Cyto- and genotoxicity of a vanadyl(IV) complex with oxodiacetate in human colon adenocarcinoma (Caco-2) cells: potential use in cancer therapy
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.
KeywordsVanadyl(IV) cation Multidentate ligands Cytotoxicity Genotoxicity Caco-2 tumoral cells
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.
- Baggio R, Garland MT, Perec M (2003) A new polymeric phase of zinc (II)oxidiacetate. Acta Cryst C Cryst Struct Commun 59(1):30–32Google 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:S183Google 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 340–351Google 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 595–616Google 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 359–394Google Scholar
- Farrell NP (1999) Chapter 1 “Overview” In: Farrell NP (ed) Uses of inorganic chemistry in medicine. The Royal Society of Chemistry, Cambridge, p 16Google Scholar
- Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine. Oxford University Press, OxfordGoogle Scholar
- Lippard SL, Berg JM (1984) Principles of bioinorganic chemistry. University Science Books, Mill ValleyGoogle 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 7:391–408PubMedCrossRefGoogle Scholar
- Sakurai H (1994) Vanadium distribution in rats and DNA cleavage by vanadyl complex: implication for vanadium toxicity and biological effects. Environ Health Perspect 3:35–36Google Scholar