Trimidox, an inhibitor of ribonucleotide reductase, synergistically enhances the inhibition of colony formation by Ara-C in HL-60 human promyelocytic leukemia cells.
Ribonucleotide reductase is the rate-limiting enzyme for the de novo synthesis of deoxynucleoside triphosphates and therefore represents a good target for cancer chemotherapy. Trimidox (3,4,5-trihydroxybenzamidoxime) was identified as a potent inhibitor of this enzyme and was shown to significantly decrease deoxycytidine triphosphate (dCTP) pools in HL-60 leukemia cells. We now investigated the ability of trimidox to increase the antitumor effect of 1-beta-D-arabinofuranosyl cytosine (Ara-C). Ara-C is phosphorylated by deoxycytidine kinase, which is subject to negative allosteric regulation by dCTP. Therefore, a decrease of dCTP may cause increased Ara-C phosphorylation and enhanced incorporation of Ara-C into DNA. Ara-C incorporation indeed increased 1.51- and 1.89-fold after preincubation with 75 and 100 microM trimidox, respectively. This was due to the significantly increased 1-beta-D-arabinofuranosyl cytosine triphosphate pools (1.9- and 2.5-fold) after preincubation with trimidox. We also investigated the effects of a combination of trimidox and Ara-C on the colony formation of HL-60 cells. A synergistic potentiation of the effect of Ara-C could be observed, when trimidox was added. Trimidox, which decreases intracellular deoxynucleoside triphosphate concentrations thus leading to apoptosis, enhanced the induction of apoptosis caused by Ara-C. We conclude, that trimidox is capable of synergistically enhancing the effects of Ara-C and therefore this drug combination might be further tested in animals.
Fritzer-Szekeres
Monika
M
Clinical Institute for Medical and Chemical Laboratory Diagnostics, General Hospital of Vienna, Medical School, University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria.
Salamon
Alexandra
A
Grusch
Michael
M
Horvath
Zsuzsanna
Z
Höchtl
Thomas
T
Steinbrugger
Richard
R
Jäger
Walter
W
Krupitza
Georg
G
Elford
Howard L
HL
Szekeres
Thomas
T
D017209:Apoptosis; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001550:Benzamidines / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D019384:Nucleic Acid Synthesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
C074761:3,4,5-trihydroxybenzamidoxime; D001550:Benzamidines; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D004247:DNA; D012264:Ribonucleotide Reductases