Sodium ascorbate induces apoptosis in neuroblastoma cell lines by interfering with iron uptake.
BACKGROUND
Neuroblastoma (NB) is an extra-cranial solid tumour of childhood. In spite of the good clinical response to first-line therapy, complete eradication of NB cells is rarely achieved. Thus, new therapeutic strategies are needed to eradicate surviving NB cells and prevent relapse. Sodium ascorbate has been recently reported to induce apoptosis of B16 melanoma cells through down-regulation of the transferrin receptor, CD71. Since NB and melanoma share the same embryologic neuroectodermal origin, we used different human NB cell lines to assess whether the same findings occurred.


RESULTS
We could observe dose- and time-dependent induction of apoptosis in all NB cell lines. Sodium ascorbate decreased the expression of CD71 and caused cell death within 24 h. An increase in the global and specific caspase activity took place, as well as an early loss of the mitochondrial transmembrane potential. Moreover, intracellular iron was significantly decreased after exposure to sodium ascorbate. Apoptotic markers were reverted when the cells were pretreated with the iron donor ferric ammonium citrate (FAC), further confirming that iron depletion is responsible for the ascorbate-induced cell death in NB cells.


CONCLUSIONS
Sodium ascorbate is highly toxic to neuroblastoma cell lines and the specific mechanism of vitamin C-induced apoptosis is due to a perturbation of intracellular iron levels ensuing TfR-downregulation.
Carosio
Roberta
R
Laboratory of Oncology, G, Gaslini Institute, Genova, Italy. robertacarosio@ospedale-gaslini.ge.it
Zuccari
Guendalina
G
Orienti
Isabella
I
Mangraviti
Salvatore
S
Montaldo
Paolo G
PG
D017304:Annexin A5 / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D014343:Trypan Blue
D017304:Annexin A5; D000975:Antioxidants; D011990:Receptors, Transferrin; D007501:Iron; D020169:Caspases; D014343:Trypan Blue; D001205:Ascorbic Acid