This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brodie, C. Articles by Seligman, P. Search for Related Content PubMed PubMed Citation Articles by Brodie, C. Articles by Seligman, P.

Neuroblastoma Sensitivity to Growth Inhibition by Deferrioxamine: Evidence for a Block in G₁ Phase of the Cell Cycle¹

Department of Medicine, Division of Hematology, University of Colorado Health Sciences Center, Denver, Colorado 80262 [G. S., R. S., P. S.], and Department of Pediatrics, Division of Basic Sciences, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206 [C. B., J. L., N. T., A. S., E. G.]

Iron (Fe) is known to be necessary for cellular proliferation. Previous studies have suggested that neuroblastoma cells appear to be relatively sensitive to growth inhibition by a specific Fe chelator, deferrioxamine (DFO), in vitro. Also, DFO has been recently used for the treatment of neuroblastoma patients. In this paper we demonstrate that neuroblastoma cell proliferation in vitro is extremely sensitive to inhibition by DFO as compared to another cell line with almost identical growth kinetics. Neuroblastoma cells treated with DFO adapt appropriately to Fe chelation as measured by marked upregulation of transferrin receptor mRNA, increased functional transferrin receptor, and decreased cellular ferritin concentration. Further studies that quantitated cellular incorporation of ⁵⁹Fe from added transferrin-⁵⁹Fe in the presence of DFO indicated that neuroblastoma cells were more sensitive to inhibition of Fe incorporation by the chelator as compared to the other cell line. Neuroblastoma cells treated with DFO showed a consistent arrest in the G₁ phase of the cell cycle. For cells taken from the "resting" state this block occurred before the vast majority of cells had entered S or G₂-M phases of the cell cycle. Further evidence that neuroblastoma cells were arrested before the G₁-S interface was provided when cells inhibited by DFO and released into aphidicolin exhibit arrest at the G₁-S interface, whereas release from aphidicolin into DFO resulted in entry into S phase. Also, DFO-treated cells exhibited a decrease in both p34^cdc2 immunoreactive protein as well as kinase activity. The results of these latter studies strongly indicate evidence for a Fe requirement for malignant cell proliferation before the onset of DNA synthesis. Our results also provide a basis for further studies that will better define a therapeutic approach to patients with neuroblastoma utilizing DFO treatment.

¹ Supported by American Cancer Society Grant CH-536 (P. S.) and Grant AI-26490 from the NIH (E. G.).

² To whom requests for reprints should be addressed, at Department of Medicine, Division of Hematology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Campus Box B170, Denver, CO 80262.

Received 2/25/93. Accepted 6/28/93.

This article has been cited by other articles:

				E. Nurtjahja-Tjendraputra, D. Fu, J. M. Phang, and D. R. Richardson Iron chelation regulates cyclin D1 expression via the proteasome: a link to iron deficiency-mediated growth suppression Blood, May 1, 2007; 109(9): 4045 - 4054. [Abstract] [Full Text] [PDF]

				M. Whitnall, J. Howard, P. Ponka, and D. R. Richardson A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics PNAS, October 3, 2006; 103(40): 14901 - 14906. [Abstract] [Full Text] [PDF]

				H. Y. Yeung, K. P. Lai, H. Y. Chan, N. K. Mak, G. F. Wagner, and C. K. C. Wong Hypoxia-Inducible Factor-1-Mediated Activation of Stanniocalcin-1 in Human Cancer Cells Endocrinology, November 1, 2005; 146(11): 4951 - 4960. [Abstract] [Full Text] [PDF]

				J. Turner, C. Koumenis, T. E. Kute, R. P. Planalp, M. W. Brechbiel, D. Beardsley, B. Cody, K. D. Brown, F. M. Torti, and S. V. Torti Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation Blood, November 1, 2005; 106(9): 3191 - 3199. [Abstract] [Full Text] [PDF]

				N. T.V. Le and D. R. Richardson Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation Blood, November 1, 2004; 104(9): 2967 - 2975. [Abstract] [Full Text] [PDF]

				S.X. Liang and D.R. Richardson The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1 Carcinogenesis, October 1, 2003; 24(10): 1601 - 1614. [Abstract] [Full Text] [PDF]

				N. T.V. Le and D. R. Richardson Potent iron chelators increase the mRNA levels of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1, but paradoxically inhibit its translation: a potential mechanism of cell cycle dysregulation Carcinogenesis, June 1, 2003; 24(6): 1045 - 1058. [Abstract] [Full Text] [PDF]

				K. J. Thompson, M. G. Fried, Z. Ye, P. Boyer, and J. R. Connor Regulation, mechanisms and proposed function of ferritin translocation to cell nuclei J. Cell Sci., May 15, 2002; 115(10): 2165 - 2177. [Abstract] [Full Text] [PDF]

				J. Gao and D. R. Richardson The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression Blood, August 1, 2001; 98(3): 842 - 850. [Abstract] [Full Text] [PDF]

				N. Rakba, P. Loyer, D. Gilot, J. G. Delcros, D. Glaise, P. Baret, J. L. Pierre, P. Brissot, and G. Lescoat Antiproliferative and apoptotic effects of O-Trensox, a new synthetic iron chelator, on differentiated human hepatoma cell lines Carcinogenesis, May 1, 2000; 21(5): 943 - 951. [Abstract] [Full Text] [PDF]

				A. COPANI, F. CONDORELLI, A. CARUSO, C. VANCHERI, A. SALA, A. M. GIUFFRIDA STELLA, P. L. CANONICO, F. NICOLETTI, and M. A. SORTINO Mitotic signaling by {beta}-amyloid causes neuronal death FASEB J, December 1, 1999; 13(15): 2225 - 2234. [Abstract] [Full Text]

				G. Darnell and D.R. Richardson The Potential of Iron Chelators of the Pyridoxal Isonicotinoyl Hydrazone Class as Effective Antiproliferative Agents III: The Effect of the Ligands on Molecular Targets Involved in Proliferation Blood, July 15, 1999; 94(2): 781 - 792. [Abstract] [Full Text] [PDF]

				K. Wu, A. Polack, and R. Dalla-Favera Coordinated Regulation of Iron-Controlling Genes, H-Ferritin and IRP2, by c-MYC Science, January 29, 1999; 283(5402): 676 - 679. [Abstract] [Full Text]

				D.R. Richardson and K. Milnes The Potential of Iron Chelators of the Pyridoxal Isonicotinoyl Hydrazone Class as Effective Antiproliferative Agents II: The Mechanism of Action of Ligands Derived From Salicylaldehyde Benzoyl Hydrazone and 2-Hydroxy-1-Naphthylaldehyde Benzoyl Hydrazone Blood, April 15, 1997; 89(8): 3025 - 3038. [Abstract] [Full Text] [PDF]

				P. M. B. Pahl, X.-D. Yan, Y. K. Hodges, E. A. Rosenthal, M. A. Horwitz, and L. D. Horwitz An Exochelin of Mycobacterium tuberculosis Reversibly Arrests Growth of Human Vascular Smooth Muscle Cells in Vitro J. Biol. Chem., June 2, 2000; 275(23): 17821 - 17826. [Abstract] [Full Text] [PDF]