Skip to main content

Advertisement

SpringerLink
Log in

Cyto- and genotoxicity of a vanadyl(IV) complex with oxodiacetate in human colon adenocarcinoma (Caco-2) cells: potential use in cancer therapy

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

The complex of vanadyl(IV) cation with oxodiacetate, VO(oda) caused an inhibitory effect on the proliferation of the human colon adenocarcinoma cell line Caco-2 in the range of 25–100 μM (P < 0.001). This inhibition was partially reversed by scavengers of free radicals. The difference in cell proliferation in the presence and the absence of scavengers was statistically significant in the range of 50–100 μM (P < 0.05). VO(oda) altered lysosomal and mitochondria metabolisms (neutral red and MTT bioassays) in a dose–response manner from 10 μM (P < 0.001). Morphological studies showed important transformations that correlated with the disassembly of actin filaments and a decrease in the number of cells in a dose response manner. Moreover, VO(oda) caused statistically significant genotoxic effects on Caco-2 cells in the low range of concentration (5–25 μM) (Comet assay). Increment in the oxidative stress and a decrease in the GSH level are the main cytotoxic mechanisms of VO(oda). These effects were partially reversed by scavengers of free radicals in the range of 50–100 μM (P < 0.05). Besides, VO(oda) interacted with plasmidic DNA causing single and double strand cleavage, probably through the action of free radical species. Altogether, these results suggest that VO(oda) is a good candidate to be evaluated for alternative therapeutics in cancer treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

References

  • Altamirano-Lozano M, Valverde M, Alvarez-Barrera L, Molina B, Rojas E (1999) Reprotoxic and genotoxic studies of vanadium pentoxide (V2)O(5) in male mice. II. Effects in several mouse tissues. Teratog Carcinog Mutagen 19:243–255

    Article  PubMed  CAS  Google Scholar 

  • Aubrecht J, Narla RK, Ghosh P, Stanek J, Uckun FM (1999) Molecular genotoxicity profiles of apoptosis-inducing vanadocene complexes. Toxicol Appl Pharmacol 154:228–235

    Article  PubMed  CAS  Google Scholar 

  • Baggio R, Garland MT, Perec M (2003) A new polymeric phase of zinc (II)oxidiacetate. Acta Cryst C Cryst Struct Commun 59(1):30–32

    Google Scholar 

  • Barrio DA, Williams PAM, Cortizo AM, Etcheverry SB (2003) Synthesis of a new vanadyl(IV) complex with trehalose (TreVO): insulin-mimetic activities in osteoblast-like cells in culture. J Biol Inorg Chem 8:459–468

    PubMed  CAS  Google Scholar 

  • Bernadou J, Pratviel G, Bennis F, Girardot M, Meunier B (1989) Potassium monopersulfate and a water-soluble manganese porphyrin complex, [Mn(TMPyP)](OAc)5, as an efficient reagent for the oxidative cleavage of DNA. Biochemistry 28:7268–7275

    Article  PubMed  CAS  Google Scholar 

  • Bishayee A, Roy S, Chatterjee M (1999) Characterization of selective induction and alteration of xenobiotic biotransforming enzymes by vanadium during diethylnitrosamine-induced chemical rat liver carcinogenesis. Oncol Res 11:41–53

    PubMed  CAS  Google Scholar 

  • Borenfreund E, Puerner JA (1984) A simple quantitative procedure using monolayer culture for toxicity assays. J Tissue Cult Methods 9:7–9

    Article  Google Scholar 

  • Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:249–254

    Article  Google Scholar 

  • Butenko N, Tomaz AI, Nouri O, Escribano E, Moreno V, Gama S, Ribeiro V, Telo JP, Costa Pessoa J, Cavaco I (2009) DNA cleavage activity of VIVO(acac)2 and derivatives. J Inorg Biochem 103:622–632

    Article  PubMed  CAS  Google Scholar 

  • Cavaco I, Butenko N, Tomaz AI, Ribeiro V, Costa Pessoa J (2009) Studies on the mechanism of action of an efficient vanadium inorganic nuclease, VO(acac)2. J Biol Inorg Chem 14:S183

    Google Scholar 

  • Chao J, Xiang Z, Zhao-Peng Y, Zhi-Yong W (2003) Molecular chains: two new isomorphous coordination polymers of oxydiacetate. Inorg Chem Commun 6:706–709

    Article  Google Scholar 

  • Cortizo AM, Bruzzone L, Molinuevo MS, Etcheverry SB (2000) A possible role of oxidative stress in the vanadium-induced cytotoxicity in the MC3T3E1 osteoblast and UMR106 osteosarcoma cell lines. Toxicology 147:89–99

    Article  PubMed  CAS  Google Scholar 

  • Cortizo MS, Alessandrini JL, Etcheverry SB, Cortizo AM (2001) A vanadium/aspirin complex controlled release using a poly(beta-propiolactone) film: effects on osteosarcoma cells. J Biomater Sci Polym 12:945–959

    Article  CAS  Google Scholar 

  • Costa Pessoa J, Cavaco I, Correia I, Tomaz AI, Adão P, Vale I, Ribeiro V, Castro MM, Geraldes CC (2007) Vanadium schiff base complexes: chemistry, properties, and concerns about possible therapeutic applications. In: Kustin K, Costa Pessoa J, Crans DC (eds) Vanadium: the versatile metal. ACS symposium series, vol 974. ACS, pp 340–351

  • Costas M, Mehn MP, Jensen L (2004) Dioxygen activation at mononuclear nonheme iron active sites: enzymes, models, and intermediates. Chem Rev 104:939–986

    Article  PubMed  CAS  Google Scholar 

  • Crans DC (2000) Chemistry and insulin-like properties of vanadium(IV) and vanadium(V) compounds. J Inorg Biochem 80:123–131

    Article  PubMed  CAS  Google Scholar 

  • Del Río D, Galindo A, Vicente R, Mealli C, Ienco A, Masi D (2003) Synthesis, molecular structure and properties of oxo vanadium(IV) complexes containing the oxydiacetate ligand. Dalton Trans 9:1813–1820

    Article  Google Scholar 

  • Dharwan S, Singh S, Aggarwal BB (1997) Induction of endothelial cell surface adhesion molecules by tumor necrosis factor is blocked by protein tyrosine phosphatase inhibitors: role of nuclear transcription factor NF-κB. Eur Immunol 27:2172–2179

    Article  Google Scholar 

  • Djordjevic C (1995) Antitumor activity of vanadium compounds. In: Sigel H, Sigel A (eds) Metal ions in biological systems, vol 31. Marcel Dekker, New York, pp 595–616

    Google Scholar 

  • El-Naggara MM, El-Waseefa AM, El-Halafawyb KM, El-Sayed IH (1998) Antitumor activities of vanadium(IV), manganese(IV), iron(III), cobalt(II) and copper(II) complexes of 2-methylaminopyridine. Cancer Lett 33:71–76

    Article  Google Scholar 

  • Etcheverry SB, Cortizo AM (1998) Bioactivity of vanadium compounds on cells in culture. In: Nriagu JO (ed) Vanadium in the environment. Advances in environmental science and technology; part A (chap 15). Wiley, New York, pp 359–394

    Google Scholar 

  • Etcheverry SB, Ferrer EG, Naso L, Barrio DA, Lezama L, Rojo T, Williams PAM (2007) Losartan and its interaction with copper(II): biological effects. Bioorg Med Chem 15:6418–6424

    Article  PubMed  CAS  Google Scholar 

  • Evangelou AM (2002) Vanadium in cancer treatment. Crit Rev Oncol Hematol 42:249–265

    Article  PubMed  Google Scholar 

  • Evangelou AM, Karkabounas S, Kalpouzos G, Malamas M, Liasko R, Stefanou D, Vlahos AT, Kabanos TA (1997) Comparison of the therapeutic effects of two vanadium complexes administered at low dose on benzo[a]pyrene-induced malignant tumors in rats. Cancer Lett 119:221–225

    Article  PubMed  CAS  Google Scholar 

  • Farrell NP (1999) Chapter 1 “Overview” In: Farrell NP (ed) Uses of inorganic chemistry in medicine. The Royal Society of Chemistry, Cambridge, p 16

  • Fisher MB, Thompson SJ, Ribeiro V, Lechner MC, Rettie A (1998) P450-catalyzed in-chain desaturation of valproic acid: isoform selectivity and mechanism of formation of Delta 3-valproic acid generated by baculovirus-expressed CYP3A1. Arch Biochem Biophys 356:63–70

    Article  PubMed  CAS  Google Scholar 

  • Fu Y, Wang Q, Yang XG, Yang XD, Wang K (2008) Vanadyl bisacetylacetonate induced G1/S cell cycle arrest via high-intensity ERK phosphorylation in HepG2 cells. J Biol Inorg Chem 13:1001–1009

    Article  PubMed  CAS  Google Scholar 

  • Ghosh P, D’Cruz OJ, Narla RK, Uckun FM (2000) Apoptosis-inducing vanadocene compounds against human testicular cancer. Clin Cancer Res 6:1536–1545

    PubMed  CAS  Google Scholar 

  • Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine. Oxford University Press, Oxford

    Google Scholar 

  • Hanauske U, Hanauske AR, Marshall MH, Muggia VA, Von Hoff DD (1987) Biphasic effect of vanadium salts on in vitro tumor colony growth. Int J Cell Cloning 5:170–178

    Article  PubMed  CAS  Google Scholar 

  • Harding MM, Moksdi G (2000) Antitumor metallocenes: structure-activity studies and interactions with biomolecules. Curr Med Chem 7:1289–1293

    PubMed  CAS  Google Scholar 

  • Harding MM, Harden GJ, Field LD (1993) A 31P NMR study of the interaction of the antitumor active metallocene Cp2MoCl2 with calf thymus DNA. FEBS Lett 322:291–294

    Article  PubMed  CAS  Google Scholar 

  • Henderson L, Wolfreys A, Fedyk J, Bourner C, Windebank S (1998) The ability of the Comet assay to discriminate between genotoxins and cytotoxins. Mutagenesis 113:89–94

    Article  Google Scholar 

  • Hissin PJ, Hilf R (1996) A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem 74:214–226

    Article  Google Scholar 

  • Holko P, Ligeza J, Kisielewska J, Kordowiak AM, Klein A (2008) The effect of vanadyl sulphate (VOSO4) on autocrine growth of human epithelial cancer cell lines. Pol J Pathol 59:3–8

    PubMed  CAS  Google Scholar 

  • Klein A, Holko P, Ligeza J, Kordowiak AM (2008) Sodium orthovanadate affects growth of some human epithelial cancer cells (A549, HTB44, DU145). Folia Biol (Krakow) 56:115–121

    Article  CAS  Google Scholar 

  • Kopf-Maier P, Wagner W, Kopf H (1981) In vitro cell growth inhibition by metallocene dichlorides. Cancer Chemother Pharmacol 5:237–241

    Article  PubMed  CAS  Google Scholar 

  • Kostova I (2009) Titanium and vanadium complexes as anticancer agents. Anticancer Agents Med Chem 9:827–842

    PubMed  CAS  Google Scholar 

  • Liao W, McNutt MA, Zhu WG (2009) The comet assay: a sensitive method for detecting DNA damage in individual cells. Methods 48:46–53

    Article  PubMed  CAS  Google Scholar 

  • Lippard SL, Berg JM (1984) Principles of bioinorganic chemistry. University Science Books, Mill Valley

    Google Scholar 

  • Lloyd DR, Phillips DH, Carmichael PL (1997) Generation of putative intrastrand cross-links and strand breaks in DNA by transition metal ion-mediated oxygen radical attack. Chem Res Toxicol 10:393–400

    Article  PubMed  CAS  Google Scholar 

  • Luber B, Candidus S, Handsbusch G, Mentele E, Hutzler P, Feller S, Voss J, Höfler H, Becker KF (2000) Tumor derived mutated E-cadherin influences beta-catenin localization and increases susceptibility to actin cytoskeletal changes induced by pervanadate. Cell Adhes Commun 7:391–408

    Article  PubMed  CAS  Google Scholar 

  • Majumder S, Dutta P, Mookerjee A, Choudhuri SK (2006) The role of a novel copper complex in overcoming doxorubicin resistance in Ehrlich ascites carcinoma cells in vivo. Chem Biol Interact 159:90–103

    Article  PubMed  CAS  Google Scholar 

  • Molinuelo MS, Cortizo AM, Etcheverry SB (2008) Vanadium(IV) complexes inhibit adhesion, migration and colony formation of UMR106 osteosarcoma cells. Cancer Chemother Pharmacol 61:767–773

    Article  Google Scholar 

  • Molinuevo MS, Barrio DA, Cortizo AM, Etcheverry SB (2004) Antitumoral properties of two new vanadyl(IV) complexes in osteoblasts in culture: role of apoptosis and oxidative stress. Cancer Chemother Pharmacol 53:163–172

    Article  PubMed  CAS  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  PubMed  CAS  Google Scholar 

  • Mueller S, Riedel HD, Stremmel W (1997) Determination of catalase activity at physiological hydrogen peroxide concentrations. Anal Biochem 245:55–60

    Article  PubMed  CAS  Google Scholar 

  • Murray JH, Harding MM (1994) Organometallic anticancer agents: the effects of central metal and halide ligands on the interaction of metallocene dihalides Cp2MX2 with nucleic acid constituents. J Med Chem 37:1936–1941

    Article  PubMed  CAS  Google Scholar 

  • Narla RK, Dong Y, Klis D, Uckun FM (2001) Bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) as a novel antileukemic agent with matrix metalloproteinase inhibitory activity. Clin Cancer Res 7:1094–1101

    PubMed  CAS  Google Scholar 

  • Navara CS, Benyumov A, Vassilev A, Narla RK, Ghosh P, Uckun FM (2001) Vanadocenes as potent anti-proliferative agents disrupting mitotic spindle formation in cancer cells. Anticancer Drugs 12:369–376

    Article  PubMed  CAS  Google Scholar 

  • Okajima T, Nakamura K, Zhang H, Ling N, Tanabe T, Yasuda T, Rosenfeld RG (1992) Sensitive colorimetric bioassays for insulin-like growth factor (IGF) stimulation of cell proliferation and glucose consumption: use in studies of IGF analogs. Endocrinology 130:2201–2212

    Article  PubMed  CAS  Google Scholar 

  • Rivadeneira J, Barrio DA, Etcheverry SB, Baran EJ (2007) Spectroscopic characterization of a VO2+ complex of oxodiacetic acid and its bioactivity on osteoblast-like cells in culture. Biol Trace Elem Res 118:159–166

    Article  PubMed  CAS  Google Scholar 

  • Rivadeneira J, Di Virgilio AL, Barrio DA, Muglia CI, Bruzzone L, Etcheverry SB (2010) Cytotoxicity of a vanadyl(IV) complex with a multidentate oxygen donor in osteoblast cell lines in culture. Med Chem 6:9–23

    Article  PubMed  CAS  Google Scholar 

  • Rodríguez-Mercado JJ, Roldán-Reyes E, Altamirano-Lozano M (2003) Genotoxic effects of vanadium(IV) in human peripheral blood cells. Toxicol Lett 144:359–369

    Article  PubMed  Google Scholar 

  • Rojas E, Valverde M, Herrera LA, Altamirano-Lozano M, Ostrosky-Wegman P (1996) Genotoxicity of vanadium pentoxide evaluated by the single cell gel electrophoresis in human lymphocytes. Mutat Res 359:77–84

    PubMed  Google Scholar 

  • Sakurai H (1994) Vanadium distribution in rats and DNA cleavage by vanadyl complex: implication for vanadium toxicity and biological effects. Environ Health Perspect 3:35–36

    Google Scholar 

  • Sakurai H, Tamura H, Okatani K (1995) Mechanism for a new vanadium complex: hydroxyl radical-dependent DNA cleavage by 1,10-phenanthroline-vanadyl complex in the presence of hydrogen peroxide. Biochem Biophys Res Commun 206:133–137

    Article  PubMed  CAS  Google Scholar 

  • Samanta S, Chatterjee M, Ghosh B, Rajkumar M, Rana A, Chatterjee M (2008) Vanadium and 1,25(OH)2 vitamin D3 combination in inhibitions of 1,2-dimethylhydrazine-induced rat colon carcinogenesis. Biochim Biophys Acta 1780:1106–1114

    Article  PubMed  CAS  Google Scholar 

  • Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175:184–191

    Article  PubMed  CAS  Google Scholar 

  • Sit KH, Paramananthan R, Bay B, Wong KP, Chan HL, Thong P, Watt E (1996) Sequestration of mitotic (M-phase) chromosomes in autophagosomes: mitotic programmed cell death in human Chang liver cells induced by an OH burst from vanadyl(IV). Anat Rec 245:1–8

    Article  PubMed  CAS  Google Scholar 

  • Soares SS, Henao F, Aureliano M, Gutiérrez-Merino C (2008) Vanadote induces necrotic death in neonatal rat cardiomyocytes through mitochondrial membrane depolarization. Chem Res Toxicol 21:607–618

    Article  PubMed  CAS  Google Scholar 

  • Toney JH, Brock CP, Marks TJ (1986) Aqueous coordination chemistry of vanadocene dichloride, with nucleotides and phosphoesters. Mechanistic implication for a new class of antitumor agents. J Am Chem Soc 108:7263–7274

    Article  CAS  Google Scholar 

  • Wozniak K, Blasiak J (2004) Vanadyl sulfate can differentially damage DNA in human lymphocytes and HeLa cells. Arch Toxicol 78:7–15

    Article  PubMed  CAS  Google Scholar 

  • Yang XG, Yang XD, Yuan L, Wang K, Crans DC (2004) The permeability and cytotoxicity of insulin-mimetic vanadium compounds. Pharm Res 21:1026–1033

    Article  PubMed  CAS  Google Scholar 

  • Younes M, Kayserb E, Strubelt O (1991) Effect of antioxidants on vanadate-induced toxicity towards isolated perfused rat livers. Toxicology 70:141–149

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Prof. Dr. E.J. Baran for the preparation of VO(oda) complex and Prof. Dr. L. Bruzzone for the fluorometric measurements of DHR experiments. This work was supported by UNLP, CONICET (PIP 1125) and ANPCyT (PICT 2218), and the Erasmus Mundus Programme, EMQAL 2008-0095, for mobility funding. JR is a postdoctoral fellowship from CONICET, Argentina. ALDV, CIM and SBE are members of the Carrera del Investigador, CONICET, Argentina. MAR is a member of Carrera de Personal de Apoyo, CONICET, Argentina. NB is a doctoral student of the Erasmus Mundus External Cooperation Window—Lot 6. IC is Prof. of the Algarve University, Faro, Portugal.

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. Cátedra de Bioquímica Patológica, Facultad de Ciencias Exactas, UNLP, 47 y 115 (1900), La Plata, Argentina

    Ana L. Di Virgilio, Josefina Rivadeneira, Cecilia I. Muglia & Susana B. Etcheverry

  2. CEQUINOR (CONICET-UNLP), Facultad de Ciencias Exactas, UNLP, La Plata, Argentina

    Josefina Rivadeneira & Susana B. Etcheverry

  3. Instituto Multidisciplinario de Biología Celular (IMBICE), 526 y Cno. Gral. Belgrano, La Plata, Argentina

    Miguel A. Reigosa

  4. Departamento de Química, Bioquímica e Farmácia, Universidade do Algarve, Campus de Gambelas, 8005-139, Faro, Portugal

    Nataliya Butenko & Isabel Cavaco

  5. Centro de Química Estrutural, Instituto Superior Técnico, TU Lisbon, Av Rovisco Pais, 1049-001, Lisbon, Portugal

    Nataliya Butenko & Isabel Cavaco

Authors
  1. Ana L. Di Virgilio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Josefina Rivadeneira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cecilia I. Muglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miguel A. Reigosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nataliya Butenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Isabel Cavaco
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Susana B. Etcheverry
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susana B. Etcheverry.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Di Virgilio, A.L., Rivadeneira, J., Muglia, C.I. et al. Cyto- and genotoxicity of a vanadyl(IV) complex with oxodiacetate in human colon adenocarcinoma (Caco-2) cells: potential use in cancer therapy. Biometals 24, 1153–1168 (2011). https://doi.org/10.1007/s10534-011-9474-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-011-9474-x

Keywords

Search

Navigation