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Inhibition of leukemic HL60 cell growth by transferrin-gallium: effects on
ribonucleotide reductase and demonstration of drug synergy with hydroxyurea
[see comments]
CR Chitambar, WG Matthaeus, WE Antholine, K Graff and WJ O'Brien
Department of Medicine, Medical College of Wisconsin, Milwaukee 53226.
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.
Volume 72,
Issue 6,
pp. 1930-1936,
12/01/1988
Copyright © 1988 by The American Society of Hematology
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