Epigallocatechin gallate (EGCG),
ellagic acid (EA) and
rosmarinic acid (RA) are natural
polyphenols exerting
cancer chemopreventive effects.
Ribonucleotide reductase (RR; EC 1.17.4.1) converts ribonucleoside
diphosphates into deoxyribonucleoside
diphosphates being essential for DNA replication, which is why the
enzyme is considered an excellent target for anticancer
therapy. EGCG, EA, and RA dose-dependently inhibited the growth of human HL-60 promyelocytic
leukemia cells, exerted strong
free radical scavenging potential, and significantly imbalanced nuclear deoxyribonucleoside
triphosphate (dNTP) concentrations without distinctly affecting the
protein levels of RR subunits (R1, R2, p53R2). Incorporation of (14)C-cytidine into nascent
DNA of
tumor cells was also significantly lowered, being equivalent to an inhibition of
DNA synthesis. Consequently, treatment with EGCG and RA attenuated cells in the G0/G1 phase of the cell cycle, finally resulting in a pronounced induction of apoptosis. Sequential combination of EA and RA with the first-line antileukemic agent
arabinofuranosylcytosine (AraC) synergistically potentiated the antiproliferative effect of AraC, whereas EGCG plus AraC yielded additive effects. Taken together, we show for the first time that EGCG, EA, and RA perturbed dNTP levels and inhibited cell proliferation in human HL-60 promyelocytic
leukemia cells, with EGCG and RA causing a pronounced induction of apoptosis. Due to these effects and synergism with AraC, these
food ingredients deserve further preclinical and in vivo testing as inhibitors of leukemic cell proliferation.