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

• Cas increase 5-12 times inhibition potency against CHP-212 respect to cisplatin.
• Antitumor activity of Cas in CHP-212 is due to ROS generation and depletion of GSH.
• Mitochondrial apoptosis increase the Bax/Bcl-2 ratio by pro-oxidant environment.
• Casiopeínas have revealed as good candidates against neuroblastoma.

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 2 h 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.

Copper(II) coordination compounds Casiopeínas ® cell growth inhibition on stromal neuroblastoma human cell line CHP-212. CasIIIEa has shown a 12 times increment of growth cell inhibition capacity compared with the commonly used drug, cisplatin.Figure optionsDownload as PowerPoint slide