Cell cycle synchronization and growth inhibition by 3-hydroxypyridin-4-one iron chelators in leukemia cell lines.
The effect of bidentate 3-hydroxypyridin-4-one (HPO) iron chelators on cell cycle arrest with subsequent cycle synchronization has been compared with that of the hexadentate desferrioxamine (DFO) in K562 and Daudi cells. The relationships between chelator concentration and inhibition of growth, DNA synthesis and ribonucleotide reductase, and phase of cell cycle arrest have also been explored. HPOs and DFO arrest the cell cycle in a dose-dependent manner causing a blockade at the G1-S border after 24 h at concentrations above 30 microM iron-binding equivalents. This is associated with reduced ribonucleotide reductase activity and concomitant cessation of DNA synthesis and growth. When the chelator is subsequently removed, HPO-treated cells synchronously cascade into S phase, unlike DFO-treated cells which resume cycling in a nonsynchronous manner. Chelator concentrations of approximately 25 microM and 3 microM iron-binding equivalents inhibited growth, DNA synthesis, and ribonucleotide reductase activity by 50% in K562 and Daudi cells, respectively. Concentrations less than 10 microM iron-binding equivalents inhibited K562 cell growth without an effect on DNA synthesis but with accumulation of cells in G2 and M phases. These results suggest that HPOs have advantages over DFO as cell cycle synchronization agents and may be useful adjuncts in cell cycle-specific treatment regimens.
Hoyes
K P
KP
Department of Haematology, University College and Middlesex School of Medicine, London, United Kingdom.
Hider
R C
RC
Porter
J B
JB
D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003676:Deferoxamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007502:Iron Chelating Agents / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011728:Pyridones / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D004273:DNA, Neoplasm; D007502:Iron Chelating Agents; D009363:Neoplasm Proteins; D011728:Pyridones; D012334:RNA, Neoplasm; C068543:1,2-diethyl-3-hydroxypyridin-4-one; D012264:Ribonucleotide Reductases; D003676:Deferoxamine