This Article Full Text 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 Green, D. A. Articles by Chitambar, C. R. Search for Related Content PubMed PubMed Citation Articles by Green, D. A. Articles by Chitambar, C. R.

Inhibition of Malignant Cell Growth by 311, a Novel Iron Chelator of the Pyridoxal Isonicotinoyl Hydrazone Class

Effect on the R2 subunit of Ribonucleotide Reductase

Division of Hematology/Oncology [D. A. G., S. J. W., C. R. C.] and the Biophysics Research Institute [W. E. A.], Medical College of Wisconsin, Milwaukee, Wisconsin 53226, and the Heart Research Institute, Sydney, New South Wales, Australia 2050 [D. R. R.]

The key roles of iron and iron proteins in cell proliferation make them potential targets for cancer therapy. However, clinical trials directed toward perturbation of tumor iron homeostasis by iron chelation have been limited to the use of deferoxamine (DFO). There is thus a need to develop agents with greater efficacy. In the present study, we investigated the mechanism of cytotoxicity of 311 (2-hydroxy-1-naphthylaldehyde benzoyl hydrazone), a novel iron chelator of the pyridoxal isonicotinoyl class. We found that 311 inhibited the growth of CCRF-CEM cells in a time- and concentration-dependent fashion with an IC₅₀ that was 20-fold lower than that of DFO. 311 also inhibited the growth of breast, bladder, and head and neck cancer cell lines. Using electron spin resonance (ESR) spectroscopy analysis, we found that a 12-h exposure of CCRF-CEM cells to 311 inhibited the tyrosyl radical ESR signal of the R2 subunit of ribonucleotide reductase. However, overproduction of the R2 subunit in hydroxyurea-resistant CCRF-CEM cells was associated with a decrease in sensitivity of cells to 311 but not to DFO. Our studies show that 311 is a more potent cytotoxic agent than DFO, with activity against both hematopoietic and nonhematopoietic cell lines regardless of their p53 status. Furthermore, the ESR studies suggest that inhibition of the R2 subunit of ribonucleotide reductase is at least one mechanism by which 311 blocks cell proliferation.

This article has been cited by other articles:

				S. J. Assinder, Q. Dong, H. Mangs, and D. R. Richardson Pharmacological Targeting of the Integrated Protein Kinase B, Phosphatase and Tensin Homolog Deleted on Chromosome 10, and Transforming Growth Factor-{beta} Pathways in Prostate Cancer Mol. Pharmacol., March 1, 2009; 75(3): 429 - 436. [Abstract] [Full Text] [PDF]

				V. A. Rao, S. R. Klein, K. K. Agama, E. Toyoda, N. Adachi, Y. Pommier, and E. B. Shacter The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase II{alpha} in Breast Cancer Cells Cancer Res., February 1, 2009; 69(3): 948 - 957. [Abstract] [Full Text] [PDF]

				O. Popelova, M. Sterba, T. Simunek, Y. Mazurova, I. Guncova, M. Hroch, M. Adamcova, and V. Gersl Deferiprone Does Not Protect against Chronic Anthracycline Cardiotoxicity in Vivo J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 259 - 269. [Abstract] [Full Text] [PDF]

				D. Fu and D. R. Richardson Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion Blood, July 15, 2007; 110(2): 752 - 761. [Abstract] [Full Text] [PDF]

				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]

				Y. Yu, J. Wong, D. B. Lovejoy, D. S. Kalinowski, and D. R. Richardson Chelators at the Cancer Coalface: Desferrioxamine to Triapine and Beyond Clin. Cancer Res., December 1, 2006; 12(23): 6876 - 6883. [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]

				T. B. Chaston, R. N. Watts, J. Yuan, and D. R. Richardson Potent Antitumor Activity of Novel Iron Chelators Derived from Di-2-Pyridylketone Isonicotinoyl Hydrazone Involves Fenton-Derived Free Radical Generation Clin. Cancer Res., November 1, 2004; 10(21): 7365 - 7374. [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]

				J. Yuan, D. B. Lovejoy, and D. R. Richardson Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment Blood, September 1, 2004; 104(5): 1450 - 1458. [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]

				Y. Lee, A. Vassilakos, N. Feng, V. Lam, H. Xie, M. Wang, H. Jin, K. Xiong, C. Liu, J. Wright, et al. GTI-2040, an Antisense Agent Targeting the Small Subunit Component (R2) of Human Ribonucleotide Reductase, Shows Potent Antitumor Activity against a Variety of Tumors Cancer Res., June 1, 2003; 63(11): 2802 - 2811. [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]

				D. B. Lovejoy and D. R. Richardson Novel "hybrid" iron chelators derived from aroylhydrazones and thiosemicarbazones demonstrate selective antiproliferative activity against tumor cells Blood, June 28, 2002; 100(2): 666 - 676. [Abstract] [Full Text] [PDF]