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Ascorbic Acid Enhances the Effects of 6-Hydroxydopamine and H₂O₂ on Iron-dependent DNA Strand Breaks and Related Processes in the Neuroblastoma Cell Line SK-N-SH

Department of Immunology, Research Institute of Scripps Clinic, La Jolla, California 92037 [G. B., I. U. S., C. G. C.], and Department of Hematology and Oncology, Children's Hospital, University of Tuebingen, Ruemelinstrasse 23, D-7400 Tuebingen, Federal Republic of Germany [D. N.]

Neuroblastoma cells accumulate ascorbic acid and iron. It was hypothesized that these features could be exploited for sensitizing neuroblastoma cells for therapy in combination with reactive oxygen intermediates. In the present study the effects of 6-hydroxydopamine (6-OHDA) and H₂O₂ on metabolic parameters critical for cell survival were investigated in cells with low and high ferritin content in the presence and absence of ascorbate. Human neuroblastoma SK-N-SH cells were pretreated with 100 µM FeSO₄ and 10 µM desferrioxamine, respectively, for 24 h yielding cells with different ferritin contents. The effects of 6-OHDA and H₂O₂ (25 µM-250 µM) in the absence and presence of 1 mM ascorbic acid on DNA strand break formation, activation of poly(ADP-ribose) polymerase, and finally decrease in NAD⁺ and ATP concentration were investigated. All these parameters were influenced by 6-OHDA and H₂O₂ in a concentration-dependent manner in a similar way. The effects were most pronounced in ferritin-rich cells and in the presence of ascorbic acid. Using isolated CCC PM2 DNA, 6-OHDA and ascorbic acid caused strand breaks that were prevented in the presence of mannitol or desferrithiocine. H₂O₂-mediated strand breaks were observed only in the presence of ascorbic acid. Based on these data and data published by others a model explaining the deleterious effects of ascorbic acid on neuroblastoma cells is presented. It is suggested that continuous application of a high dosage of ascorbic acid might be a useful approach in neuroblastoma therapy.

¹ Recipient of a grant of Förderverein Leukämiekranker Kinder,e.V., Tuebingen, Federal Republic of Germany. Supported by the Deutsche Krebshilfe, Grant W54/89/Ni4. To whom requests for reprints should be addressed. Permanent address: Department of Hematology and Oncology, Children's Hospital, University of Tuebingen, Ruemelinstrasse 23, D-7400 Tuebingen, Federal Republic of Germany.

Received 8/ 7/91. Accepted 9/ 9/91.