Induction of Granulocytic Maturation in HL-60 Human Leukemia Cells by Free Radicals: A Hypothesis of Cell Differentiation Involving Hydroxyl Radicals

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Abstract
Tumor cells usually contain lower superoxide dismutase (SOD) activity than differentiating cells, suggesting the involvement of oxygen free radicals in cell maturation. The effects of a system known to produce the OH˙ radicals were tested on HL-60 cells cultured under optimum conditions for 96 hr. Hydroxyl radicals were generated by a Fenton reaction, involving an ADP-Fe2+ (or ATP-Fe2+) complex and H2O2. Changes induced by OH˙ were compared to the effects of DMSO-induced differentiation of HL-60 cells. Cell numbers, viability, thymidine incorporation, TPA-induced NBT reduction and propidium iodide staining in flow cytometry were determined. The OH generating system inhibited the growth and thymidine incorporation of leukemic cells in a manner dependent on the dose of added H2O2 (from 0.005 to 0.05 mM). In addition, an increasing proportion of the treated cells displayed signs of cell differentiation. In DMSO-treated cells, SOD and catalase activities increased after 6 days of culturing. The results show that a portion of the OH˙ free radicals derived from H2O2, produced by the action of SOD, may be a necessary prerequisite for differentiation, whereas an overproduction of OH causes cell lethality or aging. We suggest that OH˙ free radicals may have a more complex role in cell physiology than simply causing oxidative damage.

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