Copper(II) mixed chelate compounds induce apoptosis through reactive oxygen species in neuroblastoma cell line CHP-212

J Inorg Biochem. 2013 Sep:126:17-25. doi: 10.1016/j.jinorgbio.2013.05.001. Epub 2013 May 7.

Abstract

In the present work we report the antiproliferative activity of Cu(II) coordination compounds, CasIIgly ([Cu(4,7-dimethyl-1,10-phenanthroline) (glycinato) (H2O)]NO3), CasIIIia ([Cu(4,4'-dimethyl-2,2'-bipyridine) (glycinato) (H2O)]NO3), and CasIIIEa ([Cu(4,7-dimethyl-1,10-phenanthroline) (acetylacetonato) (H2O)]NO3), against human tumoral cell line CHP-212 (estromal neuroblastoma). Additionally, the molecular structure of CasIIIEa was reported. The IC50 values obtained for the evaluated compounds are in the range 18 to 47 μM, representing an inhibition potency increase of 5 to 12 times compared with cisplatin (IC50=226.7 μM). After 2h of incubation with the evaluated compounds, cells showed high levels of reactive oxygen species and a considerable GSH depletion, besides an important disruption of the mitochondrial membrane with release of cytochrome C and besides the presence of caspase-3, an effector caspase that is activated in the last step of apoptosis cascade. The results confirm that cell death in neuroblastoma CHP-212 treated with Casiopeínas occurs via apoptosis. Due to the lack of expression of caspase-8, cell death is principally by the mitochondrial pathway. Thus, one of the most interesting findings of this work is the identification of a very important damage in neuroblastoma cells induced by Cu(II) coordination compounds in a very short exposition times.

Keywords: Casiopeínas; Copper(II) compounds; Glutathione; Mitochondrial apoptosis; Neuroblastoma; Reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Cations, Divalent
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / pharmacology*
  • Copper / chemistry*
  • Crystallography, X-Ray
  • Cytochromes c / metabolism
  • Gene Expression Regulation, Neoplastic
  • Glutathione / antagonists & inhibitors
  • Glutathione / metabolism
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Organometallic Compounds
  • Phenanthrolines / chemical synthesis
  • Phenanthrolines / pharmacology*
  • Reactive Oxygen Species / agonists*
  • Reactive Oxygen Species / metabolism

Substances

  • (Cu(4,4'-dimethyl-2,2'-bipyridine)(glycinato)(H2O))NO3
  • (Cu(4,7-dimethyl-1,10-phenanthroline)(acetylacetonato)(H2O))NO3
  • Antineoplastic Agents
  • Cations, Divalent
  • Coordination Complexes
  • Organometallic Compounds
  • Phenanthrolines
  • Reactive Oxygen Species
  • casiopeina II-glycine
  • Copper
  • Cytochromes c
  • Caspase 3
  • Caspase 8
  • Glutathione
  • Cisplatin