleeberg, K. Mross, L. Edler, G. Saß, and D. K. Hossfeld, “Phase II clinical trial of titanocene dichloride in patients with metastatic breast cancer,” Onkologie, vol. 23, no. 1, pp. 60–62, 2000. View at Google Scholar · View at Scopus
  80. G. Lümmen, H. Sperling, H. Luboldt, T. Otto, and H. Rübben, “Phase II trial of titanocene dichloride in advanced renal-cell carcinoma,” Cancer Chemotherapy and Pharmacology, vol. 42, no. 5, pp. 415–417, 1998. View at Publisher · View at Google Scholar · View at Scopus
  81. E. Meléndez, “Titanium complexes in cancer treatment,” Critical Reviews in Oncology/Hematology, vol. 42, no. 3, pp. 309–315, 2002. View at Publisher · View at Google Scholar · View at Scopus
  82. F. Caruso and M. Rossi, “Antitumor titanium compounds and related metallocenes,” in Metal Ions in Biological System, A. Sigel and H. Sigel, Eds., vol. 42 of Metal Complexes in Tumor Diagnostics and as Anticancer Agents, Marcel Dekker, New York, NY, USA, 2004. View at Google Scholar
  83. J. C. Dabrowiak, Metals in Medicine, John Wiley & Sons, West Sussex, UK, 2009.
  84. U. Olszewski and G. Hamilton, “Mechanisms of cytotoxicity of anticancer titanocenes,” Anti-Cancer Agents in Medicinal Chemistry, vol. 10, no. 4, pp. 302–311, 2010. View at Google Scholar · View at Scopus
  85. K. Strohfeldt and M. Tacke, “Bioorganometallic fulvene-derived titanocene anti-cancer drugs,” Chemical Society Reviews, vol. 37, no. 6, pp. 1174–1187, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. R. Hernández, J. Lamboy, L. M. Gao, J. Matta, F. R. Román, and E. Meléndez, “Structure-activity studies of Ti(IV) complexes: aqueous stability and cytotoxic properties in colon cancer HT-29 cells,” Journal of Biological Inorganic Chemistry, vol. 13, no. 5, pp. 685–692, 2008. View at Publisher · View at Google Scholar · View at Scopus
  87. R. Hernández, J. Méndez, J. Lamboy, M. Torres, F. R. Román, and E. Meléndez, “Titanium(IV) complexes: cytotoxicity and cellular uptake of titanium(IV) complexes on caco-2 cell line,” Toxicology in Vitro, vol. 24, no. 1, pp. 178–183, 2010. View at Publisher · View at Google Scholar · View at Scopus
  88. L. M. Gao, J. Matta, A. L. Rheingold, and E. Meléndez, “Synthesis, structure and biological activity of amide-functionalized titanocenyls: improving their cytotoxic properties,” Journal of Organometallic Chemistry, vol. 694, no. 26, pp. 4134–4139, 2009. View at Publisher · View at Google Scholar · View at Scopus
  89. A. Gansäuer, I. Winkler, D. Worgull et al., “Carbonyl-substituted titanocenes: a novel class of cytostatic compounds with high antitumor and antileukemic activity,” Chemistry, vol. 14, no. 14, pp. 4160–4163, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. O. R. Allen, L. Croll, A. L. Gott, R. J. Knox, and P. C. McGowan, “Functionalized cyclopentadienyl titanium organometallic compounds as new antitumor drugs,” Organometallics, vol. 23, no. 2, pp. 288–292, 2004. View at Publisher · View at Google Scholar · View at Scopus
  91. O. R. Allen, A. L. Gott, J. A. Hartley, J. M. Hartley, R. J. Knox, and P. C. McGowan, “Functionalised cyclopentadienyl titanium compounds as potential anticancer drugs,” Dalton Transactions, no. 43, pp. 5082–5090, 2007. View at Publisher · View at Google Scholar · View at Scopus
  92. G. D. Potter, M. C. Baird, and S. P. C. Cole, “A new series of titanocene dichloride derivatives bearing chiral alkylammonium groups; Assessment of their cytotoxic properties,” Inorganica Chimica Acta, vol. 364, no. 1, pp. 16–22, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. L. M. Gao, J. L. Vera, J. Matta, and E. Meléndez, “Synthesis and cytotoxicity studies of steroid-functionalized titanocenes as potential anticancer drugs: sex steroids as potential vectors for titanocenes,” Journal of Biological Inorganic Chemistry, vol. 15, no. 6, pp. 851–859, 2010. View at Publisher · View at Google Scholar · View at Scopus
  94. S. Gómez-Ruiz, G. N. Kaluđerović, S. Prashar et al., “Cytotoxic studies of substituted titanocene and ansa-titanocene anticancer drugs,” Journal of Inorganic Biochemistry, vol. 102, no. 8, pp. 1558–1570, 2008. View at Publisher · View at Google Scholar · View at Scopus
  95. S. Gómez-Ruiz, G. N. Kaluđerović, Ž. Žižak et al., “Anticancer drugs based on alkenyl and boryl substituted titanocene complexes,” Journal of Organometallic Chemistry, vol. 694, no. 13, pp. 1981–1987, 2009. View at Publisher · View at Google Scholar · View at Scopus
  96. G. N. Kaluđerović, V. Tayurskaya, R. Paschke, S. Prashar, M. Fajardo, and S. Gómez-Ruiz, “Synthesis, characterization and biological studies of alkenyl-substituted titanocene(IV) carboxylate complexes,” Applied Organometallic Chemistry, vol. 24, no. 9, pp. 656–662, 2010. View at Publisher · View at Google Scholar · View at Scopus
  97. H. Sun, H. Li, R. A. Weir, and P. J. Sadler, “You have full text access to this content the first specific TiIV-protein complex: potential relevance to anticancer activity of titanocenes,” Angewandte Chemie International Edition, vol. 37, no. 11, pp. 1577–1579, 1998. View at Google Scholar
  98. M. Guo and P. J. Sadler, “Competitive binding of the anticancer drug titanocene dichloride to N,N′-ethylenebis(o-hydroxyphenylglycine) and adenosine triphosphate: a model for TiIV uptake and release by transferrin,” Journal of the Chemical Society, Dalton Transactions, vol. 1, pp. 7–9, 2000. View at Google Scholar · View at Scopus
  99. M. Guo, H. Sun, S. Bihari et al., “Stereoselective formation of seven-coordinate titanium(IV) monomer and dimer complexes of ethylenebis(o-hydroxyphenyl)glycine,” Inorganic Chemistry, vol. 39, no. 2, pp. 206–215, 2000. View at Publisher · View at Google Scholar · View at Scopus
  100. M. Guo, H. Sun, H. J. McArdle, L. Gambling, and P. J. Sadler, “Ti(IV) uptake and release by human serum transferrin and recognition of Ti(IV)-transferrin by cancer cells: understanding the mechanism of action of the anticancer drug titanocene dichloride,” Biochemistry, vol. 39, no. 33, pp. 10023–10033, 2000. View at Publisher · View at Google Scholar · View at Scopus
  101. P. Köpf-Maier and D. Krahl, “Tumor inhibition by metallogenes: ultrastructural localization of titanium and vanadium in treated tumor cells by electron energy loss spectroscopy,” Chemico-Biological Interactions, vol. 44, no. 3, pp. 317–328, 1983. View at Publisher · View at Google Scholar · View at Scopus
  102. P. Köpf-Maier, “Intracellular localization of titanium within xenografted sensitive human tumors after treatment with the antitumor agent titanocene dichloride,” Journal of Structural Biology, vol. 105, no. 1–3, pp. 35–45, 1990. View at Google Scholar · View at Scopus
  103. A. D. Tinoco, C. D. Incarvito, and A. M. Valentine, “Calorimetric, spectroscopic, and model studies provide insight into the transport of Ti(IV) by human serum transferrin,” Journal of the American Chemical Society, vol. 129, no. 11, pp. 3444–3454, 2007. View at Publisher · View at Google Scholar · View at Scopus
  104. A. D. Tinoco, E. V. Eames, and A. M. Valentine, “Reconsideration of serum Ti(IV) transport: albumin and transferrin trafficking of Ti(IV) and its complexes,” Journal of the American Chemical Society, vol. 130, no. 7, pp. 2262–2270, 2008. View at Publisher · View at Google Scholar · View at Scopus
  105. M. Pavlaki, K. Debeli, I. E. Triantaphyllidou, N. Klouras, E. Giannopoulou, and A. J. Aletras, “A proposed mechanism for the inhibitory effect of the anticancer agent titanocene dichloride on tumour gelatinases and other proteolytic enzymes,” Journal of Biological Inorganic Chemistry, vol. 14, no. 6, pp. 947–957, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. O. R. Allen, R. J. Knox, and P. C. McGowan, “Functionalised cyclopentadienyl zirconium compounds as potential anticancer drugs,” Dalton Transactions, no. 39, pp. 5293–5295, 2008. View at Google Scholar · View at Scopus
  107. D. Wallis, J. Claffey, B. Gleeson, M. Hogan, H. Müller-Bunz, and M. Tacke, “Novel zirconocene anticancer drugs?” Journal of Organometallic Chemistry, vol. 694, no. 6, pp. 828–833, 2009. View at Publisher · View at Google Scholar · View at Scopus
  108. S. Gómez-Ruiz, G. N. Kaluderović, D. Polo-Cerón et al., “A novel alkenyl-substituted ansa-zirconocene complex with dual application as olefin polymerization catalyst and anticancer drug,” Journal of Organometallic Chemistry, vol. 694, no. 18, pp. 3032–3038, 2009. View at Publisher · View at Google Scholar · View at Scopus
  109. P. Köpf-Maier, “Antitumor bis(cyclopentadienyl) metal complexes,” in Metal Complexes in Cancer Chemotherapy, B. K. Keppler, Ed., pp. 259–296, VCH Verlagsgesellschaft, Weinheim, Germany, 1993. View at Google Scholar
  110. C. S. Navara, A. Benyumov, A. Vassilev, R. K. Narla, P. Ghosh, and F. M. Uckun, “Vanadocenes as potent anti-proliferative agents disrupting mitotic spindle formation in cancer cells,” Anti-Cancer Drugs, vol. 12, no. 4, pp. 369–376, 2001. View at Publisher · View at Google Scholar · View at Scopus
  111. P. Ghosh, O. J. D'Cruz, R. K. Narla, and F. M. Uckun, “Apoptosis-inducing vanadocene compounds against human testicular cancer,” Clinical Cancer Research, vol. 6, no. 4, pp. 1536–1545, 2000. View at Google Scholar · View at Scopus
  112. H. Paláčková, J. Vinklárek, J. Holubová, I. Císařová, and M. Erben, “The interaction of antitumor active vanadocene dichloride with sulfur-containing amino acids,” Journal of Organometallic Chemistry, vol. 692, no. 17, pp. 3758–3764, 2007. View at Publisher · View at Google Scholar · View at Scopus
  113. J. Vinklárek, J. Honzíček, and J. Holubová, “Interaction of the antitumor agent vanadocene dichloride with phosphate buffered saline,” Inorganica Chimica Acta, vol. 357, no. 12, pp. 3765–3769, 2004. View at Publisher · View at Google Scholar · View at Scopus
  114. J. Vinklárek, H. Paláčková, J. Honzíček, J. Holubová, M. Holčapek, and I. Císařová, “Investigation of vanadocene(IV) α-amino acid complexes: synthesis, structure, and behavior in physiological solutions, human plasma, and blood,” Inorganic Chemistry, vol. 45, no. 5, pp. 2156–2162, 2006. View at Publisher · View at Google Scholar · View at Scopus
  115. B. Gleeson, J. Claffey, A. Deally et al., “Synthesis and cytotoxicity studies of fluorinated derivatives of vanadocene Y,” European Journal of Inorganic Chemistry, no. 19, pp. 2804–2810, 2009. View at Publisher · View at Google Scholar · View at Scopus
  116. B. Gleeson, J. Claffey, M. Hogan, H. Müller-Bunz, D. Wallis, and M. Tacke, “Novel benzyl-substituted vanadocene anticancer drugs,” Journal of Organometallic Chemistry, vol. 694, no. 9-10, pp. 1369–1374, 2009. View at Publisher · View at Google Scholar · View at Scopus
  117. B. Gleeson, J. Claffey, A. Deally et al., “Novel benzyl-substituted molybdocene anticancer drugs,” Inorganica Chimica Acta, vol. 363, no. 8, pp. 1831–1836, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. B. Gleeson, M. Hogan, H. Müller-Bunz, and M. Tacke, “Synthesis and preliminary cytotoxicity studies of indole-substituted vanadocenes,” Transition Metal Chemistry, vol. 35, no. 8, pp. 973–983, 2010. View at Publisher · View at Google Scholar · View at Scopus
  119. J. Honzíček, I. Klepalová, J. Vinklárek et al., “Synthesis, characterization and cytotoxic effect of ring-substituted and ansa-bridged vanadocene complexes,” Inorganica Chimica Acta, vol. 373, no. 1, pp. 1–7, 2011. View at Publisher · View at Google Scholar · View at Scopus
  120. J. B. Waern and M. M. Harding, “Bioorganometallic chemistry of molybdocene dichloride,” Journal of Organometallic Chemistry, vol. 689, no. 25, pp. 4655–4668, 2004. View at Publisher · View at Google Scholar · View at Scopus
  121. J. B. Waern, C. T. Dillon, and M. M. Harding, “Organometallic anticancer agents: cellular uptake and cytotoxicity studies on thiol derivatives of the antitumor agent molybdocene dichloride,” Journal of Medicinal Chemistry, vol. 48, no. 6, pp. 2093–2099, 2005. View at Publisher · View at Google Scholar · View at Scopus
  122. J. B. Waern, H. H. Harris, B. Lai, Z. Cai, M. M. Harding, and C. T. Dillon, “Intracellular mapping of the distribution of metals derived from the antitumor metallocenes,” Journal of Biological Inorganic Chemistry, vol. 10, no. 5, pp. 443–452, 2005. View at Publisher · View at Google Scholar · View at Scopus
  123. J. B. Waern, P. Turner, and M. M. Harding, “Synthesis and hydrolysis of thiol derivatives of molybdocene dichloride incorporating electron-withdrawing substituents,” Organometallics, vol. 25, no. 14, pp. 3417–3421, 2006. View at Publisher · View at Google Scholar · View at Scopus
  124. K. S. Campbell, A. J. Foster, C. T. Dillon, and M. M. Harding, “Genotoxicity and transmission electron microscopy studies of molybdocene dichloride,” Journal of Inorganic Biochemistry, vol. 100, no. 7, pp. 1194–1198, 2006. View at Publisher · View at Google Scholar · View at Scopus
  125. J. H. Toney and T. J. Marks, “Hydrolysis chemistry of the metallocene dichlorides M(η5-C5H5)2Cl2, M = Ti, V, Zr. Aqueous kinetics, equilibria, and mechanistic implications for a new class of antitumor agents,” Journal of the American Chemical Society, vol. 107, no. 4, pp. 947–953, 1985. View at Google Scholar · View at Scopus
  126. C. Balzarek, T. J. R. Weakley, L. Y. Kuo, and D. R. Tyler, “Investigation of the monomer-dimer equilibria of molybdocenes in water,” Organometallics, vol. 19, no. 15, pp. 2927–2931, 2000. View at Publisher · View at Google Scholar · View at Scopus
  127. L. Y. Kuo, M. G. Kanatzidis, M. Sabat, A. L. Tipton, and T. J. Marks, “Metallocene antitumor agents. Solution and solid-state molybdenocene coordination chemistry of DNA constituents,” Journal of the American Chemical Society, vol. 113, no. 24, pp. 9027–9045, 1991. View at Google Scholar · View at Scopus
  128. P. M. Abeysinghe and M. M. Harding, “Antitumour bis(cyclopentadienyl) metal complexes: titanocene and molybdocene dichloride and derivatives,” Dalton Transactions, no. 32, pp. 3474–3482, 2007. View at Publisher · View at Google Scholar · View at Scopus
  129. M. M. Harding and G. Mokdsi, “Antitumour metallocenes: structure-activity studies and interactions with biomolecules,” Current Medicinal Chemistry, vol. 7, no. 12, pp. 1289–1303, 2000. View at Google Scholar · View at Scopus
  130. K. S. Campbell, C. T. Dillon, S. V. Smith, and M. M. Harding, “Radiotracer studies of the antitumor metallocene molybdocene dichloride with biomolecules,” Polyhedron, vol. 26, no. 2, pp. 456–459, 2007. View at Publisher · View at Google Scholar · View at Scopus
  131. P. Köpf-Maier, H. Köpf, and E. W. Neuse, “Ferrocenium salts—the first antineoplastic iron compounds,” Angewandte Chemie—International Edition in English, vol. 23, no. 6, pp. 456–457, 1984. View at Google Scholar · View at Scopus
  132. P. Köpf-Maier, H. Kopf, and E. W. Neuse, “Ferricenium complexes: a new type of water-soluble antitumor agent,” Journal of Cancer Research and Clinical Oncology, vol. 108, no. 3, pp. 336–340, 1984. View at Google Scholar · View at Scopus
  133. S. Top, J. Tang, A. Vessières, D. Carrez, C. Provot, and G. Jaouen, “Ferrocenyl hydroxytamoxifen: a prototype for a new range of oestradiol receptor site-directed cytotoxics,” Chemical Communications, vol. 8, pp. 955–956, 1996. View at Google Scholar · View at Scopus
  134. S. Top, B. Dauer, J. Vaissermann, and G. Jaouen, “Facile route to ferrocifen, 1-[4-(2-dimethylaminoethoxy)]-1-(phenyl-2-ferrocenyl-but-1-ene), first organometallic analogue of tamoxifen, by the McMurry reaction,” Journal of Organometallic Chemistry, vol. 541, no. 1-2, pp. 355–361, 1997. View at Google Scholar · View at Scopus
  135. S. Top, A. Vessières, C. Cabestaing et al., “Studies on organometallic selective estrogen receptor modulators. (SERMs) Dual activity in the hydroxy-ferrocifen series,” Journal of Organometallic Chemistry, vol. 637–639, no. 1, pp. 500–506, 2001. View at Publisher · View at Google Scholar · View at Scopus
  136. S. Top, A. Vessières, G. Leclercq et al., “Synthesis, biochemical properties and molecular modelling studies of organometallic Specific Estrogen Receptor Modulators (SERMs), the ferrocifens and hydroxyferrocifens: evidence for an antiproliferative effect of hydroxyferrocifens on both hormone-dependent and hormone-independent breast cancer cell lines,” Chemistry, vol. 9, no. 21, pp. 5223–5236, 2003. View at Publisher · View at Google Scholar · View at Scopus
  137. G. Jaouen, S. Top, A. Vessières, G. Leclercq, and M. J. McGlinchey, “The first organometallic selective estrogen receptor modulators (SERMs) and their relevance to breast cancer,” Current Medicinal Chemistry, vol. 11, no. 18, pp. 2505–2517, 2004. View at Google Scholar · View at Scopus
  138. D. Plazuk, A. Vessières, E. A. Hillard et al., “A [3]ferrocenophane polyphenol showing a remarkable antiproliferative activity on breast and prostate cancer cell lines,” Journal of Medicinal Chemistry, vol. 52, no. 15, pp. 4964–4967, 2009. View at Publisher · View at Google Scholar · View at Scopus
  139. E. A. Hillard, A. Vessières, and G. Jaouen, “Ferrocene functionalized endocrine modulators as anticancer agents,” Topics in Organometallic Chemistry, vol. 32, pp. 81–117, 2010. View at Publisher · View at Google Scholar · View at Scopus
  140. D. P. Buck, P. M. Abeysinghe, C. Cullinane, A. I. Day, J. G. Collins, and M. M. Harding, “Inclusion complexes of the antitumour metallocenes Cp2MCl2 (M = Mo, Ti) with cucurbit[n]urils,” Dalton Transactions, no. 17, pp. 2328–2334, 2008. View at Publisher · View at Google Scholar · View at Scopus
  141. C. C. L. Pereira, C. V. Diogo, A. Burgeiro et al., “Complex formation between heptakis(2,6-di-O-methyl)-β-cyclodextrin and cyclopentadienyl molybdenum(II) dicarbonyl complexes: structural studies and cytotoxicity evaluations,” Organometallics, vol. 27, no. 19, pp. 4948–4956, 2008. View at Publisher · View at Google Scholar · View at Scopus
  142. D. Pérez-Quintanilla, S. Gomez-Ruiz, Ž. Žižak et al., “A new generation of anticancer drugs: mesoporous materials modified with titanocene complexes,” Chemistry, vol. 15, no. 22, pp. 5588–5597, 2009. View at Publisher · View at Google Scholar · View at Scopus
  143. G. N. Kaluđerović, D. Pérez-Quintanilla, I. Sierra et al., “Study of the influence of the metal complex on the cytotoxic activity of titanocene-functionalized mesoporous materials,” Journal of Materials Chemistry, vol. 20, no. 4, pp. 806–814, 2010. View at Publisher · View at Google Scholar · View at Scopus
  144. G. N. Kaluđerović, D. Pérez-Quintanilla, Ž. Žižak, Z. D. Juranić, and S. Gómez-Ruiz, “Improvement of cytotoxicity of titanocene-functionalized mesoporous materials by the increase of the titanium content,” Dalton Transactions, vol. 39, no. 10, pp. 2597–2608, 2010. View at Publisher · View at Google Scholar · View at Scopus
  145. A. García-Peñas, S. Gómez-Ruiz, D. Pérez-Quintanilla et al., “Study of the cytotoxicity and particle action in human cancer cells of titanocene-functionalized materials,” Journal of Inorganic Biochemistry, vol. 106, no. 2, pp. 100–110, 2012. View at Publisher · View at Google Scholar