Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Antitumour and Toxicity Evaluation of a Ru(II)-Cyclopentadienyl Complex in a Prostate Cancer Model by Imaging Tools

Author(s): Lurdes Gano, Teresa Pinheiro, António P. Matos, Francisco Tortosa, Tiago F. Jorge, Maria S. Gonçalves, Marta Martins, Tânia S. Morais, Andreia Valente, Ana I. Tomaz, Maria H. Garcia and Fernanda Marques*

Volume 19, Issue 10, 2019

Page: [1262 - 1275] Pages: 14

DOI: 10.2174/1871520619666190318152726

Price: $65

Abstract

Background: Ruthenium complexes have been extensively investigated for their prospective value as alternatives to cisplatin. Recently, we reported the in vitro anticancer properties of a family of organometallic ruthenium( II)-cyclopentadienyl complexes and have explored their mechanism of action.

Objective: The purpose of this study was to evaluate the in vivo antitumour efficacy and toxicity of one of these Ru(II) compounds, [RuCp(mTPPMSNa)(2,2′-bipy)][CF3SO2] (TM85) which displayed an interesting spectrum of activity against several cancer cells.

Methods: Studies to assess the antitumour activity and toxicity were performed in a metastatic prostate (PC3) mice model using ICP-MS, nuclear microscopy, elemental analysis and Transmission Electron Microscopy (TEM).

Results: TM85 showed low systemic toxicity but no significant tumour reduction, when administered at tolerated dose (20mg/kg) over 10 days. Ru was mainly retained in the liver and less in kidneys, with low accumulation in tumour. Increased bilirubin levels, anomalous Ca and Fe concentrations in liver and mitochondria alterations were indicative of liver injury. The hepatotoxicity observed was less severe than that of cisplatin and no nephrotoxicity was found.

Conclusion: Under the experimental conditions of this study, TM85 is less toxic than cisplatin, induces similar tumour reduction and avoids the formation of metastatic foci. No renal toxicity was observed by the analysis of creatinine levels and the effective renal plasma flow by 99mTc-MAG3 clearance. Hence, it can be considered a valuable compound for further studies in the field of Ru-based anticancer drugs.

Keywords: Ru(II) complexes, in vivo studies, antitumour activity, toxicity, transmission electron microscopy (TEM), microprobe imaging.

Graphical Abstract

[1]
Milosavljevic, N.; Duranton, C.; Djerbi, N.; Puech, P.H.; Gounon, P.; Lagadic-Gossmann, D.; Dimanche-Boitrel, M.T.; Rauch, C.; Tauc, M.; Counillon, L.; Poet, M. Nongenomic effects of cisplatin: Acute inhibition of mechanosensitive transporters and channels without actin remodeling. Cancer Res., 2010, 70(19), 7514-7522.
[2]
Florea, A-M.; Büsselberg, D. Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects. Cancers, 2011, 3(1), 1351-1371.
[3]
Dasari, S.; Tchounwou, P.B. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur. J. Pharmacol., 2014, 740, 364-378.
[4]
Muhammad, N.; Guo, Z. Metal-based anticancer chemotherapeutic agents. Curr. Opin. Chem. Biol., 2014, 19, 144-153.
[5]
Kostova, I. Ruthenium complexes as anticancer agents. Curr. Med. Chem., 2006, 13(9), 1085-1107.
[6]
Levina, A.; Mitra, A.; Lay, P.A. Recent developments in ruthenium anticancer drugs. Metallomics, 2009, 1(6), 458-470.
[7]
Abid, M.; Shamsi, F.; Azam, A. Ruthenium Complexes: An emerging ground to the development of metallopharmaceuticals for cancer therapy. Mini Rev. Med. Chem., 2016, 16(10), 772-786.
[8]
Hartinger, C.G.; Jakupec, M.A.; Zorbas-Seifried, S.; Groessl, M.; Egger, A.; Berger, W.; Zorbas, H.; Dyson, P.J.; Keppler, B.K. KP1019, a new redox-active anticancer agent-preclinical development and results of a clinical phase I study in tumor patients. Chem. Biodivers., 2008, 5(10), 2140-2155.
[9]
Antonarakis, E.S.; Emadi, A. Ruthenium-based chemotherapeutics: Are they ready for prime time? Cancer Chemother. Pharmacol., 2010, 66(1), 1-9.
[10]
Weiss, A.; Berndsen, R.H.; Dubois, M.; Muller, C.; Schibli, R.; Griffioen, A.W.; Dyson, P.J.; Nowak-Sliwinska, P. In vivo anti-tumor activity of the organometallic ruthenium(ii)-arene complex [Ru([small eta]6-p-cymene)Cl2(pta)] (RAPTA-C) in human ovarian and colorectal carcinomas. Chem. Sci., 2014, 5(12), 4742-4748.
[11]
Bergamo, A.; Sava, G. Linking the future of anticancer metal-complexes to the therapy of tumour metastases. Chem. Soc. Rev., 2015, 44(24), 8818-8835.
[12]
Zhao, G.; Lin, H. Metal complexes with aromatic N-containing ligands as potential agents in cancer treatment. Curr. Med. Chem. Anticancer Agents, 2005, 5(2), 137-147.
[13]
Gasser, G.; Ott, I.; Metzler-Nolte, N. Organometallic anticancer compounds. J. Med. Chem., 2011, 54(1), 3-25.
[14]
Yan, Y.K.; Melchart, M.; Habtemariam, A.; Sadler, P.J. Organometallic chemistry, biology and medicine: Ruthenium arene anticancer complexes. Chem. Commun. (Cambridge, England), 2005, 38, 4764-4776.
[15]
Habtemariam, A.; Melchart, M.; Fernández, R.; Parsons, S.; Oswald, I.D.H.; Parkin, A.; Fabbiani, F.P.A.; Davidson, J.E.; Dawson, A.; Aird, R.E.; Jodrell, D.I.; Sadler, P.J. Structure-activity relationships for cytotoxic Ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands. J. Med. Chem., 2006, 49(23), 6858-6868.
[16]
Motswainyana, W.M.; Ajibade, P.A. Anticancer activities of mononuclear Ruthenium(II) coordination complexes. Adv. Chem, 2015, 2015, 21.
[17]
Tomaz, A.I.; Jakusch, T.; Morais, T.S.; Marques, F.; de Almeida, R.F.; Mendes, F.; Enyedy, E.A.; Santos, I.; Pessoa, J.C.; Kiss, T.; Garcia, M.H. [RuII(eta(5)-C(5)H(5))(bipy)(PPh(3))](+), a promising large spectrum antitumour agent: cytotoxic activity and interaction with human serum albumin. J. Inorg. Biochem., 2012, 117, 261-269.
[18]
Corte-Real, L.; Matos, A.P.; Alho, I.; Morais, T.S.; Tomaz, A.I.; Garcia, M.H.; Santos, I.; Bicho, M.P.; Marques, F. Cellular uptake mechanisms of an antitumour ruthenium compound: The endosomal/lysosomal system as a target for anticancer metal-based drugs. Microsc. Microanal., 2013, 19(5), 1122-1130.
[19]
Morais, T.S.; Santos, F.C.; Jorge, T.F.; Corte-Real, L.; Madeira, P.J.; Marques, F.; Robalo, M.P.; Matos, A.; Santos, I.; Garcia, M.H. New water-soluble ruthenium(II) cytotoxic complex: Biological activity and cellular distribution. J. Inorg. Biochem., 2014, 130, 1-14.
[20]
Corte-Real, L.; Mendes, F.; Coimbra, J.; Morais, T.S.; Tomaz, A.I.; Valente, A.; Garcia, M.H.; Santos, I.; Bicho, M.; Marques, F. Anticancer activity of structurally related ruthenium(II) cyclopentadienyl complexes. JBIC, 2014, 19(6), 853-867.
[21]
Morais, T.S.; Valente, A.; Tomaz, A.I.; Marques, F.; Garcia, M.H. Tracking antitumour metallodrugs: Promising agents with the Ru(II)- and Fe(II)-cyclopentadienyl scaffolds. Future Med. Chem., 2016, 8(5), 527-544.
[22]
Chatterjee, S.; Roy, A.; Laskar, A.; Swarnakar, S. Electron microscopy in the perspective of modern biology: Ultravision and ultradimension. Curr. Microsc. Cont. Adv. Sci. Technol. (A. Méndez- Vilas, Ed.), 2012, 891, 902.
[23]
Ortega, R.; Deves, G.; Carmona, A. Bio-metals imaging and speciation in cells using proton and synchrotron radiation X-ray microspectroscopy. J. R. Soc. Interface, 2009, 6(5), S649-S658.
[24]
Lopes, J.; Alves, D.; Morais, T.S.; Costa, P.J.; Piedade, M.F.
Marques, F.; Villa de Brito, M.J.; Garcia, H.M. New copper(I) and heteronuclear copper(I)-ruthenium(II) complexes: Synthesis, structural characterization and cytotoxicity. J. Inorg. Chem, 2017, 169, 68-78.
[25]
Silva, F.; Zambre, A.; Campello, M.P.; Gano, L.; Santos, I.; Ferraria, A.M.; Ferreira, M.J.; Singh, A.; Upendran, A.; Paulo, A.; Kannan, R. Interrogating the role of receptor-mediated mechanisms: biological fate of peptide-functionalized radiolabeled gold nanoparticles in tumor mice. Bioconjug. Chem., 2016, 27(4), 1153-1164.
[26]
Wu, X.; Gong, S.; Roy-Burman, P.; Lee, P.; Culig, Z. Current mouse and cell models in prostate cancer research. Endocr. Relat. Cancer, 2013, 20(4), R155-R170.
[27]
Mendes, N.; Tortosa, F.; Valente, A.; Marques, F.; Matos, A.; Morais, T.S.; Tomaz, A.I.; Gartner, F.; Garcia, M.H. In vivo performance of a ruthenium-cyclopentadienyl compound in an orthotopic triple negative breast cancer model. Anticancer. Agents Med. Chem., 2017, 17(1), 126-136.
[28]
Pinheiro, T.; Pallon, J.; Alves, L.C.; Veríssimo, A.; Filipe, P.; Silva, J.N.; Silva, R. The influence of corneocyte structure on the interpretation of permeation profiles of nanoparticles across skin. Nucl. Instrum. Methods Phys. Res. Secti B: Beam Interact. Mater. Atoms, 2007, 260(1), 119-123.
[29]
Verissimo, A.; Alves, L.C.; Filipe, P.; Silva, J.N.; Silva, R.; Ynsa, M.D.; Gontier, E.; Moretto, P.; Pallon, J.; Pinheiro, T. Nuclear microscopy: A tool for imaging elemental distribution and percutaneous absorption in vivo. Microsc. Res. Tech., 2007, 70(4), 302-309.
[30]
Ynsa, M.D.; Minquin, R.; Rajendran, R.; Pinheiro, T.; Watt, F. Consequences of a fat diet in the distribution of minerals within pancreatic tissues of rats and rabbits. Microsc. Microanal., 2012, 18(5), 1060-1066.
[31]
Pinheiro, T.; Silva, R.; Fleming, R.; Goncalves, A.; Barreiros, M.A.; Silva, J.N.; Morliere, P.; Santus, R.; Filipe, P. Distribution and quantitation of skin iron in primary haemochromatosis: Correlation with total body iron stores in patients undergoing phlebotomy. Acta Derm. Venereol., 2014, 94(1), 14-19.
[32]
Grime, G.W. The “Q factor” method: Quantitative microPIXE analysis using RBS normalisation. Nucl. Instrum. Methods Phys. Res. Secti B: Beam Interact. Mater. Atoms, 1996, 109-110, 170-174.
[33]
Stacklies, W.; Redestig, H.; Scholz, M.; Walther, D.; Selbig, J. pcaMethods--a bioconductor package providing PCA methods for incomplete data. Bioinformatics (Oxford, England), 2007, 23(9), 1164-1167.
[34]
Redza-Dutordoir, M.; Averill-Bates, D.A. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim. Biophys. Acta, 2016, 1863(12), 2977-2992.
[35]
MacKenzie, S.H.; Clark, A.C. Targeting cell death in tumors by activating caspases. Curr. Cancer Drug Targets, 2008, 8(2), 98-109.
[36]
Park, S.I.; Kim, S.J.; McCauley, L.K.; Gallick, G.E. Pre-clinical mouse models of human prostate cancer and their utility in drug discovery. Curr. Protocols Pharmacol, 2010, 14, Unit 14.15.
[37]
Fisher, D.M.; Fenton, R.R.; Aldrich-Wright, J.R. In vivo studies of a platinum(ii) metallointercalator. Chem. Commun., 2008, 43, 5613-5615.
[38]
Ivanov, A.I.; Christodoulou, J.; Parkinson, J.A.; Barnham, K.J.; Tucker, A.; Woodrow, J.; Sadler, P.J. Cisplatin binding sites on human albumin. J. Biol. Chem., 1998, 273(24), 14721-14730.
[39]
Ferraro, G.; Massai, L.; Messori, L.; Merlino, A. Cisplatin binding to human serum albumin: A structural study. Chem. Commun. (Cambridge, England), 2015, 51(46), 9436-9439.
[40]
Itoh, K. 99mTc-MAG3: Review of pharmacokinetics, clinical application to renal diseases and quantification of renal function. Ann. Nucl. Med., 2001, 15(3), 179-190.
[41]
Kim, S.K.; Demetri, G.D. Chemotherapy and neutropenia. Hematol. Oncol. Clin., 1996, 10(2), 377-395.
[42]
Hagerling, C.; Werb, Z. Neutrophils: Critical components in experimental animal models of cancer. Semin. Immunol., 2016, 28(2), 197-204.
[43]
Coffelt, S.B.; Wellenstein, M.D.; de Visser, K.E. Neutrophils in cancer: Neutral no more. Nat. Rev. Cancer, 2016, 16(7), 431-446.
[44]
Muscella, A.; Vetrugno, C.; Migoni, D.; Biagioni, F.; Fanizzi, F.P.; Fornai, F.; De Pascali, S.A.; Marsigliante, S. Antitumour activity of [Pt(O,O′-acac)(γ-acac)(DMS)] in mouse xenograft model of breast cancer. Cell Death Dis., 2014, 5(1)e1014
[45]
Miller, R.P.; Tadagavadi, R.K.; Ramesh, G.; Reeves, W.B. Mechanisms of cisplatin nephrotoxicity. Toxins, 2010, 2(11), 2490-2518.
[46]
Fisher, K.; Vuppalanchi, R.; Saxena, R. Drug-induced liver injury. Arch. Pathol. Lab. Med., 2015, 139(7), 876-887.
[47]
Ganz, T.; Nemeth, E. Hepcidin and iron homeostasis. Biochim. Biophys. Acta, 2012, 1823(9), 1434-1443.
[48]
Wang, Y.; Juan, L.V.; Ma, X.; Wang, D.; Ma, H.; Chang, Y.; Nie, G.; Jia, L.; Duan, X.; Liang, X.J. Specific hemosiderin deposition in spleen induced by a low dose of cisplatin: Altered iron metabolism and its implication as an acute hemosiderin formation model. Curr. Drug Metab., 2010, 11(6), 507-515.
[49]
Liu, N.; Deng, Y.; Pan, J.; Wu, Y.; Zhou, C. Effects of cisplatin on element distribution in mouse kidney tissue assayed by multivariate statistical analysis. Int. J. PIXE, 1996, 06(01n02), 409-414.
[50]
Chandra, S. Quantitative imaging of chemical composition in single cells by secondary ion mass spectrometry: Cisplatin affects calcium stores in renal epithelial cells. Methods Mol. Biol (Clifton, N.J.), 2010, 656, 113-130.
[51]
Eljack, N.D.; Ma, H.Y.; Drucker, J.; Shen, C.; Hambley, T.W.; New, E.J.; Friedrich, T.; Clarke, R.J. Mechanisms of cell uptake and toxicity of the anticancer drug cisplatin. Metallom.: Integrated Biometal Sci., 2014, 6(11), 2126-2133.
[52]
Davis, K.J.; Carrall, J.A.; Lai, B.; Aldrich-Wright, J.R.; Ralph, S.F.; Dillon, C.T. Does cytotoxicity of metallointercalators correlate with cellular uptake or DNA affinity? Dalton Trans., 2012, 41(31), 9417-9426.
[53]
Mandal, A.; Viswanathan, C. Natural killer cells: In health and disease. Hematol. Oncol. Stem Cell Ther., 2015, 8(2), 47-55.
[54]
Zarjou, A.; Bolisetty, S.; Joseph, R.; Traylor, A.; Apostolov, E.O.; Arosio, P.; Balla, J.; Verlander, J.; Darshan, D.; Kuhn, L.C.; Agarwal, A. Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury. J. Clin. Invest., 2013, 123(10), 4423-4434.
[55]
Oh, G-S.; Kim, H-J.; Shen, A.; Lee, S.B.; Khadka, D.; Pandit, A.; So, H-S. Cisplatin-induced kidney dysfunction and perspectives on improving treatment strategies. Electrolytes Blood Press. E & BP, 2014, 12(2), 55-65.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy