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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. Clin Cancer Res 2001 Nov;7(11):3574-9

Date

11/14/2001

Pubmed ID

11705879

Scopus ID

2-s2.0-0035181433   75 Citations

Abstract

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 IC(50) that was approximately 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.

Author List

Green DA, Antholine WE, Wong SJ, Richardson DR, Chitambar CR

Authors

Christopher R. Chitambar MD Professor in the Medicine department at Medical College of Wisconsin
Stuart J. Wong MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Cell Division
Deferoxamine
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Humans
Hydroxyurea
Iron Chelating Agents
Isoniazid
Mutation
Protein Subunits
Ribonucleotide Reductases
Time Factors
Tumor Cells, Cultured
Tumor Suppressor Protein p53
jenkins-FCD Prod-411 e00897e83867fcfa48419861683711f8d99adb75