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Inhibition of N-myc Expression and Induction of Apoptosis by Iron Chelation in Human Neuroblastoma Cells¹

Department of Pediatrics and the Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201 [L. F., A. E. E.]; Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642 [J. I., K. K. F.]; Pediatric Oncology Branch, National Cancer Institute, NIH, Gaithersburg, Maryland 20877 [S. Z.]; Molecular Carcinogenesis, Cancer Research Center of Hawaii and the Kapi’olani Health Research Institute, Honolulu, Hawaii 96813 [R. K. W.]; Department of Biochemistry and Molecular Biology, The George Washington University, Washington, DC 20037 [P. E. B.]; Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 [N. I.]; Department of Biology, Wheaton College, Wheaton, Illinois 60187 [R. H. K.]; and Department of Medicine, Children’s Hospital and Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115 [C. N. F.]

Neuroblastoma is the second most common solid malignancy of childhood. Enhanced expression of the amplified N-myc gene in the tumor cells may be associated with poor patient prognosis and may contribute to tumor development and progression. The use of deferoxamine mesylate (DFO), an iron chelator, to treat neuroblastoma is being investigated in national clinical studies. We show here by TUNEL assay and DNA laddering that DFO induces apoptosis in cultured human neuroblastoma cells, which is preceded by a decrease in the expression of N-myc and the altered expression of some other oncogenes (up-regulating c-fos and down-regulating c-myb) but not housekeeping genes. The decrease in N-myc expression is iron-specific but does not result from inhibition of ribonucleotide reductase, because specific inhibition of this iron-containing enzyme by hydroxyurea does not affect N-myc protein levels. Nuclear run-on and transient reporter gene expression experiments show that the decrease in N-myc expression occurs at the level of initiation of transcription and by inhibiting N-myc promoter activity. Comparison across neuroblastoma cell lines of the amount of residual cellular N-myc protein with the extent of apoptosis measured as pan-caspase activity after 48 h of iron chelation reveals no correlation, suggesting that the decrease in N-myc expression is unlikely to mediate apoptosis. In conclusion, chelation of cellular iron by DFO may alter the expression of multiple genes affecting the malignant phenotype by multiple pathways. Given the clinical importance of N-myc overexpression in neuroblastoma malignancy, decreasing N-myc expression by DFO might be useful as an adjunct to current therapy.

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