Inhibition of leukemic HL60 cell growth by transferrin-gallium: effects on ribonucleotide reductase and demonstration of drug synergy with hydroxyurea. Blood 1988 Dec;72(6):1930-6
Date
12/01/1988Pubmed ID
3058232DOI
10.1182/blood.v72.6.1930.1930Scopus ID
2-s2.0-0024209928 (requires institutional sign-in at Scopus site) 157 CitationsAbstract
Cellular requirements for iron during DNA synthesis are related to the increased activity of the iron-containing M2 subunit of ribonucleotide reductase, the enzyme responsible for the reduction of ribonucleotides to deoxyribonucleotides. We have previously shown that transferrin-gallium (Tf-Ga) inhibits cellular iron incorporation. In the present study, Tf-Ga-induced inhibition of HL60 cell growth and upregulation of Tf receptor density was reversed with hemin. Cells exposed to 2 mumol/L Tf-Ga for six hours or longer displayed a diminution in the electron spin resonance (ESR) spectroscopy signal of the tyrosyl radical of the M2 subunit of ribonucleotide reductase. The effect of Tf-Ga on the ESR signal was reversed by hemin. Tf-Ga decreased the incorporation of 14C-adenosine into DNA and decreased intracellular deoxyribonucleotide pools, with the maximum diminution seen in deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) pools. Exposure of cells to combinations of Tf-Ga and hydroxyurea (a known inhibitor of ribonucleotide reductase) resulted in a marked inhibition of cell growth that was consistent with drug synergy. Our studies suggest that Tf-Ga inhibits DNA synthesis through action on the M2 subunit of ribonucleotide reductase and that combinations of Ga and hydroxyurea should be further evaluated in in vivo tumor models.
Author List
Chitambar CR, Matthaeus WG, Antholine WE, Graff K, O'Brien WJAuthor
Christopher Chitambar MBBS Emeritus Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cell DivisionDNA Replication
DNA, Neoplasm
Drug Synergism
Gallium
Hemin
Humans
Hydroxyurea
Iron
Leukemia, Promyelocytic, Acute
Receptors, Transferrin
Ribonucleotide Reductases
Transferrin
Tumor Cells, Cultured
