Increased susceptibility of copper-deficient neuroblastoma cells to oxidative stress-mediated apoptosis

Treatment of neuroblastoma cells with the copper chelator triethylene tetra mine tetrahydrochloride induced intracellular decrease of copper content pa ralleled by diminished activity of the enzymes Cu, Zn superoxide dismutase, and cytochrome c oxidase. This effect appears to be specific for copper-en zymes and the treatment affects neither viability nor growth capability of cells. However, molecular markers of apoptosis Bcl-2, p53, and caspase-3 we re slightly affected in these cells. When copper-deficient cells were chall enged with oxidative stress generated by paraquat or puromycin, they underw ent a higher degree of apoptosis with respect to copper-adequate control ce lls. The mechanism underlying paraquat-triggered apoptosis implies dramatic activation of caspase-3 and induction of the transcription factor p53. The se results demonstrate that impairment of copper balance predisposes neuron al cells to apoptosis induced by oxidative stress. Overall findings represe nt a contribution to the comprehension of the link between copper-imbalance and neurodegeneration, which has recently been repeatedly suggested for th e most invalidating pathologies of the central nervous system. (C) 2001 Els evier Science Inc.